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Li J, Wang Z, Li J, Zhao H, Ma Q. HMGB1: A New Target for Ischemic Stroke and Hemorrhagic Transformation. Transl Stroke Res 2025; 16:990-1015. [PMID: 38740617 PMCID: PMC12045843 DOI: 10.1007/s12975-024-01258-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/27/2024] [Accepted: 05/01/2024] [Indexed: 05/16/2024]
Abstract
Stroke in China is distinguished by its high rates of morbidity, recurrence, disability, and mortality. The ultra-early administration of rtPA is essential for restoring perfusion in acute ischemic stroke, though it concurrently elevates the risk of hemorrhagic transformation. High-mobility group box 1 (HMGB1) emerges as a pivotal player in neuroinflammation after brain ischemia and ischemia-reperfusion. Released passively by necrotic cells and actively secreted, including direct secretion of HMGB1 into the extracellular space and packaging of HMGB1 into intracellular vesicles by immune cells, glial cells, platelets, and endothelial cells, HMGB1 represents a prototypical damage-associated molecular pattern (DAMP). It is intricately involved in the pathogenesis of atherosclerosis, thromboembolism, and detrimental inflammation during the early phases of ischemic stroke. Moreover, HMGB1 significantly contributes to neurovascular remodeling and functional recovery in later stages. Significantly, HMGB1 mediates hemorrhagic transformation by facilitating neuroinflammation, directly compromising the integrity of the blood-brain barrier, and enhancing MMP9 secretion through its interaction with rtPA. As a systemic inflammatory factor, HMGB1 is also implicated in post-stroke depression and an elevated risk of stroke-associated pneumonia. The role of HMGB1 extends to influencing the pathogenesis of ischemia by polarizing various subtypes of immune and glial cells. This includes mediating excitotoxicity due to excitatory amino acids, autophagy, MMP9 release, NET formation, and autocrine trophic pathways. Given its multifaceted role, HMGB1 is recognized as a crucial therapeutic target and prognostic marker for ischemic stroke and hemorrhagic transformation. In this review, we summarize the structure and redox properties, secretion and pathways, regulation of immune cell activity, the role of pathophysiological mechanisms in stroke, and hemorrhage transformation for HMGB1, which will pave the way for developing new neuroprotective drugs, reduction of post-stroke neuroinflammation, and expansion of thrombolysis time window.
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Affiliation(s)
- Jiamin Li
- Department of Neurology and Cerebrovascular Diseases Research Institute, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China
| | - Zixin Wang
- Department of Neurology and Cerebrovascular Diseases Research Institute, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China
| | - Jiameng Li
- Department of Neurology and Cerebrovascular Diseases Research Institute, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China
| | - Haiping Zhao
- Department of Neurology and Cerebrovascular Diseases Research Institute, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China.
| | - Qingfeng Ma
- Department of Neurology and Cerebrovascular Diseases Research Institute, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, China.
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Zhang Q, Niu Y, Li Y, Xia C, Chen Z, Chen Y, Feng H. Meningeal lymphatic drainage: novel insights into central nervous system disease. Signal Transduct Target Ther 2025; 10:142. [PMID: 40320416 PMCID: PMC12050339 DOI: 10.1038/s41392-025-02177-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 12/04/2024] [Accepted: 02/06/2025] [Indexed: 05/08/2025] Open
Abstract
In recent years, increasing evidence has suggested that meningeal lymphatic drainage plays a significant role in central nervous system (CNS) diseases. Studies have indicated that CNS diseases and conditions associated with meningeal lymphatic drainage dysfunction include neurodegenerative diseases, stroke, infections, traumatic brain injury, tumors, functional cranial disorders, and hydrocephalus. However, the understanding of the regulatory and damage mechanisms of meningeal lymphatics under physiological and pathological conditions is currently limited. Given the importance of a profound understanding of the interplay between meningeal lymphatic drainage and CNS diseases, this review covers seven key aspects: the development and structure of meningeal lymphatic vessels, methods for observing meningeal lymphatics, the function of meningeal lymphatics, the molecular mechanisms of meningeal lymphatic injury, the relationships between meningeal lymphatic vessels and CNS diseases, potential regulatory mechanisms of meningeal lymphatics, and conclusions and outstanding questions. We will explore the relationship between the development, structure, and function of meningeal lymphatics, review current methods for observing meningeal lymphatic vessels in both animal models and humans, and identify unresolved key points in meningeal lymphatic research. The aim of this review is to provide new directions for future research and therapeutic strategies targeting meningeal lymphatics by critically analyzing recent advancements in the field, identifying gaps in current knowledge, and proposing innovative approaches to address these gaps.
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Affiliation(s)
- Qiang Zhang
- Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Department of Neurosurgery, The 961st Hospital of the Chinese People's Liberation Army Joint Logistic Support Force, Qiqihar Medical University, Qiqihar, 161000, Heilongjiang, China
- Chongqing Key Laboratory of Intelligent Diagnosis, Treatment and Rehabilitation of Central Nervous System Injuries, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Yin Niu
- Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Chongqing Key Laboratory of Intelligent Diagnosis, Treatment and Rehabilitation of Central Nervous System Injuries, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Yingpei Li
- Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Chongqing Key Laboratory of Intelligent Diagnosis, Treatment and Rehabilitation of Central Nervous System Injuries, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Chenyang Xia
- Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Chongqing Key Laboratory of Intelligent Diagnosis, Treatment and Rehabilitation of Central Nervous System Injuries, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Zhi Chen
- Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
- Chongqing Key Laboratory of Intelligent Diagnosis, Treatment and Rehabilitation of Central Nervous System Injuries, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
| | - Yujie Chen
- Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
- Chongqing Key Laboratory of Intelligent Diagnosis, Treatment and Rehabilitation of Central Nervous System Injuries, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
| | - Hua Feng
- Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Chongqing Key Laboratory of Intelligent Diagnosis, Treatment and Rehabilitation of Central Nervous System Injuries, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
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3
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Yang X, Pan Y, Cai L, Wang W, Zhai X, Zhang Y, Wu Q, Chen J, Zhang C, Wang Y. Calycosin Ameliorates Neuroinflammation via TLR4-Mediated Signal Following Cerebral Ischemia/Reperfusion Injury in vivo and in vitro. J Inflamm Res 2024; 17:10711-10727. [PMID: 39677283 PMCID: PMC11645956 DOI: 10.2147/jir.s480262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 11/29/2024] [Indexed: 12/17/2024] Open
Abstract
Background Cerebral ischemia-reperfusion injury (CIRI) is a key pathophysiological process that leads to stroke mortality, with TLR4-mediated inflammation playing a crucial role. Our previous research highlighted the neuroprotective effects of the phytoestrogen calycosin on CIRI, although the precise mechanism remains unclear. This study aimed to explore the effects of calycosin on the HMGB1/TLR4/NF-κB signaling pathway in rat models of CIRI, both in vivo and in vitro. Methods In vivo, a rat CIRI model was established using middle cerebral artery occlusion (MCAO), inducing ischemia for 1.5 h followed by 24 h of reperfusion. Calycosin was administered intraperitoneally 1 h after ischemia. Neurological deficits and brain infarct volumes were evaluated. Histological changes and key protein expressions around the ischemic penumbra were assessed by H&E staining and immunofluorescence. In vitro, primary neurons and PC12 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to mimic CIRI. Cell viability was measured using a CCK8 assay, and alterations in HMGB1/TLR4/NF-κB pathway components were analyzed using qRT-PCR, Western blotting, and ELISA. Results In the MCAO rat model, calycosin significantly reduced neurological deficits and infarct sizes, and improved brain tissue damage following reperfusion. Similarly, in the OGD/R model, calycosin attenuated neuronal injury in PC12 cells and in primary neurons. Additionally, calycosin inhibited LPS-induced activation of the HMGB1/TLR4/NF-κB signaling pathway in PC12 cells. Both in vitro and in vivo studies have shown that calycosin effectively downregulates HMGB1 and TLR4 expression, decreases NF-κB and IκB phosphorylation, and reduces the secretion of inflammatory cytokines such as IL-6 and IL-18. Conclusion These findings suggest that calycosin mitigates cerebral ischemia-reperfusion injury and neuroinflammation by inhibiting the HMGB1/TLR4/NF-κB signaling pathway, thereby providing neuroprotection.
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Affiliation(s)
- Xin Yang
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199, People’s Republic of China
| | - Yanjin Pan
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199, People’s Republic of China
| | - Le Cai
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199, People’s Republic of China
| | - Wenbo Wang
- Department of Neurosurgery, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, 541002, People’s Republic of China
| | - Xiaoya Zhai
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199, People’s Republic of China
| | - Yuhui Zhang
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199, People’s Republic of China
| | - Qiguang Wu
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199, People’s Republic of China
| | - Jian Chen
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199, People’s Republic of China
| | - Chong Zhang
- Department of Neurology, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, People’s Republic of China
- Guangxi Medical and Health Key Cultivation Discipline Construction Project, Guilin, 541199, People’s Republic of China
| | - Yong Wang
- Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541199, People’s Republic of China
- Guangxi Medical and Health Key Cultivation Discipline Construction Project, Guilin, 541199, People’s Republic of China
- Department of Physiology, Guilin Medical University, Guilin, 541199, People’s Republic of China
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Ruggieri E, Di Domenico E, Locatelli AG, Isopo F, Damanti S, De Lorenzo R, Milan E, Musco G, Rovere-Querini P, Cenci S, Vénéreau E. HMGB1, an evolving pleiotropic protein critical for cellular and tissue homeostasis: Role in aging and age-related diseases. Ageing Res Rev 2024; 102:102550. [PMID: 39427887 DOI: 10.1016/j.arr.2024.102550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 10/05/2024] [Accepted: 10/13/2024] [Indexed: 10/22/2024]
Abstract
Aging is a universal biological process characterized by a progressive, cumulative decline in homeostatic capabilities and physiological functions, which inevitably increases vulnerability to diseases. A number of molecular pathomechanisms and hallmarks of aging have been recognized, yet we miss a thorough understanding of their complex interconnectedness. This review explores the molecular and cellular mechanisms underlying human aging, with a focus on the multiple roles of high mobility group Box 1 protein (HMGB1), the archetypal damage-associated molecular pattern (DAMP) molecule. In the nucleus, this non-histone chromatin-associated protein functions as a DNA chaperone and regulator of gene transcription, influencing DNA structure and gene expression. Moreover, this versatile protein can translocate to the cytoplasm to orchestrate other processes, such as autophagy, or be unconventionally secreted into the extracellular environment, where it acts as a DAMP, combining inflammatory and regenerative properties. Notably, lower expression of HMGB1 within the cell and its heightened extracellular release have been associated with diverse age-associated traits, making it a suitable candidate as a universal biomarker of aging. In this review, we outline the evidence implicating HMGB1 in aging, also in light of an evolutionary perspective on its functional pleiotropy, and propose critical issues that need to be addressed to gauge the value of HMGB1 as a potential biomarker across age-related diseases and therapeutic target to promote healthy longevity.
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Affiliation(s)
- Elena Ruggieri
- IRCCS Ospedale San Raffaele, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy
| | - Erika Di Domenico
- IRCCS Ospedale San Raffaele, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy
| | | | - Flavio Isopo
- IRCCS Ospedale San Raffaele, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy
| | - Sarah Damanti
- IRCCS Ospedale San Raffaele, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy
| | - Rebecca De Lorenzo
- IRCCS Ospedale San Raffaele, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy
| | - Enrico Milan
- IRCCS Ospedale San Raffaele, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy
| | | | - Patrizia Rovere-Querini
- IRCCS Ospedale San Raffaele, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy
| | - Simone Cenci
- IRCCS Ospedale San Raffaele, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy.
| | - Emilie Vénéreau
- IRCCS Ospedale San Raffaele, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy.
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Zeng J, Cao J, Yang H, Wang X, Liu T, Chen Z, Shi F, Xu Z, Lin X. Overview of mechanism of electroacupuncture pretreatment for prevention and treatment of cardiovascular and cerebrovascular diseases. CNS Neurosci Ther 2024; 30:e14920. [PMID: 39361504 PMCID: PMC11448663 DOI: 10.1111/cns.14920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 07/19/2024] [Accepted: 08/01/2024] [Indexed: 10/05/2024] Open
Abstract
Cardio-cerebrovascular disease (CCVD) is a serious threat to huma strategy to prevent the occurrence and development of disease by giving electroacupuncture intervention before the disease occurs. EAP has been shown in many preclinical studies to relieve ischemic symptoms and improve damage from ischemia-reperfusion, with no comprehensive review of its mechanisms in cardiovascular disease yet. In this paper, we first systematically discussed the meridian and acupoint selection law of EAP for CCVD and focused on the progress of the mechanism of action of EAP for the prevention and treatment of CCVD. As a result, in preclinical studies, AMI and MCAO models are commonly used to simulate ischemic injury in CCVD, while MIRI and CI/RI models are used to simulate reperfusion injury caused by blood flow recovery after focal tissue ischemia. According to the meridian matching rules of EAP for CCVD, PC6 in the pericardial meridian is the most commonly used acupoint in cardiovascular diseases, while GV20 in the Du meridian is the most commonly used acupoint in cerebrovascular diseases. In terms of intervention parameters, EAP intervention generally lasts for 30 min, with acupuncture depths mostly between 1.5 and 5 mm, stimulation intensities mostly at 1 mA, and commonly used frequencies being low frequencies. In terms of molecular mechanisms, the key pathways of EAP in preventing and treating cardiovascular and cerebrovascular diseases are partially similar. EAP can play a protective role in cardiovascular and cerebrovascular diseases by promoting autophagy, regulating Ca2+ overload, and promoting vascular regeneration through anti-inflammatory reactions, antioxidant stress, and anti-apoptosis. Of course, both pathways involved have their corresponding specificities. When using EAP to prevent and treat cardiovascular diseases, it involves the metabolic pathway of glutamate, while when using EAP to prevent and treat cerebrovascular diseases, it involves the homeostasis of the blood-brain barrier and the release of neurotransmitters and nutritional factors. I hope these data can provide experimental basis and reference for the clinical promotion and application of EAP in CCVD treatment.
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Affiliation(s)
- Jiaming Zeng
- Research Center of Experimental Acupuncture Science, School of Acupuncture‐Moxibustion and TuinaTianjin University of Traditional Chinese MedicineTianjinChina
| | - Jiaojiao Cao
- Research Center of Experimental Acupuncture Science, School of Acupuncture‐Moxibustion and TuinaTianjin University of Traditional Chinese MedicineTianjinChina
| | - Haitao Yang
- Research Center of Experimental Acupuncture Science, School of Acupuncture‐Moxibustion and TuinaTianjin University of Traditional Chinese MedicineTianjinChina
| | - Xue Wang
- Research Center of Experimental Acupuncture Science, School of Acupuncture‐Moxibustion and TuinaTianjin University of Traditional Chinese MedicineTianjinChina
| | - Tingting Liu
- Research Center of Experimental Acupuncture Science, School of Acupuncture‐Moxibustion and TuinaTianjin University of Traditional Chinese MedicineTianjinChina
| | - Zhihan Chen
- Research Center of Experimental Acupuncture Science, School of Acupuncture‐Moxibustion and TuinaTianjin University of Traditional Chinese MedicineTianjinChina
| | - Fangyuan Shi
- Research Center of Experimental Acupuncture Science, School of Acupuncture‐Moxibustion and TuinaTianjin University of Traditional Chinese MedicineTianjinChina
| | - Zhifang Xu
- Research Center of Experimental Acupuncture Science, School of Acupuncture‐Moxibustion and TuinaTianjin University of Traditional Chinese MedicineTianjinChina
- Tianjin Key Laboratory of Modern Chinese Medicine Theory of Innovation and Application, School of Traditional Chinese MedicineTianjin University of Traditional Chinese MedicineTianjinChina
- National Clinical Research Center for Chinese Medicine Acupuncture and MoxibustionTianjinChina
| | - Xiaowei Lin
- Research Center of Experimental Acupuncture Science, School of Acupuncture‐Moxibustion and TuinaTianjin University of Traditional Chinese MedicineTianjinChina
- Tianjin Key Laboratory of Modern Chinese Medicine Theory of Innovation and Application, School of Traditional Chinese MedicineTianjin University of Traditional Chinese MedicineTianjinChina
- National Clinical Research Center for Chinese Medicine Acupuncture and MoxibustionTianjinChina
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Planas AM. Role of microglia in stroke. Glia 2024; 72:1016-1053. [PMID: 38173414 DOI: 10.1002/glia.24501] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 12/07/2023] [Accepted: 12/19/2023] [Indexed: 01/05/2024]
Abstract
Microglia play key roles in the post-ischemic inflammatory response and damaged tissue removal reacting rapidly to the disturbances caused by ischemia and working to restore the lost homeostasis. However, the modified environment, encompassing ionic imbalances, disruption of crucial neuron-microglia interactions, spreading depolarization, and generation of danger signals from necrotic neurons, induce morphological and phenotypic shifts in microglia. This leads them to adopt a proinflammatory profile and heighten their phagocytic activity. From day three post-ischemia, macrophages infiltrate the necrotic core while microglia amass at the periphery. Further, inflammation prompts a metabolic shift favoring glycolysis, the pentose-phosphate shunt, and lipid synthesis. These shifts, combined with phagocytic lipid intake, drive lipid droplet biogenesis, fuel anabolism, and enable microglia proliferation. Proliferating microglia release trophic factors contributing to protection and repair. However, some microglia accumulate lipids persistently and transform into dysfunctional and potentially harmful foam cells. Studies also showed microglia that either display impaired apoptotic cell clearance, or eliminate synapses, viable neurons, or endothelial cells. Yet, it will be essential to elucidate the viability of engulfed cells, the features of the local environment, the extent of tissue damage, and the temporal sequence. Ischemia provides a rich variety of region- and injury-dependent stimuli for microglia, evolving with time and generating distinct microglia phenotypes including those exhibiting proinflammatory or dysfunctional traits and others showing pro-repair features. Accurate profiling of microglia phenotypes, alongside with a more precise understanding of the associated post-ischemic tissue conditions, is a necessary step to serve as the potential foundation for focused interventions in human stroke.
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Affiliation(s)
- Anna M Planas
- Cerebrovascular Research Laboratory, Department of Neuroscience and Experimental Therapeutics, Instituto de Investigaciones Biomédicas de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain
- Cerebrovascular Diseases, Area of Clinical and Experimental Neuroscience, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Barcelona, Spain
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Chikviladze M, Mamulashvili N, Sepashvili M, Narmania N, Ramsden J, Shanshiashvili L, Mikeladze D. Citrullinated isomer of myelin basic protein can induce inflammatory responses in astrocytes. IBRO Neurosci Rep 2024; 16:127-134. [PMID: 38288135 PMCID: PMC10823069 DOI: 10.1016/j.ibneur.2023.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 12/15/2023] [Indexed: 01/31/2024] Open
Abstract
Purpose During the course of demyelinating inflammatory diseases, myelin-derived proteins, including myelin basic protein(MBP), are secreted into extracellular space. MBP shows extensive post-translational modifications, including deimination/citrullination. Deiminated MBP is structurally less ordered, susceptible to proteolytic attack, and more immunogenic than unmodified MBP. This study investigated the effect of the deiminated/citrullinated isomer of MBP(C8) and the unmodified isomer of MBP(C1) on cultured primary astrocytes. Methods MBP charge isomers were isolated/purified from bovine brain. Primary astrocyte cultures were prepared from the 2-day-old Wistar rats. For evaluation of glutamate release/uptake a Fluorimetric glutamate assay was used. Expression of peroxisome proliferator-activated receptor-gamma(PPAR-γ), excitatory amino acid transporter 2(EAAT2), the inhibitor of the nuclear factor kappa-B(ikB) and high mobility group-B1(HMGB1) protein were assayed by Western blot analysis. IL-17A expression was determined in cell medium by ELISA. Results We found that MBP(C8) and MBP(C1) acted differently on the uptake/release of glutamate in astrocytes: C1 increased glutamate uptake and did not change its release, whereas C8 decreased glutamate release but did not change its uptake. Both isomers increased the expression of PPAR-γ and EAAT2 to the same degree. Western blots of cell lysates revealed decreased expression of ikB and increased expression of HMGB1 proteins after treatment of astrocytes by C8. Moreover, C8-treated cells released more nitric oxide and proinflammatory IL-17A than C1-treated cells. Conclusions These data suggest that the most immunogenic deiminated isomer C8, in parallel to the decreases in glutamate release, elicits an inflammatory response and enhances the secretion of proinflammatory molecules via activation of nuclear factor kappa B(NF-kB). Summary statement The most modified-citrullinated myelin basic protein charge isomer decreases glutamate release, elicits an inflammatory response and enhances the secretion of proinflammatory molecules via activation of nuclear factor kappa B in astrocytes.
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Affiliation(s)
| | - Nino Mamulashvili
- Institute of Chemical Biology, Ilia State University, Tbilisi, Georgia
| | - Maia Sepashvili
- Institute of Chemical Biology, Ilia State University, Tbilisi, Georgia
- Department of Biochemistry, I. Beritashvili Center of Experimental Biomedicine, Tbilisi, Georgia
| | - Nana Narmania
- Institute of Chemical Biology, Ilia State University, Tbilisi, Georgia
- Department of Biochemistry, I. Beritashvili Center of Experimental Biomedicine, Tbilisi, Georgia
| | - Jeremy Ramsden
- Department of Biomedical Research, The University of Buckingham, Hunter Street, Buckingham MK18 1EG, UK
| | - Lali Shanshiashvili
- Institute of Chemical Biology, Ilia State University, Tbilisi, Georgia
- Department of Biochemistry, I. Beritashvili Center of Experimental Biomedicine, Tbilisi, Georgia
| | - David Mikeladze
- Institute of Chemical Biology, Ilia State University, Tbilisi, Georgia
- Department of Biochemistry, I. Beritashvili Center of Experimental Biomedicine, Tbilisi, Georgia
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8
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Duan M, Xu Y, Li Y, Feng H, Chen Y. Targeting brain-peripheral immune responses for secondary brain injury after ischemic and hemorrhagic stroke. J Neuroinflammation 2024; 21:102. [PMID: 38637850 PMCID: PMC11025216 DOI: 10.1186/s12974-024-03101-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 04/15/2024] [Indexed: 04/20/2024] Open
Abstract
The notion that the central nervous system is an immunologically immune-exempt organ has changed over the past two decades, with increasing evidence of strong links and interactions between the central nervous system and the peripheral immune system, both in the healthy state and after ischemic and hemorrhagic stroke. Although primary injury after stroke is certainly important, the limited therapeutic efficacy, poor neurological prognosis and high mortality have led researchers to realize that secondary injury and damage may also play important roles in influencing long-term neurological prognosis and mortality and that the neuroinflammatory process in secondary injury is one of the most important influences on disease progression. Here, we summarize the interactions of the central nervous system with the peripheral immune system after ischemic and hemorrhagic stroke, in particular, how the central nervous system activates and recruits peripheral immune components, and we review recent advances in corresponding therapeutic approaches and clinical studies, emphasizing the importance of the role of the peripheral immune system in ischemic and hemorrhagic stroke.
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Affiliation(s)
- Mingxu Duan
- Department of Neurosurgery, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), 29 Gaotanyan Street, Shapingba District, Chongqing, 400038, China
- Chongqing Key Laboratory of Intelligent Diagnosis, Treatment and Rehabilitation of Central Nervous System Injuries, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Ya Xu
- Department of Neurosurgery, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), 29 Gaotanyan Street, Shapingba District, Chongqing, 400038, China
- Chongqing Key Laboratory of Intelligent Diagnosis, Treatment and Rehabilitation of Central Nervous System Injuries, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Yuanshu Li
- Department of Neurosurgery, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), 29 Gaotanyan Street, Shapingba District, Chongqing, 400038, China
- Chongqing Key Laboratory of Intelligent Diagnosis, Treatment and Rehabilitation of Central Nervous System Injuries, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Hua Feng
- Department of Neurosurgery, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), 29 Gaotanyan Street, Shapingba District, Chongqing, 400038, China
- Chongqing Key Laboratory of Intelligent Diagnosis, Treatment and Rehabilitation of Central Nervous System Injuries, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Yujie Chen
- Department of Neurosurgery, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), 29 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.
- Chongqing Key Laboratory of Intelligent Diagnosis, Treatment and Rehabilitation of Central Nervous System Injuries, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
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9
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Lyu Y, Tu H, Luo J, Wang C, Li A, Zhou Y, Zhao J, Wang H, Hu J. Increased serum levels of high-mobility group box 1 protein and the location characteristics in the patients of intracranial aneurysms. Brain Res 2024; 1828:148759. [PMID: 38242523 DOI: 10.1016/j.brainres.2024.148759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 01/04/2024] [Accepted: 01/07/2024] [Indexed: 01/21/2024]
Abstract
OBJECTIVE Inflammation-related factors play a crucial role in intracranial aneurysms (IA) initiation, progression, and rupture. High mobility group box 1 (HMGB-1) serves as an alarm to drive the pathogenesis of the inflammatory disease. This study aimed to evaluate the role of HMGB-1 in IA and explore the correlation with other inflammatory-related factors. METHODS A total of twenty-eight adult male Japanese white rabbits were included in with elastase-induced aneurysms, n = 18) and the control group (normal rabbits, n = 10). To assess the expression of HMGB-1, both reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) was performed on serum samples obtained from human subjects (10 patients with IA and 10 healthy donors) as well as from rabbits (aneurysm group and control group). Immunohistochemistry and immunofluorescence were employed to evaluate the expression levels of elastic fibers, HMGB-1, tumor necrosis factor-alpha (TNF-α), and triggering receptor expressed on myeloid cells-1 (TREM-1). RESULTS The expression of HMGB-1 was found to be significantly higher in the IA group compared to the control group, both at the mRNA and protein levels (P < 0.0001). Similar findings were observed in the rabbit aneurysm model group compared to the control group (P < 0.0001). HMGB-1 expression was observed to be more abundant in the inner wall of the aneurysm compared to the external wall, whereas in the control group, it was rarely scattered. Additionally, the localization patterns of TNF-α and TREM-1 exhibited similar characteristics to HMGB-1. CONCLUSION Our findings demonstrate that HMGB-1 is highly expressed in both IA patients and rabbit aneurysm models. Furthermore, the similar localization patterns of HMGB-1, TNF-α, and TREM-1 suggest their potential involvement in the inflammatory processes associated with IA. These results highlight the potential of HMGB-1 as a novel therapeutic target for IA.
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Affiliation(s)
- YanXia Lyu
- Department of Physiology, Hubei University of Medicine, Shiyan, Hubei Province, China
| | - HanJun Tu
- Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China
| | - Jie Luo
- Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China
| | - ChaoJia Wang
- Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China
| | - AnRong Li
- Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China
| | - Yi Zhou
- Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China
| | - JunShuang Zhao
- Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China
| | - Hui Wang
- Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China
| | - JunTao Hu
- Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, China.
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10
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Koide H, Kiyokawa C, Okishima A, Saito K, Yoshimatsu K, Fukuta T, Hoshino Y, Asai T, Nishimura Y, Miura Y, Oku N, Shea KJ. Design of an Anti-HMGB1 Synthetic Antibody for In Vivo Ischemic/Reperfusion Injury Therapy. J Am Chem Soc 2023; 145:23143-23151. [PMID: 37844138 PMCID: PMC10603801 DOI: 10.1021/jacs.3c06799] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Indexed: 10/18/2023]
Abstract
High-mobility group box 1 (HMGB1) is a multifunctional protein. Upon injury or infection, HMGB1 is passively released from necrotic and activated dendritic cells and macrophages, where it functions as a cytokine, acting as a ligand for RAGE, a major receptor of innate immunity stimulating inflammation responses including the pathogenesis of cerebral ischemia/reperfusion (I/R) injury. Blocking the HMGB1/RAGE axis offers a therapeutic approach to treating these inflammatory conditions. Here, we describe a synthetic antibody (SA), a copolymer nanoparticle (NP) that binds HMGB1. A lightly cross-linked N-isopropylacrylamide (NIPAm) hydrogel copolymer with nanomolar affinity for HMGB1 was selected from a small library containing trisulfated 3,4,6S-GlcNAc and hydrophobic N-tert-butylacrylamide (TBAm) monomers. Competition binding experiments with heparin established that the dominant interaction between SA and HMGB1 occurs at the heparin-binding domain. In vitro studies established that anti-HMGB1-SA inhibits HMGB1-dependent ICAM-1 expression and ERK phosphorylation of HUVECs, confirming that SA binding to HMGB1 inhibits the proteins' interaction with the RAGE receptor. Using temporary middle cerebral artery occlusion (t-MCAO) model rats, anti-HMGB1-SA was found to accumulate in the ischemic brain by crossing the blood-brain barrier. Significantly, administration of anti-HMGB1-SA to t-MCAO rats dramatically reduced brain damage caused by cerebral ischemia/reperfusion. These results establish that a statistical copolymer, selected from a small library of candidates synthesized using an "informed" selection of functional monomers, can yield a functional synthetic antibody. The knowledge gained from these experiments can facilitate the discovery, design, and development of a new category of drug.
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Affiliation(s)
- Hiroyuki Koide
- Department
of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
| | - Chiaki Kiyokawa
- Department
of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
| | - Anna Okishima
- Department
of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
| | - Kaito Saito
- Department
of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
| | - Keiichi Yoshimatsu
- Department
of Chemistry, Missouri State University, 901 South National Avenue, Springfield, Missouri 65897, United States
| | - Tatsuya Fukuta
- Department
of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
| | - Yu Hoshino
- Department
of Chemical Engineering, Kyushu University, 744 Motooka, Fukuoka 819-0395, Japan
| | - Tomohiro Asai
- Department
of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
| | - Yuri Nishimura
- Department
of Chemical Engineering, Kyushu University, 744 Motooka, Fukuoka 819-0395, Japan
| | - Yoshiko Miura
- Department
of Chemical Engineering, Kyushu University, 744 Motooka, Fukuoka 819-0395, Japan
| | - Naoto Oku
- Department
of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
| | - Kenneth J. Shea
- Department
of Chemistry, University of California Irvine, Irvine, California 92697, United States
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11
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Dincel GC, Yavuz O, Yildirim S, Al-Olayan EM, El-Ashram S. ADAMTS-13 and HMGB1-induced oxidative stress in Taenia multiceps-infected animals. Sci Rep 2023; 13:17929. [PMID: 37863934 PMCID: PMC10589341 DOI: 10.1038/s41598-023-44376-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 10/07/2023] [Indexed: 10/22/2023] Open
Abstract
This study investigated the cytotoxic effects of oxidative stress (OS), high mobility group box 1 (HMGB1), ADAMTS (A disintegrin and metalloproteinase with thrombospondin motifs), and neuropathology associated with coenurus cerebralis (Taenia multiceps). ADAMTS-13, HMGB1, glutathione reductase (GR), copper/zinc superoxide dismutase (Cu/Zn SOD), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) expression levels were studied. The study found that ADAMTS-13 (P < 0.005), HMGB1 (P < 0.005), GR (P < 0.005), Cu/Zn SOD (P < 0.005), and 8-OHdG (P < 0.005) levels were significantly higher in T. multiceps (c. cerebralis)-infected animals compared to healthy control animals. This study's most important finding was that HMGB1 up-regulation in neurons, endothelial cells, and glial cells can directly cause brain parenchymal destruction and that HMGB1-mediated oxidative stress plays a crucial role in the neuropathogenesis of coenurosis. The results also showed that increased levels of ADAMTS-13 may play a pivotal role in regulating and protecting the blood-brain barrier integrity and neuroprotection. These findings also suggest that ADAMTS-13 and HMGB1 compete in the prevention or formation of microthrombi, which was regarded as a remarkable finding. ADAMTS-13 and HMGB1 are valuable biomarkers for disease risk assessment, estimating host neuropathy following T. multiceps (c. cerebralis) exposure, and providing a new therapeutic target. This is the first study to show that HMGB1 and ADAMTS-13 are expressed in reactive cells and are associated with neuroimmunopathology in coenurosis.
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Affiliation(s)
- Gungor Cagdas Dincel
- Eskil Vocational School, Laboratory and Veterinary Science, Aksaray University, Aksaray, Turkey.
| | - Orhan Yavuz
- Department of Pathology, Faculty of Veterinary Medicine, Aksaray University, Aksaray, Turkey
| | - Serkan Yildirim
- Department of Pathology, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey
| | - Ebtesam M Al-Olayan
- Department of Zoology, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Saeed El-Ashram
- Zoology Department, Faculty of Science, Kafrelsheikh University, Kafr El-Sheikh, 33516, Egypt.
- College of Life Science and Engineering, Foshan University, 18 Jiangwan Street, Foshan, 528231, Guangdong Province, China.
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12
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Xu SY, Jia JQ, Sun M, Bao XY, Xia SN, Shu S, Liu PY, Ji SL, Ye L, Cao X, Xu Y. QHRD106 ameliorates ischemic stroke injury as a long-acting tissue kallikrein preparation. iScience 2023; 26:107268. [PMID: 37496671 PMCID: PMC10366503 DOI: 10.1016/j.isci.2023.107268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 06/07/2023] [Accepted: 06/28/2023] [Indexed: 07/28/2023] Open
Abstract
Ischemic stroke is the second leading cause of death worldwide, and there are limited effective treatment strategies. QHRD106, a polyethyleneglycol (PEG)-modified long-acting tissue kallikrein preparation, has not been reported previously. In this study, we aimed to investigate the therapeutic effect of QHRD106 in ischemic stroke and its possible mechanism. We found that QHRD106 treatment alleviated brain injury after stroke via bradykinin (BK) receptor B2 (B2R) instead of BK receptor B1 (B1R). Mechanistically, QHRD106 reduced high-mobility group box 1 (HMGB1)-induced apoptosis and inflammation after ischemic stroke in vivo and in vitro. Moreover, we confirmed that QHRD106 reduced the level of acetylated HMGB1 and reduced the binding between heat shock protein 90 alpha family class A member 1 (HSP90AA1) and HMGB1, thus inhibiting the translocation and release of HMGB1. In summary, these findings indicate that QHRD106 treatment has therapeutic potential for cerebral ischemic stroke.
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Affiliation(s)
- Si-Yi Xu
- Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, Jiangsu 210008, P.R. China
- Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, Jiangsu 210008, P.R. China
| | - Jun-Qiu Jia
- Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, Jiangsu 210008, P.R. China
| | - Min Sun
- Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, Jiangsu 210008, P.R. China
| | - Xin-Yu Bao
- Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, Jiangsu 210008, P.R. China
- Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
- Jiangsu Provincial Key Discipline of Neurology, Nanjing, Jiangsu 210008, P.R. China
- Nanjing Neurology Medical Center, Nanjing, Jiangsu 210008, P.R. China
| | - Sheng-Nan Xia
- Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, Jiangsu 210008, P.R. China
- Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
- Jiangsu Provincial Key Discipline of Neurology, Nanjing, Jiangsu 210008, P.R. China
- Nanjing Neurology Medical Center, Nanjing, Jiangsu 210008, P.R. China
| | - Shu Shu
- Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, Jiangsu 210008, P.R. China
- Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
- Jiangsu Provincial Key Discipline of Neurology, Nanjing, Jiangsu 210008, P.R. China
- Nanjing Neurology Medical Center, Nanjing, Jiangsu 210008, P.R. China
| | - Pin-yi Liu
- Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, Jiangsu 210008, P.R. China
- Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
- Jiangsu Provincial Key Discipline of Neurology, Nanjing, Jiangsu 210008, P.R. China
- Nanjing Neurology Medical Center, Nanjing, Jiangsu 210008, P.R. China
| | - Sen-lin Ji
- Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, Jiangsu 210008, P.R. China
- Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
- Jiangsu Provincial Key Discipline of Neurology, Nanjing, Jiangsu 210008, P.R. China
- Nanjing Neurology Medical Center, Nanjing, Jiangsu 210008, P.R. China
| | - Lei Ye
- Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, Jiangsu 210008, P.R. China
| | - Xiang Cao
- Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, Jiangsu 210008, P.R. China
- Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, Jiangsu 210008, P.R. China
- Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
- Jiangsu Provincial Key Discipline of Neurology, Nanjing, Jiangsu 210008, P.R. China
- Nanjing Neurology Medical Center, Nanjing, Jiangsu 210008, P.R. China
| | - Yun Xu
- Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, Jiangsu 210008, P.R. China
- Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, Jiangsu 210008, P.R. China
- Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
- Jiangsu Provincial Key Discipline of Neurology, Nanjing, Jiangsu 210008, P.R. China
- Nanjing Neurology Medical Center, Nanjing, Jiangsu 210008, P.R. China
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13
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Gao B, Wang S, Li J, Han N, Ge H, Zhang G, Chang M. HMGB1, angel or devil, in ischemic stroke. Brain Behav 2023; 13:e2987. [PMID: 37062906 PMCID: PMC10176004 DOI: 10.1002/brb3.2987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 03/03/2023] [Accepted: 03/14/2023] [Indexed: 04/18/2023] Open
Abstract
INTRODUCTION High-mobility group box 1 protein (HMGB1) is extensively involved in causing ischemic stroke, pathological damage of ischemic brain injury, and neural tissue repair after ischemic brain injury. However, the precise role of HMGB1 in ischemic stroke remains to be elucidated. METHODS Comprehensive literature search and narrative review to summarize the current field of HMGB1 in cerebral ischemic based on the basic structure, structural modification, and functional roles of HMGB1 described in the literature. RESULTS Studies have exhibited the crucial roles of HMGB1 in cell death, immunity and inflammation, thrombosis, and remodeling and repair. HMGB1 released after cerebral infarction is extensively involved in the pathological injury process in the early stage of cerebral infarction, whereas it is involved in the promotion of brain tissue repair and remodeling in the late stage of cerebral infarction. HMGB1 plays a neurotrophic role in acute white matter stroke, whereas it causes sustained activation of inflammation and plays a damaging role in chronic white matter ischemia. CONCLUSIONS HMGB1 plays a complex role in cerebral infarction, which is related to not only the modification of HMGB1 and bound receptors but also different stages and subtypes of cerebral infarction. future studies on HMGB1 should investigate the spatial and temporal dynamics of HMGB1 after cerebral infarction. Moreover, future studies on HMGB1 should attempt to integrate different stages and infarct subtypes of cerebral infarction.
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Affiliation(s)
- Bin Gao
- Department of NeurologyXi'an No. 3 Hospitalthe Affiliated Hospital of Northest UniversityXi'anShaanxiP.R. China
| | - Shuwen Wang
- Department of NeurologyXi'an No. 3 Hospitalthe Affiliated Hospital of Northest UniversityXi'anShaanxiP.R. China
| | - Jiangfeng Li
- Department of Neurosurgerythe First Hospital of Yu'linYu'linShaanxiChina
| | - Nannan Han
- Department of NeurologyXi'an No. 3 Hospitalthe Affiliated Hospital of Northest UniversityXi'anShaanxiP.R. China
| | - Hanming Ge
- Department of NeurologyXi'an No. 3 Hospitalthe Affiliated Hospital of Northest UniversityXi'anShaanxiP.R. China
| | - Gejuan Zhang
- Department of NeurologyXi'an No. 3 Hospitalthe Affiliated Hospital of Northest UniversityXi'anShaanxiP.R. China
| | - Mingze Chang
- Department of NeurologyXi'an No. 3 Hospitalthe Affiliated Hospital of Northest UniversityXi'anShaanxiP.R. China
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Kawamura T, Singh Mallah G, Ardalan M, Chumak T, Svedin P, Jonsson L, Jabbari Shiadeh SM, Goretta F, Ikeda T, Hagberg H, Sandberg M, Mallard C. Therapeutic Effect of Nicotinamide Mononucleotide for Hypoxic-Ischemic Brain Injury in Neonatal Mice. ASN Neuro 2023; 15:17590914231198983. [PMID: 37787108 PMCID: PMC10548811 DOI: 10.1177/17590914231198983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 08/08/2023] [Accepted: 08/16/2023] [Indexed: 10/04/2023] Open
Abstract
SUMMARY STATEMENT Neonatal hypoxia-ischemia reduces nicotinamide adenine dinucleotide (NAD+) and SIRT6 levels in the injured hippocampus.Hippocampal high mobility group box-1 (HMGB1) release is significantly increased after neonatal hypoxia-ischemia.Nicotinamide mononucleotide (NMN) treatment normalizes hippocampal NAD+ and SIRT6 levels, with significant decrease in caspase-3 activity and HMGB1 release.NMN improves early developmental behavior, as well as motor and memory function.
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Affiliation(s)
- Takuya Kawamura
- Institute of Neuroscience and Physiology, Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Obstetrics and Gynecology, Mie University, Tsu, Japan
| | - Gagandeep Singh Mallah
- Institute of Neuroscience and Physiology, Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Maryam Ardalan
- Institute of Neuroscience and Physiology, Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Tetyana Chumak
- Institute of Neuroscience and Physiology, Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Pernilla Svedin
- Institute of Neuroscience and Physiology, Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lina Jonsson
- Institute of Neuroscience and Physiology, Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Seyedeh Marziyeh Jabbari Shiadeh
- Institute of Neuroscience and Physiology, Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Fanny Goretta
- Institute of Neuroscience and Physiology, Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Tomoaki Ikeda
- Department of Obstetrics and Gynecology, Mie University, Tsu, Japan
| | - Henrik Hagberg
- Centre of Perinatal Medicine and Health, Institute of Clinical Sciences, Gothenburg, Sweden
| | - Mats Sandberg
- Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Carina Mallard
- Institute of Neuroscience and Physiology, Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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15
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Chaudhry SR, Shafique S, Sajjad S, Hänggi D, Muhammad S. Janus Faced HMGB1 and Post-Aneurysmal Subarachnoid Hemorrhage (aSAH) Inflammation. Int J Mol Sci 2022; 23:ijms231911216. [PMID: 36232519 PMCID: PMC9569479 DOI: 10.3390/ijms231911216] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 09/04/2022] [Accepted: 09/20/2022] [Indexed: 11/16/2022] Open
Abstract
Aneurysmal subarachnoid hemorrhage (aSAH), resulting majorly from the rupture of intracranial aneurysms, is a potentially devastating disease with high morbidity and mortality. The bleeding aneurysms can be successfully secured; however, the toxic and mechanical impact of the blood extravasation into the subarachnoid space damages the brain cells leading to the release of different damage-associated molecular pattern molecules (DAMPs). DAMPs upregulate the inflammation after binding their cognate receptors on the immune cells and underlies the early and delayed brain injury after aSAH. Moreover, these molecules are also associated with different post-aSAH complications, which lead to poor clinical outcomes. Among these DAMPs, HMGB1 represents a prototypical protein DAMP that has been well characterized for its proinflammatory role after aSAH and during different post-aSAH complications. However, recent investigations have uncovered yet another face of HMGB1, which is involved in the promotion of brain tissue remodeling, neurovascular repair, and anti-inflammatory effects after SAH. These different faces rely on different redox states of HMGB1 over the course of time after SAH. Elucidation of the dynamics of these redox states of HMGB1 has high biomarker as well as therapeutic potential. This review mainly highlights these recent findings along with the conventionally described normal role of HMGB1 as a nuclear protein and as a proinflammatory molecule during disease (aSAH).
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Affiliation(s)
- Shafqat Rasul Chaudhry
- Department of Pharmacy, Obaid Noor Institute of Medical Sciences (ONIMS), Mianwali 42200, Pakistan
| | - Sumaira Shafique
- Department of Biochemistry and Biotechnology, University of Veterinary and Animal Sciences (UVAS), Lahore 54000, Pakistan
| | - Saba Sajjad
- Department of Oral-, Maxillofacial and Facial Plastic Surgery, University Hospital Düsseldorf, 40225 Düsseldorf, Germany
| | - Daniel Hänggi
- Department of Neurosurgery, Faculty of Medicine, University Hospital Düsseldorf, Heinrich-Heine University of Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Sajjad Muhammad
- Department of Neurosurgery, Faculty of Medicine, University Hospital Düsseldorf, Heinrich-Heine University of Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
- Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, 00029 Helsinki, Finland
- Correspondence: ; Tel.: +49-15168460755
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16
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Kim M, Oh J, Lee Y, Lee EH, Ko SH, Jeong JH, Park CH, Lee M. Delivery of self-replicating messenger RNA into the brain for the treatment of ischemic stroke. J Control Release 2022; 350:471-485. [PMID: 36041589 DOI: 10.1016/j.jconrel.2022.08.049] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 08/23/2022] [Accepted: 08/24/2022] [Indexed: 11/28/2022]
Abstract
Ischemic stroke is caused by the occlusion of cerebral arteries. In the ischemic stroke, ischemia-reperfusion injury increases the damage in the brain after reperfusion. In the previous study, heme oxygenase-1 (HO1) mRNA was delivered into the ischemic brain, showing that HO1-mRNA had higher therapeutic effect and less side-effect than HO1-plasmid (pHO1). However, mRNA is degraded faster than plasmid DNA reducing the duration of gene expression. In this study, self-replicating mRNA (Rep-mRNA) was developed using a replicon system from Venezuelan Equine Encephalitis virus to compensate this disadvantage of mRNA delivery. Deoxycholic acid-conjugated polyethylenimine (DA-PEI) was used as a carrier of the mRNA. The Rep-mRNA/DA-PEI complex had a size of around 90 nm and a zeta-potential of 33 mV. In the in vitro transfection assays, gene expression by the HO1-Rep-mRNA/DA-PEI complex persisted at least 14 days, while that by the HO1-mRNA/DA-PEI complex approached basal level at 3 days after transfection. Therapeutic effects of the HO1-Rep-mRNA/DA-PEI complexes were evaluated in the ischemic stroke animal models. The complexes were injected into the brain stereotaxically. HO1 expression by the HO1-Rep-mRNA/DA-PEI complex persisted at least 7 days after injection, but the pHO1/DA-PEI or HO1-mRNA/DA-PEI complex showed basal level of HO1-expression at 7 days after injection. Due to higher and longer expression of HO1, the apoptosis level and infarct size were decreased by the HO1-Rep-mRNA/DA-PEI complexes, compared with the pHO1/DA-PEI and HO1-mRNA/DA-PEI complex. These results suggest that HO1-Rep-mRNA/DA-PEI complex may have a potential as a long-lasting therapeutic system for the treatment of ischemic stroke.
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Affiliation(s)
- Minkyung Kim
- Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seondong-gu, Seoul 04763, Republic of Korea
| | - Jungju Oh
- Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seondong-gu, Seoul 04763, Republic of Korea
| | - Youngki Lee
- Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seondong-gu, Seoul 04763, Republic of Korea
| | - Eun-Hye Lee
- Hanyang Biomedical Research Institute, Hanyang University, Seoul 04763, Republic of Korea
| | - Seung Hwan Ko
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Republic of Korea
| | - Ji Hoon Jeong
- College of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Chang Hwan Park
- Hanyang Biomedical Research Institute, Hanyang University, Seoul 04763, Republic of Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Republic of Korea; Department of Microbiology, College of Medicine, Hanyang University, Seoul 04763, Republic of Korea.
| | - Minhyung Lee
- Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seondong-gu, Seoul 04763, Republic of Korea.
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Garcia-Bonilla L, Iadecola C, Anrather J. Inflammation and Immune Response. Stroke 2022. [DOI: 10.1016/b978-0-323-69424-7.00010-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Zhao PC, Xu SN, Huang ZS, Jiang GW, Deng PC, Zhang YM. Hyperbaric oxygen via mediating SIRT1-induced deacetylation of HMGB1 improved cReperfusion inj/reperfusion injury. Eur J Neurosci 2021; 54:7318-7331. [PMID: 34523745 DOI: 10.1111/ejn.15458] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 08/24/2021] [Accepted: 09/02/2021] [Indexed: 12/23/2022]
Abstract
Ischemic stroke leads to severe neurological dysfunction in adults. Hyperbaric oxygen (HBO) induces tolerance to cReperfusion inj/reperfusion (I/R) injury. Therefore, our aims were to investigate whether SIRT1 participates in regulatingin the neuro-protective effect of HBO in a cerebral I/R model and its mechanism. Mice N2a cells were used to construct an oxygen deprivation/reperfusion (OGD/R) model to simulate in vitro brain I/R injury and to evaluate the role of HBO in OGD/R stimulated cells. Cell proliferation was detected using MTT, and apoptosis was determined by flow cytometry. ELISA was used to measure the concentration of TNF-α, IL-1β and IL-6 related inflammatory factors. RT-qPCR and western blot assays were performed to test the expression of SIRT1. Immunoprecipitation was used to detect acetylation of HMGB1. Expression of SIRT1 was obviously reduced after OGD/R treatment in N2a cells, while SIRT1 was obviously enhanced in HBO treated cells. Moreover, knockdown of SIRT1 induced neuro-inflammation damage in cells and HBO effectively improved the inflammatory response in OGD/R treated cells by affecting SIRT1 levels. Furthermore, HBO induced the deacetylation of HMGB1 via regulating SIRT1. Interestingly, HBO via regulating the SIRT1-induced HMGB1 deacetylation and suppressing MMP-9 improved ischemic brain injury. HBO regulated ischemic brain injury via regulation of SIRT1-induced HMGB1 deacetylation, making it a potential treatment for ischemic brain injury treatment.
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Affiliation(s)
- Peng-Cheng Zhao
- Department of Neurosurgery, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui Province, China.,Clinical College, Anhui Medical University, Hefei, Anhui Province, China
| | - Shao-Nian Xu
- Department of Neurosurgery, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui Province, China
| | - Zhen-Shan Huang
- Department of Neurosurgery, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui Province, China
| | - Guo-Wei Jiang
- Department of Neurosurgery, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui Province, China
| | - Peng-Cheng Deng
- Department of Neurosurgery, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui Province, China
| | - Yong-Ming Zhang
- Department of Neurosurgery, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui Province, China
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Davaanyam D, Kim ID, Lee JK. Intranasal Delivery of RGD-Containing Osteopontin Heptamer Peptide Confers Neuroprotection in the Ischemic Brain and Augments Microglia M2 Polarization. Int J Mol Sci 2021; 22:ijms22189999. [PMID: 34576163 PMCID: PMC8466884 DOI: 10.3390/ijms22189999] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/07/2021] [Accepted: 09/13/2021] [Indexed: 11/16/2022] Open
Abstract
Osteopontin (OPN), a phosphorylated glycoprotein, is induced in response to tissue damage and inflammation in various organs, including the brain. In our previous studies, we reported the robust neuroprotective effects of the icosamer OPN peptide OPNpt20, containing arginine-glycine-aspartic acid (RGD) and serine-leucine-alanine-tyrosine (SLAY) motifs, in an animal model of transient focal ischemia and demonstrated that its anti-inflammatory, pro-angiogenic, and phagocytosis inducing functions are responsible for the neuroprotective effects. In the present study, we truncated OPNpt20 to 13 or 7 amino acid peptides containing RGD (R) and/or SLAY (S) motifs (OPNpt13RS, OPNpt7R, OPNpt7RS, and OPNpt7S), and their neuroprotective efficacy was examined in a rat middle cerebral artery occlusion (MCAO) model. Intranasal administration of all four peptides significantly reduced infarct volume; OPNpt7R (VPNGRGD), the 7-amino-acid peptide containing an RGD motif, was determined to be the most potent, with efficacy comparable to that of OPNpt20. Additionally, sensory–motor functional deficits of OPNpt7R-administered MCAO animals were significantly improved, as indicated by the modified neurological severity scores and rotarod test. Notably, the expression of M1 markers was suppressed, whereas that of M2 markers (Arginase 1, CD206, and VEGF) was significantly enhanced in OPNpt7R-treated primary microglia cultures. Inflammation resolution by OPNpt7R was further confirmed in MCAO animals, in which upregulation of anti-inflammatory cytokines (Arg1, IL-10, IL-4, and CD36) and enhanced efferocytosis were detected. Moreover, studies using three mutant peptides (OPNpt7R-RAA or OPNpt7R-RAD, where RGD was replaced with RAA or RAD, respectively, and OPNpt7R-sc containing scrambled sequences) revealed that the RGD motif plays a vital role in conferring neuroprotection. In conclusion, the RGD-containing OPN heptamer OPNpt7R exhibits neuroprotective effects in the post-ischemic brain by suppressing M1 markers and augmenting M2 polarization of microglia and the RGD motif plays a critical role in these activities.
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Masai K, Kuroda K, Isooka N, Kikuoka R, Murakami S, Kamimai S, Wang D, Liu K, Miyazaki I, Nishibori M, Asanuma M. Neuroprotective Effects of Anti-high Mobility Group Box-1 Monoclonal Antibody Against Methamphetamine-Induced Dopaminergic Neurotoxicity. Neurotox Res 2021; 39:1511-1523. [PMID: 34417986 DOI: 10.1007/s12640-021-00402-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 06/08/2021] [Accepted: 08/06/2021] [Indexed: 12/15/2022]
Abstract
High mobility group box-1 (HMGB1) is a ubiquitous non-histone nuclear protein that plays a key role as a transcriptional activator, with its extracellular release provoking inflammation. Inflammatory responses are essential in methamphetamine (METH)-induced acute dopaminergic neurotoxicity. In the present study, we examined the effects of neutralizing anti-HMGB1 monoclonal antibody (mAb) on METH-induced dopaminergic neurotoxicity in mice. BALB/c mice received a single intravenous administration of anti-HMGB1 mAb prior to intraperitoneal injections of METH (4 mg/kg × 2, at 2-h intervals). METH injections induced hyperthermia, an increase in plasma HMGB1 concentration, degeneration of dopaminergic nerve terminals, accumulation of microglia, and extracellular release of neuronal HMGB1 in the striatum. These METH-induced changes were significantly inhibited by intravenous administration of anti-HMGB1 mAb. In contrast, blood-brain barrier disruption occurred by METH injections was not suppressed. Our findings demonstrated the neuroprotective effects of anti-HMGB1 mAb against METH-induced dopaminergic neurotoxicity, suggesting that HMGB1 could play an initially important role in METH toxicity.
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Affiliation(s)
- Kaori Masai
- Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, 700-8558, Okayama, Japan
| | - Keita Kuroda
- Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, 700-8558, Okayama, Japan
| | - Nami Isooka
- Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, 700-8558, Okayama, Japan
| | - Ryo Kikuoka
- Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, 700-8558, Okayama, Japan
| | - Shinki Murakami
- Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, 700-8558, Okayama, Japan
| | - Sunao Kamimai
- Department of Medical Neurobiology, Okayama University Medical School, 700-8558, Okayama, Japan
| | - Dengli Wang
- Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 700-8558, Okayama, Japan
| | - Keyue Liu
- Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 700-8558, Okayama, Japan
| | - Ikuko Miyazaki
- Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, 700-8558, Okayama, Japan
| | - Masahiro Nishibori
- Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 700-8558, Okayama, Japan
| | - Masato Asanuma
- Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, 700-8558, Okayama, Japan.
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Peek V, Harden LM, Damm J, Aslani F, Leisengang S, Roth J, Gerstberger R, Meurer M, von Köckritz-Blickwede M, Schulz S, Spengler B, Rummel C. LPS Primes Brain Responsiveness to High Mobility Group Box-1 Protein. Pharmaceuticals (Basel) 2021; 14:ph14060558. [PMID: 34208101 PMCID: PMC8230749 DOI: 10.3390/ph14060558] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/04/2021] [Accepted: 06/08/2021] [Indexed: 12/30/2022] Open
Abstract
High mobility group box (HMGB)1 action contributes to late phases of sepsis, but the effects of increased endogenous plasma HMGB1 levels on brain cells during inflammation are unclear. Here, we aimed to further investigate the role of HMGB1 in the brain during septic-like lipopolysaccharide-induced inflammation in rats (LPS, 10 mg/kg, i.p.). HMGB-1 mRNA expression and release were measured in the periphery/brain by RT-PCR, immunohistochemistry and ELISA. In vitro experiments with disulfide-HMGB1 in primary neuro-glial cell cultures of the area postrema (AP), a circumventricular organ with a leaky blood–brain barrier and direct access to circulating mediators like HMGB1 and LPS, were performed to determine the direct influence of HMGB1 on this pivotal brain structure for immune-to-brain communication. Indeed, HMGB1 plasma levels stayed elevated after LPS injection. Immunohistochemistry of brains and AP cultures confirmed LPS-stimulated cytoplasmatic translocation of HMGB1 indicative of local HMGB1 release. Moreover, disulfide-HMGB1 stimulation induced nuclear factor (NF)-κB activation and a significant release of interleukin-6, but not tumor necrosis factor α, into AP culture supernatants. However, only a few AP cells directly responded to HMGB1 with increased intracellular calcium concentration. Interestingly, priming with LPS induced a seven-fold higher percentage of responsive cells to HMGB1. We conclude that, as a humoral and local mediator, HMGB1 enhances brain inflammatory responses, after LPS priming, linked to sustained sepsis symptoms.
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Affiliation(s)
- Verena Peek
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, 35392 Giessen, Germany; (V.P.); (J.D.); (S.L.); (J.R.); (R.G.)
| | - Lois M. Harden
- Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of Witwatersrand, Johannesburg 2193, South Africa;
| | - Jelena Damm
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, 35392 Giessen, Germany; (V.P.); (J.D.); (S.L.); (J.R.); (R.G.)
| | - Ferial Aslani
- Institute of Anatomy and Cell Biology of the Medical Faculty, Justus Liebig University, 35392 Giessen, Germany;
| | - Stephan Leisengang
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, 35392 Giessen, Germany; (V.P.); (J.D.); (S.L.); (J.R.); (R.G.)
| | - Joachim Roth
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, 35392 Giessen, Germany; (V.P.); (J.D.); (S.L.); (J.R.); (R.G.)
| | - Rüdiger Gerstberger
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, 35392 Giessen, Germany; (V.P.); (J.D.); (S.L.); (J.R.); (R.G.)
| | - Marita Meurer
- Department of Biochemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany and Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, 30559 Hannover, Germany; (M.M.); (M.v.K.-B.)
| | - Maren von Köckritz-Blickwede
- Department of Biochemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany and Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, 30559 Hannover, Germany; (M.M.); (M.v.K.-B.)
| | - Sabine Schulz
- Institute of Inorganic and Analytical Chemistry, Justus Liebig University Giessen, 35392 Giessen, Germany; (S.S.); (B.S.)
| | - Bernhard Spengler
- Institute of Inorganic and Analytical Chemistry, Justus Liebig University Giessen, 35392 Giessen, Germany; (S.S.); (B.S.)
| | - Christoph Rummel
- Institute of Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, 35392 Giessen, Germany; (V.P.); (J.D.); (S.L.); (J.R.); (R.G.)
- Correspondence:
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Platelets as drivers of ischemia/reperfusion injury after stroke. Blood Adv 2021; 5:1576-1584. [PMID: 33687431 DOI: 10.1182/bloodadvances.2020002888] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 02/01/2021] [Indexed: 12/14/2022] Open
Abstract
Ischemic stroke is a leading cause of morbidity and mortality worldwide and, despite reperfusion either via thrombolysis or thrombectomy, stroke patients often suffer from lifelong disabilities. These persistent neurological deficits may be improved by treating the ischemia/reperfusion (I/R) injury that occurs following ischemic stroke. There are currently no approved therapies to treat I/R injury, and thus it is imperative to find new targets to decrease the burden of ischemic stroke and related diseases. Platelets, cell fragments from megakaryocytes, are primarily known for their role in hemostasis. More recently, investigators have studied the nonhemostatic role of platelets in inflammatory pathologies, such as I/R injury after ischemic stroke. In this review, we seek to provide an overview of how I/R can lead to platelet activation and how activated platelets, in turn, can exacerbate I/R injury after stroke. We will also discuss potential mechanisms by which platelets may ameliorate I/R injury.
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Sha S, Tan J, Miao Y, Zhang Q. The Role of Autophagy in Hypoxia-Induced Neuroinflammation. DNA Cell Biol 2021; 40:733-739. [PMID: 33989049 DOI: 10.1089/dna.2020.6186] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Autophagy is a critical cytoprotective mechanism that takes a hand in innate or adaptive immune responses. Hypoxia is a common pathophysiological mechanism that can lead to systemic pathological reactions. In recent years, the impact of hypoxia on the central nervous system has attracted more attention. In the past, autophagy was thought to be directly involved in the apoptosis of nerve cells under hypoxia. An increasing amount of evidence shows that the neuroinflammatory response plays an indispensable role in the neural damage caused by hypoxia. There are many mechanisms related to the neuroinflammatory response induced by hypoxia, among which autophagy is an important aspect, but the role of autophagy is still unclear. This article focuses on how autophagy flux of central immune cells is modified under hypoxic conditions, and how this autophagy affects neuroinflammatory response.
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Affiliation(s)
- Sha Sha
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin, China
| | - Jin Tan
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin, China
| | | | - Qiang Zhang
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin, China
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Seol SI, Kim HJ, Choi EB, Kang IS, Lee HK, Lee JK, Kim C. Taurine Protects against Postischemic Brain Injury via the Antioxidant Activity of Taurine Chloramine. Antioxidants (Basel) 2021; 10:antiox10030372. [PMID: 33801397 PMCID: PMC8000369 DOI: 10.3390/antiox10030372] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/14/2021] [Accepted: 02/19/2021] [Indexed: 11/16/2022] Open
Abstract
Taurine is ubiquitously distributed in mammalian tissues and is highly concentrated in the heart, brain, and leukocytes. Taurine exerts neuroprotective effects in various central nervous system diseases and can suppress infarct formation in stroke. Taurine reacts with myeloperoxidase (MPO)-derived hypochlorous acid (HOCl) to produce taurine chloramine (Tau-Cl). We investigated the neuroprotective effects of taurine using a rat middle cerebral artery occlusion (MCAO) model and BV2 microglial cells. Although intranasal administration of taurine (0.5 mg/kg) had no protective effects, the same dose of Tau-Cl significantly reduced infarct volume and ameliorated neurological deficits and promoted motor function, indicating a robust neuroprotective effect of Tau-Cl. There was neutrophil infiltration in the post-MCAO brains, and the MPO produced by infiltrating neutrophils might be involved in the taurine to Tau-Cl conversion. Tau-Cl significantly increased the levels of antioxidant enzymes glutamate-cysteine ligase, heme oxygenase-1, NADPH:quinone oxidoreductase 1, and peroxiredoxin-1 in BV2 cells, whereas taurine slightly increased some of them. Antioxidant enzyme levels were increased in the post-MCAO brains, and Tau-Cl further increased the level of MCAO-induced antioxidant enzymes. These results suggest that the neutrophils infiltrate the area of ischemic injury area, where taurine is converted to Tau-Cl, thus protecting from brain injury by scavenging toxic HOCl and increasing antioxidant enzyme expression.
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Affiliation(s)
- Song-I Seol
- Department of Anatomy, Inha University School of Medicine, Incheon 22212, Korea; (S.-I.S.); (H.-K.L.)
- BK21, Program in Biomedical Science & Engineering, Inha University, Incheon 22212, Korea; (H.J.K.); (E.B.C.)
| | - Hyun Jae Kim
- BK21, Program in Biomedical Science & Engineering, Inha University, Incheon 22212, Korea; (H.J.K.); (E.B.C.)
- Laboratory of Leukocyte Signaling Research, Department of Pharmacology, Inha University School of Medicine, Incheon 22212, Korea;
| | - Eun Bi Choi
- BK21, Program in Biomedical Science & Engineering, Inha University, Incheon 22212, Korea; (H.J.K.); (E.B.C.)
- Laboratory of Leukocyte Signaling Research, Department of Pharmacology, Inha University School of Medicine, Incheon 22212, Korea;
| | - In Soon Kang
- Laboratory of Leukocyte Signaling Research, Department of Pharmacology, Inha University School of Medicine, Incheon 22212, Korea;
| | - Hye-Kyung Lee
- Department of Anatomy, Inha University School of Medicine, Incheon 22212, Korea; (S.-I.S.); (H.-K.L.)
| | - Ja-Kyeong Lee
- Department of Anatomy, Inha University School of Medicine, Incheon 22212, Korea; (S.-I.S.); (H.-K.L.)
- BK21, Program in Biomedical Science & Engineering, Inha University, Incheon 22212, Korea; (H.J.K.); (E.B.C.)
- Correspondence: (J.-K.L.); (C.K.); Tel.: +82-32-860-9893 (J.-K.L.); +82-32-860-9874 (C.K.); Fax: 82-32-885-8302 (J.-K.L. & C.K.)
| | - Chaekyun Kim
- BK21, Program in Biomedical Science & Engineering, Inha University, Incheon 22212, Korea; (H.J.K.); (E.B.C.)
- Laboratory of Leukocyte Signaling Research, Department of Pharmacology, Inha University School of Medicine, Incheon 22212, Korea;
- Convergent Research Center for Metabolism and Immunoregulation, Inha University, Incheon 22212, Korea
- Correspondence: (J.-K.L.); (C.K.); Tel.: +82-32-860-9893 (J.-K.L.); +82-32-860-9874 (C.K.); Fax: 82-32-885-8302 (J.-K.L. & C.K.)
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Wang Q, Zhao H, Gao Y, Lu J, Xie D, Yu W, He F, Liu W, Hisatome I, Yamamoto T, Wang W, Cheng J. Uric acid inhibits HMGB1-TLR4-NF-κB signaling to alleviate oxygen-glucose deprivation/reoxygenation injury of microglia. Biochem Biophys Res Commun 2021; 540:22-28. [PMID: 33429196 DOI: 10.1016/j.bbrc.2020.12.097] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 12/26/2020] [Indexed: 02/08/2023]
Abstract
Mounting evidence has implicated inflammation in ischemia-reperfusion injury following acute ischemic stroke (AIS). Microglia remain the primary initiator and participant of brain inflammation. Emerging evidence has indicated that uric acid has promise for the treatment of AIS, but its explicit mechanisms remain elusive. Here, we observed that uric acid reduced the severity of cerebral infarction and attenuated the activation of microglia in the cerebral cortex in a mouse middle cerebral-artery occlusion/reperfusion model. Thus, we speculated that uric acid may play a role by directly interfering with the inflammatory response of microglia. First, we investigated whether the HMGB1-TLR4-NF-κB signaling plays a role in oxygen glucose deprivation and reperfusion (OGD/R) injury of BV2 cells. Inhibition of the signaling significantly reduced the release of the proinflammatory cytokines tumor necrosis factor α (TNF-α), interleukin 1β (IL1β), and IL6 caused by OGD/R in BV2 cells. Second, uric acid weakened the decreased cell viability and lactate dehydrogenase release induced by OGD/R in BV2 cells. Finally, uric acid reduced the release of the proinflammatory cytokines TNF-α, IL1β, and IL6 caused by OGD/R in BV2 cells by dampening HMGB1-TLR4-NF-κB signaling, which was reversed by probenecid treatment, an inhibitor of the uric acid channel. Hence, uric acid halted the release of inflammatory factors and the decreased cell viability induced by ODG/R via inhibiting the microglia HMGB1-TLR4-NF-κB signaling, thereby alleviating the damage to microglia. This may be part of the molecular mechanisms by which uric acid protects mice against the brain damage of middle cerebral-artery occlusion/reperfusion.
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Affiliation(s)
- Qiang Wang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - Hairong Zhao
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - Yuan Gao
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - Jiaming Lu
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - De Xie
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - Wei Yu
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - Furong He
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - Weidong Liu
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - Ichiro Hisatome
- Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori University, Yonago, Japan
| | - Tetsuya Yamamoto
- Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Wei Wang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China; Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiamen, Fujian, China.
| | - Jidong Cheng
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China; Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiamen, Fujian, China.
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Gou X, Ying J, Yue Y, Qiu X, Hu P, Qu Y, Li J, Mu D. The Roles of High Mobility Group Box 1 in Cerebral Ischemic Injury. Front Cell Neurosci 2020; 14:600280. [PMID: 33384585 PMCID: PMC7770223 DOI: 10.3389/fncel.2020.600280] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 11/25/2020] [Indexed: 12/11/2022] Open
Abstract
High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that plays an important role in stabilizing nucleosomes and DNA repair. HMGB1 can be passively released from necrotic neurons or actively secreted by microglia, macrophages/monocytes, and neutrophils. Cerebral ischemia is a major cause of mortality and disability worldwide, and its outcome depends on the number of neurons dying due to hypoxia in the ischemic area. HMGB1 contributes to the pathogenesis of cerebral ischemia via mediating neuroinflammatory responses to cerebral ischemic injury. Extracellular HMGB1 regulates many neuroinflammatory events by interacting with its different cell surface receptors, such as receptors for advanced glycation end products, toll-like receptor (TLR)-2, and TLR-4. Additionally, HMGB1 can be redox-modified, thus exerting specific cellular functions in the ischemic brain and has different roles in the acute and late stages of cerebral ischemic injury. However, the role of HMGB1 in cerebral ischemia is complex and remains unclear. Herein, we summarize and review the research on HMGB1 in cerebral ischemia, focusing especially on the role of HMGB1 in hypoxic ischemia in the immature brain and in white matter ischemic injury. We also outline the possible mechanisms of HMGB1 in cerebral ischemia and the main strategies to inhibit HMGB1 pertaining to its potential as a novel critical molecular target in cerebral ischemic injury.
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Affiliation(s)
- Xiaoyun Gou
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects, Ministry of Education, Sichuan University, Chengdu, China
| | - Junjie Ying
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects, Ministry of Education, Sichuan University, Chengdu, China
| | - Yan Yue
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects, Ministry of Education, Sichuan University, Chengdu, China
| | - Xia Qiu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects, Ministry of Education, Sichuan University, Chengdu, China
| | - Peng Hu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects, Ministry of Education, Sichuan University, Chengdu, China
| | - Yi Qu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects, Ministry of Education, Sichuan University, Chengdu, China
| | - Jinhui Li
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects, Ministry of Education, Sichuan University, Chengdu, China
| | - Dezhi Mu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects, Ministry of Education, Sichuan University, Chengdu, China
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Nishibori M, Wang D, Ousaka D, Wake H. High Mobility Group Box-1 and Blood-Brain Barrier Disruption. Cells 2020; 9:cells9122650. [PMID: 33321691 PMCID: PMC7764171 DOI: 10.3390/cells9122650] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/01/2020] [Accepted: 12/08/2020] [Indexed: 02/07/2023] Open
Abstract
Increasing evidence suggests that inflammatory responses are involved in the progression of brain injuries induced by a diverse range of insults, including ischemia, hemorrhage, trauma, epilepsy, and degenerative diseases. During the processes of inflammation, disruption of the blood–brain barrier (BBB) may play a critical role in the enhancement of inflammatory responses and may initiate brain damage because the BBB constitutes an interface between the brain parenchyma and the bloodstream containing blood cells and plasma. The BBB has a distinct structure compared with those in peripheral tissues: it is composed of vascular endothelial cells with tight junctions, numerous pericytes surrounding endothelial cells, astrocytic endfeet, and a basement membrane structure. Under physiological conditions, the BBB should function as an important element in the neurovascular unit (NVU). High mobility group box-1 (HMGB1), a nonhistone nuclear protein, is ubiquitously expressed in almost all kinds of cells. HMGB1 plays important roles in the maintenance of chromatin structure, the regulation of transcription activity, and DNA repair in nuclei. On the other hand, HMGB1 is considered to be a representative damage-associated molecular pattern (DAMP) because it is translocated and released extracellularly from different types of brain cells, including neurons and glia, contributing to the pathophysiology of many diseases in the central nervous system (CNS). The regulation of HMGB1 release or the neutralization of extracellular HMGB1 produces beneficial effects on brain injuries induced by ischemia, hemorrhage, trauma, epilepsy, and Alzheimer’s amyloidpathy in animal models and is associated with improvement of the neurological symptoms. In the present review, we focus on the dynamics of HMGB1 translocation in different disease conditions in the CNS and discuss the functional roles of extracellular HMGB1 in BBB disruption and brain inflammation. There might be common as well as distinct inflammatory processes for each CNS disease. This review will provide novel insights toward an improved understanding of a common pathophysiological process of CNS diseases, namely, BBB disruption mediated by HMGB1. It is proposed that HMGB1 might be an excellent target for the treatment of CNS diseases with BBB disruption.
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Lin CH, Chen HY, Wei KC. Role of HMGB1/TLR4 Axis in Ischemia/Reperfusion-Impaired Extracellular Glutamate Clearance in Primary Astrocytes. Cells 2020; 9:E2585. [PMID: 33287126 PMCID: PMC7761728 DOI: 10.3390/cells9122585] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/20/2020] [Accepted: 12/01/2020] [Indexed: 11/17/2022] Open
Abstract
(1) Background: Abnormal accumulation of extracellular glutamate can occur as dysfunction of astrocytic glutamate transporters, which has been linked to ischemic brain injury. Excessive extracellular glutamate-induced abnormal excitotoxicity is the major cause of secondary neuronal damage after cerebral ischemia/reperfusion. However, the definite mechanism of impaired astrocytic glutamate reuptake remains unclear. (2) Methods: We investigated the mechanism of the HMGB1/TLR4 axis in extracellular glutamate clearance in primary astrocytes exposed to ischemia/reperfusion by using OGD/R (oxygen-glucose deprivation/reoxygenation) model. (3) Results: OGD/R insult activated the HMGB1/TLR4 axis for reducing the activity of glutamate clearance by inhibiting GLAST (glutamate aspartate transporter) expression in primary astrocytes. Interestingly, OGD/R-untreated astrocytes showed impairment of glutamate clearance after exposure to exogenous HMGB1 or conditioned medium from OGD/R-treated astrocytes culture. Inhibition of HMGB1 or TLR4 effectively prevented impaired glutamate clearance, which was induced by OGD/R, exogenous HMGB1, or conditioned medium from OGD/R-treated astrocytes. Furthermore, glycyrrhizic acid attenuated OGD/R-induced impairment of astrocytic glutamate clearance mediated by the HMGB1-TLR4 axis. (4) Conclusion: The HMGB1/TLR4 axis is a potential target for the treatment of post-ischemic excitotoxicity caused by GLAST dysfunction in astrocytes.
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Affiliation(s)
- Chia-Ho Lin
- Master and PhD Programs in Pharmacology and Toxicology, School of Medicine, Tzu Chi University, Hualien 970, Taiwan; (C.-H.L.); (H.-Y.C.)
- Department of Pharmacology, School of Medicine, Tzu Chi University, Hualien 970, Taiwan
| | - Han-Yu Chen
- Master and PhD Programs in Pharmacology and Toxicology, School of Medicine, Tzu Chi University, Hualien 970, Taiwan; (C.-H.L.); (H.-Y.C.)
| | - Kai-Che Wei
- Department of Dermatology, Kaohsiung Veterans General Hospital, Kaohsiung 802, Taiwan
- School of Medicine, National Yang-Ming University, Taipei 112, Taiwan
- Faculty of Yuh-Ing Junior College of Health Care and Management, Kaohsiung 802, Taiwan
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Hummel R, Ulbrich S, Appel D, Li S, Hirnet T, Zander S, Bobkiewicz W, Gölz C, Schäfer MK. Administration of all-trans retinoic acid after experimental traumatic brain injury is brain protective. Br J Pharmacol 2020; 177:5208-5223. [PMID: 32964418 PMCID: PMC7588818 DOI: 10.1111/bph.15259] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 09/02/2020] [Accepted: 09/04/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND AND PURPOSE All-trans retinoic acid (ATRA) is a vitamin A metabolite, important in the developing and mature brain. Pre-injury ATRA administration ameliorates ischaemic brain insults in rodents. This study examined the effects of post-traumatic ATRA treatment in experimental traumatic brain injury (TBI). EXPERIMENTAL APPROACH Male adult mice were subjected to the controlled cortical impact model of TBI or sham procedure and killed at 7 or 30 days post-injury (dpi). ATRA (10 mg kg-1, i.p.) was given immediately after the injury and 1, 2 and 3 dpi. Neurological function and sensorimotor coordination were evaluated. Brains were processed for (immuno-) histological, mRNA and protein analyses (qPCR and western blot). KEY RESULTS ATRA treatment reduced brain lesion size, reactive astrogliosis and axonal injury at 7 dpi, and hippocampal granule cell layer (GCL) integrity was protected at 7 and 30 dpi, independent of cell proliferation in neurogenic niches and blood-brain barrier damage. Neurological and motor deficits over time and the brain tissue loss at 30 dpi were not affected by ATRA treatment. ATRA decreased gene expression of markers for damage-associated molecular pattern (HMGB1), apoptosis (caspase-3 and Bax), activated microglia (TSPO), and reactive astrogliosis (GFAP, SerpinA3N) at 7 dpi and a subset of markers at 30 dpi (TSPO, GFAP). CONCLUSION AND IMPLICATIONS In experimental TBI, post-traumatic ATRA administration exerted brain protective effects, including long-term protection of GCL integrity, but did not affect neurological and motor deficits. Further investigations are required to optimize treatment regimens to enhance ATRA's brain protective effects and improve outcomes.
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Affiliation(s)
- Regina Hummel
- Department of AnesthesiologyUniversity Medical Center, Johannes Gutenberg‐University MainzMainzGermany
| | - Sebastian Ulbrich
- Department of AnesthesiologyUniversity Medical Center, Johannes Gutenberg‐University MainzMainzGermany
| | - Dominik Appel
- Department of AnesthesiologyUniversity Medical Center, Johannes Gutenberg‐University MainzMainzGermany
| | - Shuailong Li
- Department of AnesthesiologyUniversity Medical Center, Johannes Gutenberg‐University MainzMainzGermany
| | - Tobias Hirnet
- Department of AnesthesiologyUniversity Medical Center, Johannes Gutenberg‐University MainzMainzGermany
| | - Sonja Zander
- Department of AnesthesiologyUniversity Medical Center, Johannes Gutenberg‐University MainzMainzGermany
| | - Wieslawa Bobkiewicz
- Department of AnesthesiologyUniversity Medical Center, Johannes Gutenberg‐University MainzMainzGermany
| | - Christina Gölz
- Department of AnesthesiologyUniversity Medical Center, Johannes Gutenberg‐University MainzMainzGermany
| | - Michael K.E. Schäfer
- Department of AnesthesiologyUniversity Medical Center, Johannes Gutenberg‐University MainzMainzGermany
- Focus Program Translational Neurosciences (FTN)Johannes Gutenberg‐University MainzMainzGermany
- Research Center for ImmunotherapyUniversity Medical Center, Johannes Gutenberg‐University MainzMainzGermany
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Tommy T, Islam AA, Hatta M, Bukhari A. Immunomodulatory properties of high mobility group box 1 and its potential role in brain injury: Review article. Ann Med Surg (Lond) 2020; 59:106-109. [PMID: 32994992 PMCID: PMC7511818 DOI: 10.1016/j.amsu.2020.09.025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/10/2020] [Accepted: 09/12/2020] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Human mobility group box 1 (HMGB1) is a novel biomolecular agent which has a major part in inflammation process. HMGB1 has been known to be a strong pro-inflammatory factor as damage associated molecular pattern (DAMP) which its interaction with its receptor, the receptor of advanced glycation end products (RAGE), will cause positive amplification of inflammation signalling pathway.Brain injury is one of the major contributors for disability and death which neuroinflammation has a major role in its pathogenesis and influencing its outcome. In neuroinflammation, it has been described that HMGB1 may have a pivotal role in the process. OBJECTIVE The objective of this article is to review the role HMGB1 in brain injury and its immunomodulatory properties. METHODS A comprehensive search of literature was conducted in PubMed (NIH), Scopus, EMBASE, and Google Scholar database using keyword combinations of the medical subject headings (MeSH) of "HMGB1" and "Brain Injury" and relevant reference lists were also manually searched. All relevant articles of any study design published from year 1990 till June 2020, were included and narratively discussed in this review. RESULTS Twenty-four articles were shortlisted and reviewed in this article. Through these articles, we synthesis information on the function and metabolism of HMGB1, immunomodulatory effect of HMGB1, clinical findings and other potential treatment involving HMGB1, and role of HMGB1 protein in brain injury. CONCLUSION HMGB1 has a strong pro-inflammation property which predominantly acts through RAGE pathways.Review registration number reviewregistry966 in www.researchregistry.com.
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Affiliation(s)
- Thomas Tommy
- Department of Neurosurgery, Faculty of Medicine, Universitas Pelita Harapan, Tangerang, Indonesia
| | - Andi A. Islam
- Department of Neurosurgery, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia
| | - Mochammad Hatta
- Molecular Biology and Immunology Laboratory, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia
| | - Agussalim Bukhari
- Department of Nutritional Science, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia
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Glycyrrhizin Blocks the Detrimental Effects of HMGB1 on Cortical Neurogenesis After Traumatic Neuronal Injury. Brain Sci 2020; 10:brainsci10100760. [PMID: 33096930 PMCID: PMC7593920 DOI: 10.3390/brainsci10100760] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 10/17/2020] [Accepted: 10/19/2020] [Indexed: 12/20/2022] Open
Abstract
Despite medical advances, neurological recovery after severe traumatic brain injury (TBI) remains poor. Elevated levels of high mobility group box protein-1 (HMGB1) are associated with poor outcomes; likely via interaction with receptors for advanced-glycation-end-products (RAGE). We examined the hypothesis that HMGB1 post-TBI is anti-neurogenic and whether this is pharmacologically reversible. Post-natal rat cortical mixed neuro-glial cell cultures were subjected to needle-scratch injury and examined for HMGB1-activation/neuroinflammation. HMGB1-related genes/networks were examined using genome-wide RNA-seq studies in cortical perilesional tissue samples from adult mice. Post-natal rat cortical neural stem/progenitor cell cultures were generated to quantify effects of injury-condition medium (ICM) on neurogenesis with/without RAGE antagonist glycyrrhizin. Needle-injury upregulated TNF-α/NOS-2 mRNA-expressions at 6 h, increased proportions of activated microglia, and caused neuronal loss at 24 h. Transcriptome analysis revealed activation of HMGB1 pathway genes/canonical pathways in vivo at 24 h. A 50% increase in HMGB1 protein expression, and nuclear-to-cytoplasmic translocation of HMGB1 in neurons and microglia at 24 h post-injury was demonstrated in vitro. ICM reduced total numbers/proportions of neuronal cells, but reversed by 0.5 μM glycyrrhizin. HMGB1 is activated following in vivo post mechanical injury, and glycyrrhizin alleviates detrimental effects of ICM on cortical neurogenesis. Our findings highlight glycyrrhizin as a potential therapeutic agent post-TBI.
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Espinosa-Garcia C, Atif F, Yousuf S, Sayeed I, Neigh GN, Stein DG. Progesterone Attenuates Stress-Induced NLRP3 Inflammasome Activation and Enhances Autophagy following Ischemic Brain Injury. Int J Mol Sci 2020; 21:E3740. [PMID: 32466385 PMCID: PMC7312827 DOI: 10.3390/ijms21113740] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 05/18/2020] [Accepted: 05/24/2020] [Indexed: 02/07/2023] Open
Abstract
NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome inhibition and autophagy induction attenuate inflammation and improve outcome in rodent models of cerebral ischemia. However, the impact of chronic stress on NLRP3 inflammasome and autophagic response to ischemia remains unknown. Progesterone (PROG), a neuroprotective steroid, shows promise in reducing excessive inflammation associated with poor outcome in ischemic brain injury patients with comorbid conditions, including elevated stress. Stress primes microglia, mainly by the release of alarmins such as high-mobility group box-1 (HMGB1). HMGB1 activates the NLRP3 inflammasome, resulting in pro-inflammatory interleukin (IL)-1β production. In experiment 1, adult male Sprague-Dawley rats were exposed to social defeat stress for 8 days and then subjected to global ischemia by the 4-vessel occlusion model, a clinically relevant brain injury associated with cardiac arrest. PROG was administered 2 and 6 h after occlusion and then daily for 7 days. Animals were killed at 7 or 14 days post-ischemia. Here, we show that stress and global ischemia exert a synergistic effect in HMGB1 release, resulting in exacerbation of NLRP3 inflammasome activation and autophagy impairment in the hippocampus of ischemic animals. In experiment 2, an in vitro inflammasome assay, primary microglia isolated from neonatal brain tissue, were primed with lipopolysaccharide (LPS) and stimulated with adenosine triphosphate (ATP), displaying impaired autophagy and increased IL-1β production. In experiment 3, hippocampal microglia isolated from stressed and unstressed animals, were stimulated ex vivo with LPS, exhibiting similar changes than primary microglia. Treatment with PROG reduced HMGB1 release and NLRP3 inflammasome activation, and enhanced autophagy in stressed and unstressed ischemic animals. Pre-treatment with an autophagy inhibitor blocked Progesterone's (PROG's) beneficial effects in microglia. Our data suggest that modulation of microglial priming is one of the molecular mechanisms by which PROG ameliorates ischemic brain injury under stressful conditions.
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Affiliation(s)
- Claudia Espinosa-Garcia
- Department of Emergency Medicine, Emory University, Atlanta, GA 30322, USA; (F.A.); (S.Y.); (I.S.); (D.G.S.)
| | - Fahim Atif
- Department of Emergency Medicine, Emory University, Atlanta, GA 30322, USA; (F.A.); (S.Y.); (I.S.); (D.G.S.)
| | - Seema Yousuf
- Department of Emergency Medicine, Emory University, Atlanta, GA 30322, USA; (F.A.); (S.Y.); (I.S.); (D.G.S.)
| | - Iqbal Sayeed
- Department of Emergency Medicine, Emory University, Atlanta, GA 30322, USA; (F.A.); (S.Y.); (I.S.); (D.G.S.)
| | - Gretchen N. Neigh
- Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Donald G. Stein
- Department of Emergency Medicine, Emory University, Atlanta, GA 30322, USA; (F.A.); (S.Y.); (I.S.); (D.G.S.)
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Wang F, Ji S, Wang M, Liu L, Li Q, Jiang F, Cen J, Ji B. HMGB1 promoted P-glycoprotein at the blood-brain barrier in MCAO rats via TLR4/NF-κB signaling pathway. Eur J Pharmacol 2020; 880:173189. [PMID: 32417325 DOI: 10.1016/j.ejphar.2020.173189] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 05/07/2020] [Accepted: 05/10/2020] [Indexed: 01/28/2023]
Abstract
P-glycoprotein (P-gp) is located on the luminal surface of brain vascular endothelium and its status may determine the delivery of the agents into the brain tissues. Previous study showed that upregulation of P-gp at the blood-brain barrier (BBB) after ischemic stroke were mediated by nuclear factor-B (NF-kB) and tumour necrosis factor-α (TNF-α). Based on middle cerebral artery occlusion (MCAO) rats and oxygen-glucose deprivation (OGD) in co-culture of rat brain microvessel endothelial cells (rBMECs) and astrocytes system, the present data indicated that potentiated P-gp expression and activity in brain microvessels or rBMECs were associated with the increase in high-mobility group box 1 (HMGB1), Toll-like receptor 4 (TLR4) and activation of NF-kB and that HMGB1 can release from nucleus to the cytoplasm in activated astrocytes, then into the medium. Moreover, changes in TLR4, TIR domain-containing adaptor protein (TIRAP), NF-kB and P-gp in rBMECs were attenuated by addition of 1 mM ethyl pyruvate (EP), 10 μM TAK-242 and 10 μM pyrrolidine dithiocarbamate (PDTC), respectively. These results demonstrated that HMGB1 promoted P-gp at the BBB after cerebral ischemia via TLR4/NF-κB signaling pathway.
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Affiliation(s)
- Fei Wang
- Department of Cerebral Surgery, The Second People's Hospital of Zhengzhou, Zhengzhou, 450000, People's Republic of China; Key Laboratory of Natural Medicine and Immune Engineering, Henan University, Kaifeng, 475004, People's Republic of China
| | - Shenglan Ji
- Key Laboratory of Natural Medicine and Immune Engineering, Henan University, Kaifeng, 475004, People's Republic of China
| | - Muxi Wang
- Key Laboratory of Natural Medicine and Immune Engineering, Henan University, Kaifeng, 475004, People's Republic of China; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, 61801, USA
| | - Lu Liu
- Key Laboratory of Natural Medicine and Immune Engineering, Henan University, Kaifeng, 475004, People's Republic of China
| | - Qiaoling Li
- Key Laboratory of Natural Medicine and Immune Engineering, Henan University, Kaifeng, 475004, People's Republic of China
| | - Fuxia Jiang
- Key Laboratory of Natural Medicine and Immune Engineering, Henan University, Kaifeng, 475004, People's Republic of China
| | - Juan Cen
- Key Laboratory of Natural Medicine and Immune Engineering, Henan University, Kaifeng, 475004, People's Republic of China.
| | - Biansheng Ji
- Key Laboratory of Natural Medicine and Immune Engineering, Henan University, Kaifeng, 475004, People's Republic of China.
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Hisaoka-Nakashima K, Azuma H, Ishikawa F, Nakamura Y, Wang D, Liu K, Wake H, Nishibori M, Nakata Y, Morioka N. Corticosterone Induces HMGB1 Release in Primary Cultured Rat Cortical Astrocytes: Involvement of Pannexin-1 and P2X7 Receptor-Dependent Mechanisms. Cells 2020; 9:cells9051068. [PMID: 32344830 PMCID: PMC7290518 DOI: 10.3390/cells9051068] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 04/17/2020] [Accepted: 04/22/2020] [Indexed: 02/06/2023] Open
Abstract
A major risk factor for major depressive disorder (MDD) is stress. Stress leads to the release of high-mobility group box-1 (HMGB1), which in turn leads to neuroinflammation, a potential pathophysiological basis of MDD. The mechanism underlying stress-induced HMGB1 release is not known, but stress-associated glucocorticoids could be involved. To test this, rat primary cultured cortical astrocytes, the most abundant cell type in the central nervous system (CNS), were treated with corticosterone and HMGB1 release was assessed by Western blotting and ELISA. Significant HMGB1 was released with treatment with either corticosterone or dexamethasone, a synthetic glucocorticoid. HMGB1 translocated from the nucleus to the cytoplasm following corticosterone treatment. HMGB1 release was significantly attenuated with glucocorticoid receptor blocking. In addition, inhibition of pannexin-1, and P2X7 receptors led to a significant decrease in corticosterone-induced HMGB1 release. Taken together, corticosterone stimulates astrocytic glucocorticoid receptors and triggers cytoplasmic translocation and extracellular release of nuclear HMGB1 through a mechanism involving pannexin-1 and P2X7 receptors. Thus, under conditions of stress, glucocorticoids induce astrocytic HMGB1 release, leading to a neuroinflammatory state that could mediate neurological disorders such as MDD.
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Affiliation(s)
- Kazue Hisaoka-Nakashima
- Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan; (K.H.-N.); (H.A.); (F.I.); (Y.N.); (Y.N.)
| | - Honami Azuma
- Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan; (K.H.-N.); (H.A.); (F.I.); (Y.N.); (Y.N.)
| | - Fumina Ishikawa
- Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan; (K.H.-N.); (H.A.); (F.I.); (Y.N.); (Y.N.)
| | - Yoki Nakamura
- Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan; (K.H.-N.); (H.A.); (F.I.); (Y.N.); (Y.N.)
| | - Dengli Wang
- Department of Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Shikata, Okayama 700-8558, Japan; (D.W.); (K.L.); (H.W.); (M.N.)
| | - Keyue Liu
- Department of Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Shikata, Okayama 700-8558, Japan; (D.W.); (K.L.); (H.W.); (M.N.)
| | - Hidenori Wake
- Department of Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Shikata, Okayama 700-8558, Japan; (D.W.); (K.L.); (H.W.); (M.N.)
| | - Masahiro Nishibori
- Department of Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Shikata, Okayama 700-8558, Japan; (D.W.); (K.L.); (H.W.); (M.N.)
| | - Yoshihiro Nakata
- Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan; (K.H.-N.); (H.A.); (F.I.); (Y.N.); (Y.N.)
| | - Norimitsu Morioka
- Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan; (K.H.-N.); (H.A.); (F.I.); (Y.N.); (Y.N.)
- Correspondence: ; Tel.: +81-082-257-5310
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Chen H, Guan B, Wang B, Pu H, Bai X, Chen X, Liu J, Li C, Qiu J, Yang D, Liu K, Wang Q, Qi S, Shen J. Glycyrrhizin Prevents Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke with Delayed Thrombolysis Through Targeting Peroxynitrite-Mediated HMGB1 Signaling. Transl Stroke Res 2019; 11:967-982. [PMID: 31872339 DOI: 10.1007/s12975-019-00772-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 11/17/2019] [Accepted: 12/09/2019] [Indexed: 01/22/2023]
Abstract
Peroxynitrite (ONOO-) and high mobility group box 1 protein (HMGB1) are important cytotoxic factors contributing to cerebral ischemia-reperfusion injury. However, the roles of ONOO- in mediating HMGB1 expression and its impacts on hemorrhagic transformation (HT) in ischemic brain injury with delayed t-PA treatment remain unclear. In the present study, we tested the hypothesis that ONOO- could directly mediate the activation and release of HMGB1 in ischemic brains with delayed t-PA treatment. With clinical studies, we found that plasma nitrotyrosine (NT, a surrogate marker of ONOO-) was positively correlated with HMGB1 level in acute ischemic stroke patients. Hemorrhagic transformation and t-PA-treated ischemic stroke patients had increased levels of nitrotyrosine and HMGB1 in plasma. In animal experiments, we found that FeTmPyP, a representative ONOO- decomposition catalyst (PDC), significantly reduced the expression of HMGB1 and its receptor TLR2, and inhibited MMP-9 activation, preserved collagen IV and tight junction claudin-5 in ischemic rat brains with delayed t-PA treatment. ONOO- donor SIN-1 directly induced expression of HMGB1 and its receptor TLR2 in naive rat brains in vivo and induced HMGB1 in brain microvascular endothelial b.End3 cells in vitro. Those results suggest that ONOO- could activate HMGB1/TLR2/MMP-9 signaling. We then addressed whether glycyrrhizin, a natural HMGB1 inhibitor, could inhibit ONOO- production and the antioxidant properties of glycyrrhizin contribute to the inhibition of HMGB1 and the neuroprotective effects on attenuating hemorrhagic transformation in ischemic stroke with delayed t-PA treatment. Glycyrrhizin treatment downregulated the expressions of NADPH oxidase p47 phox and p67 phox and iNOS, inhibited superoxide and ONOO- production, reduced the expression of HMGB1, TLR2, MMP-9, preserved type IV collagen and claudin-5 in ischemic brains. Furthermore, glycyrrhizin significantly decreased the mortality rate, attenuated hemorrhagic transformation, brain swelling, blood-brain barrier damage, neuronal apoptosis, and improved neurological outcomes in the ischemic stroke rat model with delayed t-PA treatment. In conclusion, peroxynitrite-mediated HMGB1/TLR2 signaling contributes to hemorrhagic transformation, and glycyrrhizin could be a potential adjuvant therapy to attenuate hemorrhagic transformation, possibly through inhibiting the ONOO-/HMGB1/TLR2 signaling cascades.
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Affiliation(s)
- Hansen Chen
- School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, SAR, China.,Institute of Research and Innovation (HKU-SIRI), The University of Hong Kong-Shenzhen, Shenzhen, China
| | - Binghe Guan
- School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, SAR, China
| | - Bin Wang
- School of Medical Technology, Xuzhou Medical University, Xuzhou, 221002, China
| | - Haiwei Pu
- School of Medical Technology, Xuzhou Medical University, Xuzhou, 221002, China
| | - Xiaoyu Bai
- Department of Chemistry, Morningside Laboratory for Chemical Biology, The University of Hong Kong, Hong Kong, SAR, China
| | - Xi Chen
- School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, SAR, China.,Department of Core Facility, The People's Hospital of Bao-an, Shenzhen, China
| | - Jihong Liu
- Department of Neurology, Huizhou First Hospital, Huizhou, Guangdong, China
| | - Caiming Li
- Department of Neurology, Huizhou First Hospital, Huizhou, Guangdong, China
| | - Jinhua Qiu
- Department of Neurology, Huizhou First Hospital, Huizhou, Guangdong, China
| | - Dan Yang
- Department of Chemistry, Morningside Laboratory for Chemical Biology, The University of Hong Kong, Hong Kong, SAR, China
| | - Kejian Liu
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of New Mexico, Albuquerque, NM, 87131, USA
| | - Qi Wang
- Institution of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Suhua Qi
- School of Medical Technology, Xuzhou Medical University, Xuzhou, 221002, China.
| | - Jiangang Shen
- School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, SAR, China. .,Institute of Research and Innovation (HKU-SIRI), The University of Hong Kong-Shenzhen, Shenzhen, China. .,Institution of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China.
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Targeting high-mobility group box protein 1 (HMGB1) in pediatric traumatic brain injury: Chronic neuroinflammatory, behavioral, and epileptogenic consequences. Exp Neurol 2019; 320:112979. [DOI: 10.1016/j.expneurol.2019.112979] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 05/29/2019] [Accepted: 06/18/2019] [Indexed: 11/18/2022]
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Le K, Chibaatar Daliv E, Wu S, Qian F, Ali AI, Yu D, Guo Y. SIRT1-regulated HMGB1 release is partially involved in TLR4 signal transduction: A possible anti-neuroinflammatory mechanism of resveratrol in neonatal hypoxic-ischemic brain injury. Int Immunopharmacol 2019; 75:105779. [PMID: 31362164 DOI: 10.1016/j.intimp.2019.105779] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 07/22/2019] [Accepted: 07/23/2019] [Indexed: 12/26/2022]
Abstract
Neonatal hypoxic-ischemic brain injury (HIBI) is a knotty disease that lacks appropriate treatment. Inflammation is an important contributor to brain damage, and microglia are responsible for eliciting early and pronounced inflammatory reactions in the immature brain after hypoxic-ischemic (HI) insult. Acetylated HMGB1 can be released from immune cells into the extracellular space, where it acts as a danger-associated molecular pattern molecule to activate TLR4 signalling-mediated inflammatory responses. Resveratrol has neuroprotective and anti-inflammatory effects against HIBI, but whether these effects involve the regulation of the TLR4 signalling pathway and whether HMGB1 participates in this process is still unclear. We investigated the anti-inflammatory effects of resveratrol in HIBI and the molecular mechanisms potentially involved in the effect. The in vivo and in vitro results indicated that the level of cytoplasmic HMGB1 in microglia increased after insult and that treating experimental animals or mouse BV2 microglial cells with resveratrol attenuated HI insult-induced neuroinflammation, which was characterized by improved behavioural defects, reduced microglial activation and TLR4/MyD88/NF-κB signalling, and attenuated primary neuronal damage; this was accompanied by the inhibition of HMGB1 nucleoplasmic transfer and extracellular release. EX527 pretreatment reversed these effects. In addition, co-immunoprecipitation confirmed that SIRT1 was directly involved in the HMGB1 acetylation process in BV2 cells after oxygen glucose deprivation. These data demonstrate that resveratrol plays a neuroprotective role in neonatal HIBI by activating SIRT1 to inhibit HMGB1/TLR4/MyD88/NF-κB signalling and subsequent neuroinflammatory responses.
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Affiliation(s)
- Kai Le
- Department of Neurology, Affiliated Zhongda Hospital of Southeast University, Nanjing, Jiangsu Province 210009, China; School of Medicine, Southeast University, Nanjing, Jiangsu Province 210009, China
| | - Enkhmurun Chibaatar Daliv
- Department of Neurology, Affiliated Zhongda Hospital of Southeast University, Nanjing, Jiangsu Province 210009, China; School of Medicine, Southeast University, Nanjing, Jiangsu Province 210009, China
| | - Shanshan Wu
- Department of Neurology, Affiliated Zhongda Hospital of Southeast University, Nanjing, Jiangsu Province 210009, China; School of Medicine, Southeast University, Nanjing, Jiangsu Province 210009, China
| | - Fangyuan Qian
- Department of Neurology, Affiliated Zhongda Hospital of Southeast University, Nanjing, Jiangsu Province 210009, China; School of Medicine, Southeast University, Nanjing, Jiangsu Province 210009, China
| | - Abdoulaye Idriss Ali
- Department of Neurology, Affiliated Zhongda Hospital of Southeast University, Nanjing, Jiangsu Province 210009, China; School of Medicine, Southeast University, Nanjing, Jiangsu Province 210009, China
| | - Dafan Yu
- Department of Neurology, Affiliated Zhongda Hospital of Southeast University, Nanjing, Jiangsu Province 210009, China; School of Medicine, Southeast University, Nanjing, Jiangsu Province 210009, China
| | - Yijing Guo
- Department of Neurology, Affiliated Zhongda Hospital of Southeast University, Nanjing, Jiangsu Province 210009, China.
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Kim SW, Lee H, Lee HK, Kim ID, Lee JK. Neutrophil extracellular trap induced by HMGB1 exacerbates damages in the ischemic brain. Acta Neuropathol Commun 2019; 7:94. [PMID: 31177989 PMCID: PMC6556959 DOI: 10.1186/s40478-019-0747-x] [Citation(s) in RCA: 161] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 05/22/2019] [Indexed: 02/08/2023] Open
Abstract
It has been reported that neutrophil extracellular traps (NETs) play important roles in non-infectious diseases. In ischemic stroke, neutrophils infiltrate damaged brain tissue soon after injury and aggravate inflammation. Using a rat permanent MCAO model, we showed citrullinated histone H3+ (CitH3, a marker of NETosis) induction in neutrophils in leptomeninges and in peripheral blood soon after MCAO. Entry of CitH3+ cells occurred through leptomeninges after 6 h of MCAO and these cells were observed in cerebral cortex from 12 h and subsequently in striatum. It is interesting to note that CitH3+ induction began in circulating neutrophils before they migrated to brain parenchyma and they were detected as intact or lysed form. High mobility group box 1 (HMGB1), a danger associated molecular pattern (DAMP) molecule, was accumulated massively in serum after permanent MCAO and plays a critical role in CitH3 inductions in neutrophils in brain parenchyma and in peripheral blood. Both the all-thiol and disulfide types of HMGB1 induced CitH3 via their specific receptors, CXCR4 and TLR4, respectively. Importantly, HMGB1 not only induced NETosis but was included as a part of the extruded NETs, and contribute to NETosis-mediated neuronal death. Therefore, it would appear a vicious cycle exists between neuronal cell death and NETosis and HMGB1 mediates detrimental effects exerted by this cycle. When NETosis was suppressed by a PAD inhibitor in MCAO animals, delayed immune cell infiltrations were markedly suppressed and damages in blood vessels were significantly mitigated. The study shows NETosis with the involvement of HMGB1 as a mediator in a vicious cycle aggravates inflammation and subsequent damage in the ischemic brain.
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Nishibori M, Mori S, Takahashi HK. Anti-HMGB1 monoclonal antibody therapy for a wide range of CNS and PNS diseases. J Pharmacol Sci 2019; 140:94-101. [PMID: 31105025 DOI: 10.1016/j.jphs.2019.04.006] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 03/18/2019] [Accepted: 04/05/2019] [Indexed: 02/08/2023] Open
Abstract
High mobility group box-1 (HMGB1), a representative damage associated-molecular pattern (DAMP), has been reported to be involved in many inflammatory diseases. Several drugs are thought to have potential to control the translocation and secretion of HMGB1, or to neutralize extracellular HMGB1 by binding to it. One of these drugs, anti-HMGB1 monoclonal antibody (mAb), is highly specific for HMGB1 and has been shown to be effective for the treatment of a wide range of CNS diseases when modeled in animals, including stroke, traumatic brain injury, Parkinson's disease, epilepsy and Alzheimer's disease. Thus, anti-HMGB1 mAb not only is useful for target validation but also has extensive potential for the treatment of the above-mentioned diseases. In this review, we summarize existing knowledge on the effects of anti-HMGB1 mAb on CNS and PNS diseases, the common features of translocation and secretion of HMGB1 and the functional roles of HMGB1 in these diseases. The existing literature suggests that anti-HMGB1 mAb therapy would be effective for a wide range of CNS and PNS diseases.
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Affiliation(s)
- Masahiro Nishibori
- Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
| | - Shuji Mori
- Department of Pharmacology, School of Pharmacy, Shujitsu University, Okayama, Japan
| | - Hideo K Takahashi
- Department of Pharmacology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan
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40
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Ye Y, Zeng Z, Jin T, Zhang H, Xiong X, Gu L. The Role of High Mobility Group Box 1 in Ischemic Stroke. Front Cell Neurosci 2019; 13:127. [PMID: 31001089 PMCID: PMC6454008 DOI: 10.3389/fncel.2019.00127] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 03/14/2019] [Indexed: 12/11/2022] Open
Abstract
High-mobility group box 1 protein (HMGB1) is a novel, cytokine-like, and ubiquitous, highly conserved, nuclear protein that can be actively secreted by microglia or passively released by necrotic neurons. Ischemic stroke is a leading cause of death and disability worldwide, and the outcome is dependent on the amount of hypoxia-related neuronal death in the cerebral ischemic region. Acting as an endogenous danger-associated molecular pattern (DAMP) protein, HMGB1 mediates cerebral inflammation and brain injury and participates in the pathogenesis of ischemic stroke. It is thought that HMGB1 signals via its presumed receptors, such as toll-like receptors (TLRs), matrix metalloproteinase (MMP) enzymes, and receptor for advanced glycation end products (RAGEs) during ischemic stroke. In addition, the release of HMGB1 from the brain into the bloodstream influences peripheral immune cells. However, the role of HMGB1 in ischemic stroke may be more complex than this and has not yet been clarified. Here, we summarize and review the research into HMGB1 in ischemic stroke.
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Affiliation(s)
- Yingze Ye
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhi Zeng
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Tong Jin
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hongfei Zhang
- Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Xiaoxing Xiong
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China.,Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lijuan Gu
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
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Lee HK, Park JY, Lee H, Kim ID, Kim SW, Yoon SH, Lee JK. Anti-Inflammatory and Neuroprotective Effects of DIPOPA (N,N-Diisopropyl-2-Oxopropanamide), an Ethyl Pyruvate Bioisoster, in the Postischemic Brain. Neurotherapeutics 2019; 16:523-537. [PMID: 30680637 PMCID: PMC6554410 DOI: 10.1007/s13311-019-00711-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Abstract
Ethyl pyruvate (EP) is a simple aliphatic ester of pyruvic acid and has been shown to have protective properties, which have been attributed to its anti-inflammatory, anti-oxidative, and anti-apoptotic functions. In an effort to develop better derivatives of EP, we previously synthesized DEOPA (N,N-diethyl-2-oxopropanamide, a novel isoster of EP) which has greater neuroprotective effects than EP, probably due to its anti-inflammatory and anti-excitotoxic effects. In the present study, we synthesized 3 DEOPA derivatives, in which its diethylamino group was substituted with diisopropylamino, dipropylamino, or diisobutylamino groups. Among them, DIPOPA (N,N-diisopropyl-2-oxopropanamide) containing diisopropylamino group had a greater neuroprotective effect than DEOPA or EP when administered intravenously to a rat middle cerebral artery occlusion (MCAO) model at 9 h after MCAO. Furthermore, DIPOPA had a wider therapeutic window than DEOPA and a marked reduction of infarct volume was accompanied by greater neurological and behavioral improvements. In particular, DIPOPA exerted robust anti-inflammatory effects, as evidenced by marked suppressions of microglia activation and neutrophil infiltration in the MCAO model, in microglial cells, and in neutrophil-endothelial cocultures at lower concentration, and did so more effectively than DEOPA. In particular, DIPOPA remarkably suppressed neutrophil infiltration into brain parenchyma, and this effect was attributed to the expressional inhibitions of cell adhesion molecules in neutrophils of brain parenchyma and in circulating neutrophils via NF-κB inhibition. Together, these results indicate the robust neuroprotective effects of DIPOPA are attributable to its anti-inflammatory effects and suggest that DIPOPA offers a potential therapeutic means of ameliorating cerebral ischemic injury and other inflammation-related pathologies.
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Affiliation(s)
- Hye-Kyung Lee
- Department of Anatomy, Inha University School of Medicine, Michuhol-gu Inharo 100, Inchon, 22202, Republic of Korea
- Medical Research Center, Inha University School of Medicine, Michuhol-gu Inharo 100, Inchon, 22202, Republic of Korea
| | - Ju-Young Park
- Department of Molecular Science and Technology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hahnbie Lee
- Department of Anatomy, Inha University School of Medicine, Michuhol-gu Inharo 100, Inchon, 22202, Republic of Korea
- Medical Research Center, Inha University School of Medicine, Michuhol-gu Inharo 100, Inchon, 22202, Republic of Korea
| | - Il-Doo Kim
- Department of Anatomy, Inha University School of Medicine, Michuhol-gu Inharo 100, Inchon, 22202, Republic of Korea
- Department of Biomedical Sciences, Inha University School of Medicine, Inchon, South Korea
| | - Seung-Woo Kim
- Medical Research Center, Inha University School of Medicine, Michuhol-gu Inharo 100, Inchon, 22202, Republic of Korea
- Department of Biomedical Sciences, Inha University School of Medicine, Inchon, South Korea
| | - Sung-Hwa Yoon
- Department of Molecular Science and Technology, Ajou University School of Medicine, Suwon, Republic of Korea.
| | - Ja-Kyeong Lee
- Department of Anatomy, Inha University School of Medicine, Michuhol-gu Inharo 100, Inchon, 22202, Republic of Korea.
- Medical Research Center, Inha University School of Medicine, Michuhol-gu Inharo 100, Inchon, 22202, Republic of Korea.
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42
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Chen X, Zhang J, Kim B, Jaitpal S, Meng SS, Adjepong K, Imamura S, Wake H, Nishibori M, Stopa EG, Stonestreet BS. High-mobility group box-1 translocation and release after hypoxic ischemic brain injury in neonatal rats. Exp Neurol 2019; 311:1-14. [PMID: 30217406 PMCID: PMC6261802 DOI: 10.1016/j.expneurol.2018.09.007] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 07/13/2018] [Accepted: 09/10/2018] [Indexed: 01/17/2023]
Abstract
Inflammation contributes to neonatal brain injury. Pro-inflammatory cytokines represent key inflammatory meditators in neonatal hypoxic-ischemic (HI) brain injury. The high mobility group box-1 (HMGB1) protein is a nuclear protein with pro-inflammatory cytokine properties when it is translocated from the nucleus and released extracellularly after stroke in adult rodents. We have previously shown that HMGB1 is translocated from the nucleus to cytosolic compartment after ischemic brain injury in fetal sheep. In the current study, we utilized the Rice-Vannucci model to investigate the time course of HMGB1 translocation and release after HI injury in neonatal rats. HMGB1 was located in cellular nuclei of brains from sham control rats. Nuclear to cytoplasmic translocation of HMGB1 was detected in the ipsilateral-HI hemisphere as early as zero h after HI, and released extracellularly as early as 6 h after HI. Immunohistochemical double staining detected HMGB1 translocation mainly in neurons along with release from apoptotic cells after HI. Serum HMGB1 increased at 3 h and decreased by 24 h after HI. In addition, rat brains exposed to hypoxic injury alone also exhibited time dependent HMGB1 translocation at 3, 12 and 48 h after hypoxia. Consequently, HMGB1 responds similarly after HI injury in the brains of neonatal and adult subjects. We conclude that HMGB1 is sensitive early indicator of neonatal HI and hypoxic brain injury.
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Affiliation(s)
- Xiaodi Chen
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI, USA
| | - Jiyong Zhang
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI, USA
| | - Boram Kim
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI, USA
| | - Siddhant Jaitpal
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI, USA
| | - Steven S Meng
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI, USA
| | - Kwame Adjepong
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI, USA
| | - Sayumi Imamura
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI, USA
| | - Hidenori Wake
- Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Masahiro Nishibori
- Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Edward G Stopa
- Department of Pathology and Neurosurgery, The Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI, USA
| | - Barbara S Stonestreet
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI, USA.
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Webster KM, Sun M, Crack PJ, O'Brien TJ, Shultz SR, Semple BD. Age-dependent release of high-mobility group box protein-1 and cellular neuroinflammation after traumatic brain injury in mice. J Comp Neurol 2018; 527:1102-1117. [DOI: 10.1002/cne.24589] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 10/15/2018] [Accepted: 11/09/2018] [Indexed: 01/07/2023]
Affiliation(s)
- Kyria M. Webster
- Department of Medicine (Royal Melbourne Hospital); The University of Melbourne; Parkville Victoria Australia
| | - Mujun Sun
- Department of Medicine (Royal Melbourne Hospital); The University of Melbourne; Parkville Victoria Australia
| | - Peter J. Crack
- Department of Pharmacology and Therapeutics; The University of Melbourne; Parkville Victoria Australia
| | - Terence J. O'Brien
- Department of Medicine (Royal Melbourne Hospital); The University of Melbourne; Parkville Victoria Australia
- Department of Neuroscience; Monash University; Melbourne Victoria Australia
| | - Sandy R. Shultz
- Department of Medicine (Royal Melbourne Hospital); The University of Melbourne; Parkville Victoria Australia
- Department of Neuroscience; Monash University; Melbourne Victoria Australia
| | - Bridgette D. Semple
- Department of Medicine (Royal Melbourne Hospital); The University of Melbourne; Parkville Victoria Australia
- Department of Neuroscience; Monash University; Melbourne Victoria Australia
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Chen H, Chen X, Luo Y, Shen J. Potential molecular targets of peroxynitrite in mediating blood–brain barrier damage and haemorrhagic transformation in acute ischaemic stroke with delayed tissue plasminogen activator treatment. Free Radic Res 2018; 52:1220-1239. [PMID: 30468092 DOI: 10.1080/10715762.2018.1521519] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Hansen Chen
- School of Chinese Medicine, the University of Hong Kong, PR China
- Shenzhen Institute of Research and Innovation (HKU-SIRI), University of Hong Kong, Hong Kong, PR China
| | - Xi Chen
- Department of Core Facility, the People’s Hospital of Bao-an Shenzhen, Shenzhen, PR China
- The 8th People’s Hospital of Shenzhen, the Affiliated Bao-an Hospital of Southern Medical University, Shenzhen, PR China
| | - Yunhao Luo
- School of Chinese Medicine, the University of Hong Kong, PR China
| | - Jiangang Shen
- School of Chinese Medicine, the University of Hong Kong, PR China
- Shenzhen Institute of Research and Innovation (HKU-SIRI), University of Hong Kong, Hong Kong, PR China
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Nestor J, Arinuma Y, Huerta TS, Kowal C, Nasiri E, Kello N, Fujieda Y, Bialas A, Hammond T, Sriram U, Stevens B, Huerta PT, Volpe BT, Diamond B. Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors. J Exp Med 2018; 215:2554-2566. [PMID: 30185634 PMCID: PMC6170183 DOI: 10.1084/jem.20180776] [Citation(s) in RCA: 106] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 07/06/2018] [Accepted: 08/02/2018] [Indexed: 02/03/2023] Open
Abstract
Cognitive impairment occurs in 40-90% of patients with systemic lupus erythematosus (SLE), which is characterized by autoantibodies to nuclear antigens, especially DNA. We discovered that a subset of anti-DNA antibodies, termed DNRAbs, cross reacts with the N-methyl-d-aspartate receptor (NMDAR) and enhances NMDAR signaling. In patients, DNRAb presence associates with spatial memory impairment. In a mouse model, DNRAb-mediated brain pathology proceeds through an acute phase of excitotoxic neuron loss, followed by persistent alteration in neuronal integrity and spatial memory impairment. The latter pathology becomes evident only after DNRAbs are no longer detectable in the brain. Here we investigate the mechanism of long-term neuronal dysfunction mediated by transient exposure to antibody. We show that activated microglia and C1q are critical mediators of neuronal damage. We further show that centrally acting inhibitors of angiotensin-converting enzyme (ACE) can prevent microglial activation and preserve neuronal function and cognitive performance. Thus, ACE inhibition represents a strong candidate for clinical trials aimed at mitigating cognitive dysfunction.
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Affiliation(s)
- Jacquelyn Nestor
- Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, The Feinstein Institute for Medical Research, Manhasset, NY
- Donald & Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY
| | - Yoshiyuki Arinuma
- Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Kanagawa, Japan
| | - Tomás S Huerta
- Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, The Feinstein Institute for Medical Research, Manhasset, NY
- Donald & Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY
| | - Czeslawa Kowal
- Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, The Feinstein Institute for Medical Research, Manhasset, NY
| | - Elham Nasiri
- Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, The Feinstein Institute for Medical Research, Manhasset, NY
| | - Nina Kello
- Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, The Feinstein Institute for Medical Research, Manhasset, NY
| | - Yuichiro Fujieda
- Department of Rheumatology, Endocrinology and Nephrology Faculty of Medicine and Graduate School of Medicine Hokkaido University, Sapporo, Japan
| | - Alison Bialas
- Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA
| | - Tim Hammond
- Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA
| | - Uma Sriram
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA
| | - Beth Stevens
- Kirby Neurobiology Center Boston Children's Hospital, Boston, MA
| | - Patricio T Huerta
- Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, The Feinstein Institute for Medical Research, Manhasset, NY
- Donald & Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY
| | - Bruce T Volpe
- Center for Biomedical Sciences, The Feinstein Institute for Medical Research, Manhasset, NY
| | - Betty Diamond
- Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, The Feinstein Institute for Medical Research, Manhasset, NY
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Dhivya Bharathi M, Justin-Thenmozhi A, Manivasagam T, Ahmad Rather M, Saravana Babu C, Mohamed Essa M, Guillemin GJ. Amelioration of Aluminum Maltolate-Induced Inflammation and Endoplasmic Reticulum Stress-Mediated Apoptosis by Tannoid Principles of Emblica officinalis in Neuronal Cellular Model. Neurotox Res 2018; 35:318-330. [PMID: 30242626 DOI: 10.1007/s12640-018-9956-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 08/24/2018] [Accepted: 09/07/2018] [Indexed: 01/04/2023]
Abstract
The neuroprotective role of tannoid principles of Emblica officinalis (EoT), an Indian and Chinese traditional medicinal plant against memory loss in aluminum chloride-induced in vivo model of Alzheimer's disease through attenuating AChE activity, oxidative stress, amyloid and tau toxicity, and apoptosis, was recently reported in our lab. However, to further elucidate the mechanism of neuroprotective effect of EoT, the current study was designed to evaluate endoplasmic reticulum stress-suppressing and anti-inflammatory role of EoT in PC 12 and SH-SY 5Y cells. These cells were divided into four groups: control (aluminum maltolate (Al(mal)3), EoT + Al(mal)3, and EoT alone based on 3-(4, 5-dimethyl 2-yl)-2, and 5-diphenyltetrazolium bromide (MTT) assay. EoT significantly reduced Al(mal)3-induced cell death and attenuated ROS, mitochondrial membrane dysfunction, and apoptosis (protein expressions of Bax; Bcl-2; cleaved caspases 3, 6, 9, 12; and cytochrome c) by regulating endoplasmic reticulum stress (PKR-like ER kinase (PERK), α subunit of eukaryotic initiation factor 2 (EIF2-α), C/EBP-homologous protein (CHOP), and high-mobility group box 1 protein (HMGB1)). Moreover, inflammatory response (NF-κB, IL-1β, IL-6, and TNF-α) and Aβ toxicity (Aβ1-42) triggered by Al(mal)3 was significantly normalized by EoT. Our results suggested that EoT could be a possible/promising and novel therapeutic lead against Al-induced neurotoxicity. However, further extensive research is needed to prove its efficacy in clinical studies.
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Affiliation(s)
- Mathiyazahan Dhivya Bharathi
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalai Nagar, Tamil Nadu, 608002, India
| | - Arokiasamy Justin-Thenmozhi
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalai Nagar, Tamil Nadu, 608002, India.
| | - Thamilarasan Manivasagam
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalai Nagar, Tamil Nadu, 608002, India
| | - Mashoque Ahmad Rather
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalai Nagar, Tamil Nadu, 608002, India
| | - Chidambaram Saravana Babu
- Department of Pharmacology, JSS College of Pharmacy, JSS University, SS Nagar, Mysore, Karnataka, 570015, India
| | - Musthafa Mohamed Essa
- Department of Food Science and Nutrition, CAMS, Sultan Qaboos University, Muscat, Oman.,Ageing and Dementia Research Group, Sultan Qaboos University, Muscat, Oman.,Food and Brain Research Foundation, Chennai, Tamil Nadu, 600094, India
| | - Gilles J Guillemin
- Neuroinflammation group, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
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Kim SY, Son M, Lee SE, Park IH, Kwak MS, Han M, Lee HS, Kim ES, Kim JY, Lee JE, Choi JE, Diamond B, Shin JS. High-Mobility Group Box 1-Induced Complement Activation Causes Sterile Inflammation. Front Immunol 2018; 9:705. [PMID: 29696019 PMCID: PMC5904255 DOI: 10.3389/fimmu.2018.00705] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Accepted: 03/22/2018] [Indexed: 12/24/2022] Open
Abstract
High-mobility group box 1 (HMGB1), a well-known danger-associated molecular pattern molecule, acts as a pro-inflammatory molecule when secreted by activated immune cells or released after necrotic cell damage. HMGB1 binds to immunogenic bacterial components and augments septic inflammation. In this study, we show how HMGB1 mediates complement activation, promoting sterile inflammation. We show that HMGB1 activates the classical pathway of complement system in an antibody-independent manner after binding to C1q. The C3a complement activation product in human plasma and C5b-9 membrane attack complexes on cell membrane surface are detected after the addition of HMGB1. In an acetaminophen (APAP)-induced hepatotoxicity model, APAP injection reduced HMGB1 levels and elevated C3 levels in C1q-deficient mouse serum samples, compared to that in wild-type (WT) mice. APAP-induced C3 consumption was inhibited by sRAGE treatment in WT mice. Moreover, in a mouse model of brain ischemia–reperfusion injury based on middle cerebral arterial occlusion, C5b-9 complexes were deposited on vessels where HMGB1 was accumulated, an effect that was suppressed upon HMGB1 neutralization. We propose that the HMGB1 released after cell necrosis and in ischemic condition can trigger the classical pathway of complement activation to exacerbate sterile inflammation.
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Affiliation(s)
- Sook Young Kim
- Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea
| | - Myoungsun Son
- The Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, The Feinstein Institute for Medical Research, Manhasset, NY, United States
| | - Sang Eun Lee
- Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea
| | - In Ho Park
- Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea.,Severance Biomedical Science Institute and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea
| | - Man Sup Kwak
- Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea
| | - Myeonggil Han
- Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea
| | - Hyun Sook Lee
- Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea
| | - Eun Sook Kim
- Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea
| | - Jae-Young Kim
- Department of Anatomy, Yonsei University College of Medicine, Seoul, South Korea
| | - Jong Eun Lee
- Department of Anatomy, Yonsei University College of Medicine, Seoul, South Korea
| | - Ji Eun Choi
- Department of Pediatrics, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, South Korea
| | - Betty Diamond
- The Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, The Feinstein Institute for Medical Research, Manhasset, NY, United States
| | - Jeon-Soo Shin
- Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea.,Severance Biomedical Science Institute and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea.,Center for Nanomedicine, Institute for Basic Science (IBS), Seoul, South Korea
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48
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Aucott H, Lundberg J, Salo H, Klevenvall L, Damberg P, Ottosson L, Andersson U, Holmin S, Erlandsson Harris H. Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms. J Innate Immun 2018; 10:215-227. [PMID: 29478057 DOI: 10.1159/000487056] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 01/20/2018] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Neuroinflammation triggered by infection or trauma is the cause of central nervous system dysfunction. High-mobility group box 1 protein (HMGB1), released from stressed and dying brain cells, is a potent neuroinflammatory mediator. The proinflammatory functions of HMGB1 are tightly regulated by post-translational redox modifications, and we here investigated detailed neuroinflammatory responses induced by the individual redox isoforms. METHODS Male Dark Agouti rats received a stereotactic injection of saline, lipopolysaccharide, disulfide HMGB1, or fully reduced HMGB1, and were accessed for blood-brain barrier modifications using magnetic resonance imaging (MRI) and inflammatory responses by immunohistochemistry. RESULTS AND CONCLUSIONS Significant blood-brain barrier disruption appeared 24 h after injection of lipopolysaccharide, disulfide HMGB1, or fully reduced HMGB1 compared to controls, as assessed in post-gadolinium T1-weighted MRI images and confirmed by increased uptake of FITC-conjugated dextran. Immunohistochemistry revealed that both HMGB1 isoforms also induced a local production of IL-1β. Additionally, disulfide HMGB1 increased major histocompatibility complex class II expression and apoptosis. Together, the results demonstrate that extracellular, cerebral HMGB1 causes significant blood-brain barrier disruption in a redox-independent manner and activates several components of neuroinflammation. Blocking HMGB1 might potentially improve clinical outcome in conditions such as stroke and traumatic brain injury.
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Affiliation(s)
- Hannah Aucott
- Department of Medicine Solna, Rheumatology Unit, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Johan Lundberg
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.,Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
| | - Henna Salo
- Department of Medicine Solna, Rheumatology Unit, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Lena Klevenvall
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Peter Damberg
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Lars Ottosson
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Ulf Andersson
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Staffan Holmin
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.,Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
| | - Helena Erlandsson Harris
- Department of Medicine Solna, Rheumatology Unit, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
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Pivotal neuroinflammatory and therapeutic role of high mobility group box 1 in ischemic stroke. Biosci Rep 2017; 37:BSR20171104. [PMID: 29054968 PMCID: PMC5715129 DOI: 10.1042/bsr20171104] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 09/29/2017] [Accepted: 10/18/2017] [Indexed: 12/27/2022] Open
Abstract
Stroke is a major cause of mortality and disability worldwide. Stroke is a frequent and severe neurovascular disorder. The main cause of stroke is atherosclerosis, and the most common risk factor for atherosclerosis is hypertension. Therefore, prevention and treatment of stroke are crucial issues in humans. High mobility group box 1 (HMGB1) is non-histone nuclear protein that is currently one of the crucial proinflammatory alarmins in ischemic stroke (IS). It is instantly released from necrotic cells in the ischemic core and activates an early inflammatory response. HMGB1 may signal via its putative receptors, such as receptor for advanced glycation end products (RAGE), toll-like receptors (TLRs) as well as matrix metalloproteinase (MMP) enzymes during IS. These receptors are expressed in brain cells. Additionally, brain-released HMGB1 can be redox modified in the circulation and activate peripheral immune cells. The role of HMGB1 may be more complex. HMGB1 possesses beneficial actions, such as endothelial activation, enhancement of neurite outgrowth, and neuronal survival. HMGB1 may also provide a novel link for brain-immune communication leading to post-stroke immunomodulation. Therefore, HMGB1 is new promising therapeutic intervention aimed at promoting neurovascular repair and remodeling after stroke. In this review, we look at the mechanisms of secretion of HMGB1, the role of receptors, MMP enzymes, hypoglycemia, atherosclerosis, edema, angiogenesis as well as neuroimmunological reactions and post-ischemic brain recovery in IS. We also outline therapeutic roles of HMGB1 in IS.
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50
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Neuroprotective and Anti-inflammatory Effects of a Dodecamer Peptide Harboring Ninjurin 1 Cell Adhesion Motif in the Postischemic Brain. Mol Neurobiol 2017; 55:6094-6111. [DOI: 10.1007/s12035-017-0810-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2017] [Accepted: 10/19/2017] [Indexed: 01/09/2023]
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