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Wu J, Yan F, Li Y, Liang M, Guo Y, Yang M. Hypoxia inducible factor-1alpha expression correlates with inflammatory injury of blood-brain barrier which influences perihaematomal edema after intracerebral hemorrhage. J Stroke Cerebrovasc Dis 2025; 34:108269. [PMID: 40044094 DOI: 10.1016/j.jstrokecerebrovasdis.2025.108269] [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: 11/05/2024] [Revised: 02/21/2025] [Accepted: 02/24/2025] [Indexed: 03/10/2025] Open
Abstract
BACKROUND In patients with intracerebral hemorrhage (ICH), perihematomal edema (PHE) significantly worsens the prognosis. This condition leads to the formation of a hypoxic microenvironment surrounding the blood-brain barrier (BBB), which in turn activates hypoxia-inducible factor-1 alpha (HIF-1α), a highly sensitive hypoxia-related transcription factor. Additionally, tumor necrosis factor-alpha (TNF-α) emerges as a promising biomarker for tracking inflammation in the vicinity of the BBB. The integrity of the BBB is maintained by proteins such as zonula occludens-1 (ZO-1), which is crucial for the tight junctions that regulate the barrier's permeability. Understanding these mechanisms is vital for developing targeted therapies to mitigate the effects of ICH. OBJECT Through the collection and analysis of peripheral blood and tissue samples from ICH patients and animal models at predefined time points, we established the correlation between HIF-1α expression, inflammatory damage to the BBB, and the development of PHE. METHODS Ethical approval was secured from relevant Chinese authorities and the Ethics Committee of Qinghai Provincial People's Hospital. The clinical study included 32 ICH patients, with computerized tomographic scans and blood samples taken at 1, 3, 7, and 14 days post-ICH. HIF-1α and ZO-1 expression, as well as TNF-α levels, were measured using enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, and western blot. In the animal study, 18 adult Sprague Dawley rats were divided into sham, ICH, and HIF-1α Inhibited groups. Lificiguat YC-1 was used to inhibit HIF-1α expression, and samples were collected at the critical change point identified clinically for similar measurements. RESULTS At 3 days after onset, the highest level of HIF-1α and TNF-α, the lowest level of ZO-1 and the most obvious development in PHE appeared in ICH patients (F ≥ 10.278, P ≤ 0.004). At that day, HIF-1α expression positively correlated with TNF-α levels (r = 0.809, P<0.001); TNF-α negatively correlated with ZO-1 expression (r=-0.840, P<0.001) which negatively correlated with PHE development (r=-0.601, p<0.001). Comparing to sham group and sole ICH group, after HIF-1α expression was inhibited, all the biological indicators level of ICH rats were the lowest (F ≥ 14.953, p ≤ 0.005). Their correlation were the same as that in ICH patients. CONCLUSION At 3 days after onset of ICH, HIF-1α expression correlated with inflammatory injury of BBB, which influenced PHE.
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Affiliation(s)
- Jian Wu
- Graduate School, Qinghai University, Xining, China
| | - Fuli Yan
- Graduate School, Qinghai University, Xining, China
| | - Yiming Li
- Graduate School, Qinghai University, Xining, China
| | | | - Yu Guo
- Department of Neurosurgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China.
| | - Mingfei Yang
- Department of Neurosurgery, Qinghai Provincial People's Hospital, Xining, Qinghai, China.
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Han D, Zhang J, Li D, Wang C. Celery seed derived reconstituted lipid nanoparticles as an innate neuron-targeted neuroprotective nanomedicine for ischemic stroke treatment. J Nanobiotechnology 2025; 23:298. [PMID: 40247343 PMCID: PMC12004799 DOI: 10.1186/s12951-025-03372-4] [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: 07/29/2024] [Accepted: 04/04/2025] [Indexed: 04/19/2025] Open
Abstract
BACKGROUND Ischemic stroke (IS) is the leading cause of worldwide death while the discovery and effective delivery of neuroprotective agents for satisfied IS treatment is still challenging. RESULTS In this study, we discover that celery seed (CS) derived reconstituted lipid nanoparticles (CS-rLNPs) can effectively penetrate across blood-brain barrier (BBB) with increased distribution to the brain. Especially, CS-rLNPs show innate neuron-targeting ability to primarily bind to neuron in the cerebral ischemic area, which is not reported by any parallel studies. Moreover, CS-rLNPs are found to exert therapeutic effects on IS, which effectively restore the function of model mice. Further studies reveal that the therapeutic effects are realized through TLR4/MyD88/NF-κB p65 pathway regulated anti-inflammation and anti-apoptosis mechanisms. CONCLUSIONS Therefore, CS-rLNPs can serve as a neuron-targeted neuroprotective nanomedicine for IS treatment.
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Affiliation(s)
- Dan Han
- Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
- Nanjing Medical Center for Clinical Pharmacy, Nanjing, Jiangsu, China.
| | - Jiaxing Zhang
- School of Pharmacy, Changzhou University, Changzhou, Jiangsu, China
| | - Dingran Li
- Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Cheng Wang
- School of Pharmacy, Changzhou University, Changzhou, Jiangsu, China.
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Kamat PK, Khan MB, Siddiqui S, Williams D, da Silva Lopes Salles E, Naeini SE, Arbab AS, Rudic DR, Baban B, Dhandapani KM, Hess DC. Time Dimension Influences Severity of Stroke and Heightened Immune Response in Mice. Transl Stroke Res 2025; 16:421-437. [PMID: 38091188 DOI: 10.1007/s12975-023-01226-5] [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: 09/14/2023] [Revised: 10/18/2023] [Accepted: 12/05/2023] [Indexed: 04/08/2025]
Abstract
Ischemic stroke is caused by obstructed cerebral blood flow, which results in neurological injury and poor outcomes. Pro-inflammatory signaling from both residential and infiltrating immune cells potentiates cerebral injury and worsens patient outcomes after stroke. While the occurrence of a stroke exhibits a time-of-day-dependent pattern, it remains unclear whether disrupted circadian rhythms modulate post-stroke immunity. In this study, we hypothesized that stroke timing differentially affects immune activation in mice. Following middle cerebral artery occlusion (MCAO), circadian genes BMAL1, CLOCK, Cry1, and Cry2 elevated at ZT06, with a significant difference between ZT06 and ZT18. Conversely, expression of the negative limb circadian clock gene, Per1, decreased at ZT06 and ZT18 in stroke mice compared to sham. Paralleling these circadian gene expression changes, we observed a significant increase in TNF-α and a decrease in IL-10 expression at 48 h post-MCAO, when the procedure was performed at ZT06 (MCAO-ZT6), which corresponds to a deep sleep period, as compared to when the stroke was induced at ZT12 (MCAO-ZT12), ZT18 (MCAO-ZT18), or ZT0 (MCAO-ZT12). Similarly, increased pro-inflammatory, decreased anti-inflammatory monocytes, and increased NLRP3 were observed in blood, while changes in the expression of CD11b and Iba1 were noted within brain tissue at 48 h of MCAO-ZT06, as compared to MCAO-ZT18. Consistent with the increased immune response, infarct volume and sensorimotor deficits were greater in MCAO-ZT06 mice compared to MCAO-ZT18 mice at 48 h. Finally, we found reduced weight and length of the spleen while splenocytes showed significant time-dependent changes in Tregs, Bregs, and monocytes in MCAO-ZT06 mice. Taken together, this study demonstrates that circulating and splenic immune responses following ischemic stroke exhibit a circadian expression pattern which may contribute to time-of-day-dependent stroke outcomes.
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Affiliation(s)
- Pradip K Kamat
- Departments of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
| | | | - Shahneela Siddiqui
- Departments of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Dylan Williams
- Departments of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Evila da Silva Lopes Salles
- Departments of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, USA
| | - Sahar Emami Naeini
- Departments of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, USA
| | - Ali S Arbab
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, USA
| | - Daniel R Rudic
- Department of Pharmacology, Medical College of Georgia, Augusta University, Augusta, USA
| | - Babak Baban
- Departments of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, USA
| | - Krishnan M Dhandapani
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, USA
| | - David C Hess
- Departments of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
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McDonough A, Weinstein JR. Glial 'omics in ischemia: Acute stroke and chronic cerebral small vessel disease. Glia 2025; 73:495-518. [PMID: 39463002 PMCID: PMC11785505 DOI: 10.1002/glia.24634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 09/17/2024] [Accepted: 10/10/2024] [Indexed: 10/29/2024]
Abstract
Vascular injury and pathologies underlie common diseases including ischemic stroke and cerebral small vessel disease (CSVD). Prior work has identified a key role for glial cells, including microglia, in the multifaceted and temporally evolving neuroimmune response to both stroke and CSVD. Transcriptional profiling has led to important advances including identification of distinct gene expression signatures in ischemia-exposed, flow cytometrically sorted microglia and more recently single cell RNA sequencing-identified microglial subpopulations or clusters. There is a reassuring degree of overlap in the results from these two distinct methodologies with both identifying a proliferative and a separate type I interferon responsive microglial element. Similar patterns were later seen using multimodal and spatial transcriptomal profiling in ischemia-exposed microglia and astrocytes. Methodological advances including enrichment of specific neuroanatomic/functional regions (such as the neurovascular unit) prior to single cell RNA sequencing has led to identification of novel cellular subtypes and generation of new credible hypotheses as to cellular function based on the enhanced cell sub-type specific gene expression patterns. A ribosomal tagging strategy focusing on the cellular translatome analyses carried out in the acute phases post stroke has revealed distinct inflammation-regulating roles for microglia and astrocytes in this setting. Early spatial transcriptomics experiments using cerebral ischemia models have identified regionally distinct microglial cell clusters in ischemic core versus penumbra. There is great potential for combination of these methods for multi-omics approaches to further elucidate glial responses in the context of both acute ischemic stroke and chronic CSVD.
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Affiliation(s)
- Ashley McDonough
- Department of Neurology, School of Medicine, University of Washington, Seattle, Washington 98195-6465
| | - Jonathan R. Weinstein
- Department of Neurology, School of Medicine, University of Washington, Seattle, Washington 98195-6465
- Department of Neurological Surgery, School of Medicine, University of Washington, Seattle, Washington 98195-6465
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5
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Kim GS, Harmon E, Gutierrez MC, Kim S, Vance L, Burrous H, Stephenson JM, Chauhan A, Banerjee A, Wise Z, Doan A, Ahn J, Wu T, Bautista-Garrido J, Lee J, Tan C, Jung JE, McCullough LD, Wythe JD, Marrelli SP. Single-cell analysis identifies Ifi27l2a as a gene regulator of microglial inflammation in the context of aging and stroke in mice. Nat Commun 2025; 16:1639. [PMID: 39953063 PMCID: PMC11828888 DOI: 10.1038/s41467-025-56847-1] [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: 02/06/2023] [Accepted: 02/03/2025] [Indexed: 02/17/2025] Open
Abstract
Inflammation is a significant driver of ischemic stroke pathology in the brain. To identify potential regulators of inflammation, we performed single-cell RNA sequencing (scRNA-seq) of young and aged mouse brains following stroke and found that interferon alpha-inducible protein 27 like 2 A (Ifi27l2a) was significantly up-regulated, particularly in microglia of aged brain. Ifi27l2a is induced by interferons for viral host defense and has been linked with pro-inflammatory cellular mechanisms. However, its potential role in neurodegeneration is unknown. Using a combination of cell culture, experimental stroke models in mice, and human autopsy brain samples, we demonstrated that induction of Ifi27l2a occurs in microglia in response to aging, ischemic stroke, and pro-inflammatory molecules. We further showed that induction of Ifi27l2a in microglia was sufficient to stimulate mitochondrial ROS production and promote a pro-inflammatory phenotype. Lastly, using an ischemic stroke model, we demonstrated that hemizygous deletion of Ifi27l2a (Ifi27l2a+/- mice) reduced gliosis (microgliosis and astrogliosis), acute and chronic brain injury, and motor function deficits. Together, these findings identify Ifi27l2a as a critical neuroinflammatory mediator in ischemic stroke and provide support for the therapeutic strategy of disrupting Ifi27l2a to attenuate inflammation in the post-stroke brain.
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Affiliation(s)
- Gab Seok Kim
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
- BRAINS Research Laboratories at UTHealth, Houston, TX, USA.
| | - Elisabeth Harmon
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- BRAINS Research Laboratories at UTHealth, Houston, TX, USA
| | - Manuel C Gutierrez
- Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA
| | - Sodam Kim
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- BRAINS Research Laboratories at UTHealth, Houston, TX, USA
| | - Lauren Vance
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- BRAINS Research Laboratories at UTHealth, Houston, TX, USA
| | - Haven Burrous
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- BRAINS Research Laboratories at UTHealth, Houston, TX, USA
| | - Jessica M Stephenson
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Anjali Chauhan
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- BRAINS Research Laboratories at UTHealth, Houston, TX, USA
| | - Anik Banerjee
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- BRAINS Research Laboratories at UTHealth, Houston, TX, USA
| | - Zachary Wise
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Andrea Doan
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- BRAINS Research Laboratories at UTHealth, Houston, TX, USA
| | - John Ahn
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Ting Wu
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- BRAINS Research Laboratories at UTHealth, Houston, TX, USA
| | - Jesus Bautista-Garrido
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Juneyoung Lee
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- BRAINS Research Laboratories at UTHealth, Houston, TX, USA
| | - Chunfeng Tan
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- BRAINS Research Laboratories at UTHealth, Houston, TX, USA
| | - Joo Eun Jung
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Louise D McCullough
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- BRAINS Research Laboratories at UTHealth, Houston, TX, USA
| | - Joshua D Wythe
- Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, USA
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA
- Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, USA
- Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA, USA
- Brain, Immunology, and Glia (BIG) Center, University of Virginia School of Medicine, Charlottesville, VA, USA
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Sean P Marrelli
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
- BRAINS Research Laboratories at UTHealth, Houston, TX, USA.
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Zhai ZH, Huang ZY, Huang KX, Zhong YQ, Tao EX, Yang YF. The Role of Casr Inhibition-Mediated M2 Microglial Transformation in Ischemic Preconditioning Against Stroke. Curr Med Sci 2025; 45:82-92. [PMID: 39982646 DOI: 10.1007/s11596-025-00003-9] [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: 05/22/2024] [Revised: 10/12/2024] [Accepted: 11/28/2024] [Indexed: 02/22/2025]
Abstract
OBJECTIVE Stroke is a main cause of disability and mortality worldwide. It has been reported that ischemic preconditioning (IP) has neuroprotective effects against stroke. This study aimed to verify the mechanism by which calcium-sensing receptor (Casr) inhibition-mediated M2 microglial transformation in the IP protects against stroke, which will provide a potential therapeutic target for stroke. METHODS Middle cerebral artery occlusion (MCAO) rats and oxygen-glucose deprivation (OGD) neurons were used in this study. IP was induced via the transient MCAO and OGD methods. RNA sequencing (RNA-Seq) was used to explore the underlying key molecules. Western blotting and immunohistochemistry were performed to detect the expression of Casr and the M1 and M2 microglial markers. CCK8 was used to detect cell viability. The calcium concentration was detected via the use of Fluo-4 AM, a fluorescence probe. The Casr inhibitor NPS2143 and the Casr activator R568 were used to explore the role of Casr in M2 microglial transformation and neuroprotection. RESULTS We first revealed that IP induced M2 microglial transformation in ischemic injury. In addition, MCAO injury increased Casr expression and the calcium concentration, which was inhibited by IP. Furthermore, Casr activation inhibited the M2 microglial transformation induced by IP. Finally, we found that Casr inhibition improved the survival rate, alleviated neurological deficits, and reduced the infarct volume induced by MCAO. CONCLUSIONS We confirmed that Casr-related neuroprotection induced by IP is associated with the transformation of M2 microglia. These findings can be used to understand the protective mechanisms of IP against ischemic stroke.
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Affiliation(s)
- Zhi-Hao Zhai
- Department of Neurosurgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518000, China
- Department of Physiology, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518000, China
- Neurobiology Research Center, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518000, China
| | - Zuo-Yu Huang
- Department of Neurosurgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518000, China
- Neurobiology Research Center, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518000, China
| | - Kai-Xun Huang
- Department of Neurology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518000, China
| | - Yuan-Qiang Zhong
- Department of Neurosurgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518000, China
| | - En-Xiang Tao
- Department of Neurology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518000, China
| | - Yun-Feng Yang
- Department of Neurosurgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518000, China.
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7
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Bitar L, Puig B, Oertner TG, Dénes Á, Magnus T. Changes in Neuroimmunological Synapses During Cerebral Ischemia. Transl Stroke Res 2024:10.1007/s12975-024-01286-1. [PMID: 39103660 DOI: 10.1007/s12975-024-01286-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/24/2024] [Accepted: 07/25/2024] [Indexed: 08/07/2024]
Abstract
The direct interplay between the immune and nervous systems is now well established. Within the brain, these interactions take place between neurons and resident glial cells, i.e., microglia and astrocytes, or infiltrating immune cells, influenced by systemic factors. A special form of physical cell-cell interactions is the so-called "neuroimmunological (NI) synapse." There is compelling evidence that the same signaling pathways that regulate inflammatory responses to injury or ischemia also play potent roles in brain development, plasticity, and function. Proper synaptic wiring is as important during development as it is during disease states, as it is necessary for activity-dependent refinement of neuronal circuits. Since the process of forming synaptic connections in the brain is highly dynamic, with constant changes in strength and connectivity, the immune component is perfectly suited for the regulatory task as it is in constant turnover. Many cellular and molecular players in this interaction remain to be uncovered, especially in pathological states. In this review, we discuss and propose possible communication hubs between components of the adaptive and innate immune systems and the synaptic element in ischemic stroke pathology.
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Affiliation(s)
- Lynn Bitar
- Neurology Department, Experimental Research in Stroke and Inflammation (ERSI) Group, University Medical Center Hamburg-Eppendorf (UKE), Martinistraße, 52, Hamburg, 20246, Germany
| | - Berta Puig
- Neurology Department, Experimental Research in Stroke and Inflammation (ERSI) Group, University Medical Center Hamburg-Eppendorf (UKE), Martinistraße, 52, Hamburg, 20246, Germany
| | - Thomas G Oertner
- Institute for Synaptic Physiology, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ádám Dénes
- "Momentum" Laboratory of Neuroimmunology, Institute of Experimental Medicine, Budapest, Hungary
| | - Tim Magnus
- Neurology Department, Experimental Research in Stroke and Inflammation (ERSI) Group, University Medical Center Hamburg-Eppendorf (UKE), Martinistraße, 52, Hamburg, 20246, Germany.
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8
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Ngwa C, Al Mamun A, Qi S, Sharmeen R, Conesa MPB, Ganesh BP, Manwani B, Liu F. Central IRF4/5 Signaling Are Critical for Microglial Activation and Impact on Stroke Outcomes. Transl Stroke Res 2024; 15:831-843. [PMID: 37432594 PMCID: PMC10782817 DOI: 10.1007/s12975-023-01172-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/23/2023] [Accepted: 06/29/2023] [Indexed: 07/12/2023]
Abstract
Microglia and monocytes play a critical role in immune responses to cerebral ischemia. Previous studies have demonstrated that interferon regulatory factor 4 (IRF4) and IRF5 direct microglial polarization after stroke and impact outcomes. However, IRF4/5 are expressed by both microglia and monocytes, and it is not clear if it is the microglial (central) or monocytic (peripheral) IRF4-IRF5 regulatory axis that functions in stroke. In this work, young (8-12 weeks) male pep boy (PB), IRF4 or IRF5 flox, and IRF4 or IRF5 conditional knockout (CKO) mice were used to generate 8 types of bone marrow chimeras, to differentiate the role of central (PB-to-IRF CKO) vs. peripheral (IRF CKO-to-PB) phagocytic IRF4-IRF5 axis in stroke. Chimeras generated from PB and flox mice were used as controls. All chimeras were subjected to 60-min middle cerebral artery occlusion (MCAO) model. Three days after the stroke, outcomes and inflammatory responses were analyzed. We found that PB-to-IRF4 CKO chimeras had more robust microglial pro-inflammatory responses than IRF4 CKO-to-PB chimeras, while ameliorated microglial response was seen in PB-to-IRF5 CKO vs. IRF5 CKO-to-PB chimeras. PB-to-IRF4 or IRF5 CKO chimeras had worse or better stroke outcomes respectively than their controls, whereas IRF4 or 5 CKO-to-PB chimeras had similar outcomes compared to controls. We conclude that the central IRF4/5 signaling is responsible for microglial activation and mediates stroke outcomes.
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Affiliation(s)
- Conelius Ngwa
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Abdullah Al Mamun
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Shaohua Qi
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Romana Sharmeen
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Maria P Blasco Conesa
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Bhanu P Ganesh
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Bharti Manwani
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Fudong Liu
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
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Yu L, Huang L, Zhao Y, Liu S, Zhou R, Yue Y, Sun H, Su X, Liu Q, Li S, Ying J, Zhao F, Qu Y. Atorvastatin Promotes Pro/anti-inflammatory Phenotypic Transformation of Microglia via Wnt/β-catenin Pathway in Hypoxic-Ischemic Neonatal Rats. Mol Neurobiol 2024; 61:3559-3577. [PMID: 37996729 PMCID: PMC11087325 DOI: 10.1007/s12035-023-03777-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: 02/01/2023] [Accepted: 11/06/2023] [Indexed: 11/25/2023]
Abstract
Inflammatory reaction plays a key role in the pathogenesis of hypoxic-ischemic encephalopathy (HIE) in neonates. Microglia are resident innate immune cells in the central nervous system and are profoundly involved in neuroinflammation. Studies have revealed that atorvastatin exerts a neuroprotective effect by regulating neuroinflammation in adult animal models of brain stroke and traumatic brain injury, but its role regarding damage to the developing brain remains unclear. This study aimed to clarify the effect and mechanism of atorvastatin on the regulation of microglia function in neonatal hypoxic-ischemic brain damage (HIBD). The oxygen glucose deprivation (OGD) of microglia and neonatal rat HIBD model was established. Atorvastatin, recombinant sclerostin protein (SOST), and XAV939 (degradation of β-catenin) were administered to OGD microglia and HIBD rats. The pathological changes of brain tissue, cerebral infarction volume, learning and memory ability of rats, pro-inflammatory (CD16+/Iba1+) and anti-inflammatory (CD206+/Iba1+) microglia markers, inflammation-related indicators (Inos, Tnfα, Il6, Arg1, Tgfb, and Mrc1), and Wnt/β-catenin signaling molecules were examined. Atorvastatin reduced OGD-induced pro-inflammatory microglia and pro-inflammatory factors, while increasing anti-inflammatory microglia and anti-inflammatory factors. In vivo, atorvastatin attenuated hypoxia-ischemia (HI)-induced neuroinflammation and brain damage. Mechanistically, atorvastatin decreased SOST expression and activated the Wnt/β-catenin signaling pathway, and the administration of recombinant SOST protein or XAV939 inhibited Wnt/β-catenin signaling and attenuated the anti-inflammatory effect of atorvastatin. Atorvastatin promotes the pro/anti-inflammatory phenotypic transformation of microglia via the Wnt/β-catenin pathway in HI neonatal rats. Atorvastatin may be developed as a potent agent for the treatment of HIE in neonates.
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Affiliation(s)
- Luting Yu
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Lingyi Huang
- Department of Orthodontics, State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Yuanyuan Zhao
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Shixi Liu
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Ruixi Zhou
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yan Yue
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Hao Sun
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xiaojuan Su
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Qian Liu
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Shiping Li
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Junjie Ying
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Fengyan Zhao
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yi Qu
- Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
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10
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Kim DW, Lee TK, Ahn JH, Yang SR, Shin MC, Cho JH, Won MH, Kang IJ, Park JH. Porphyran Attenuates Neuronal Loss in the Hippocampal CA1 Subregion Induced by Ischemia and Reperfusion in Gerbils by Inhibiting NLRP3 Inflammasome-Mediated Neuroinflammation. Mar Drugs 2024; 22:170. [PMID: 38667787 PMCID: PMC11050983 DOI: 10.3390/md22040170] [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: 03/19/2024] [Revised: 04/08/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
Porphyran, a sulfated polysaccharide found in various species of marine red algae, has been demonstrated to exhibit diverse bioactivities, including anti-inflammatory effects. However, the protective effects of porphyran against cerebral ischemia and reperfusion (IR) injury have not been investigated. The aim of this study was to examine the neuroprotective effects of porphyran against brain IR injury and its underlying mechanisms using a gerbil model of transient forebrain ischemia (IR in the forebrain), which results in pyramidal cell (principal neuron) loss in the cornu ammonis 1 (CA1) subregion of the hippocampus on day 4 after IR. Porphyran (25 and 50 mg/kg) was orally administered daily for one week prior to IR. Pretreatment with 50 mg/kg of porphyran, but not 25 mg/kg, significantly attenuated locomotor hyperactivity and protected pyramidal cells located in the CA1 area from IR injury. The pretreatment with 50 mg/kg of porphyran significantly suppressed the IR-induced activation and proliferation of microglia in the CA1 subregion. Additionally, the pretreatment significantly inhibited the overexpressions of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing protein-3 (NLRP3) inflammasome complex, and pro-inflammatory cytokines (interleukin 1 beta and interleukin 18) induced by IR in the CA1 subregion. Overall, our findings suggest that porphyran exerts neuroprotective effects against brain IR injury, potentially by reducing the reaction (activation) and proliferation of microglia and reducing NLRP3 inflammasome-mediated neuroinflammation.
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Affiliation(s)
- Dae Won Kim
- Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Gangneung-Wonju National University, Gangneung 25457, Republic of Korea;
| | - Tae-Kyeong Lee
- Department of Food Science and Nutrition, Hallym University, Chuncheon 24252, Republic of Korea;
| | - Ji Hyeon Ahn
- Department of Physical Therapy, College of Health Science, Youngsan University, Yangsan 50510, Republic of Korea;
| | - Se-Ran Yang
- Department of Cardiovascular Surgery, School of Medicine, Kangwon National University, Chuncheon 24341, Republic of Korea;
| | - Myoung Cheol Shin
- Department of Emergency Medicine, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon 24289, Republic of Korea; (M.C.S.); (J.H.C.); (M.-H.W.)
| | - Jun Hwi Cho
- Department of Emergency Medicine, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon 24289, Republic of Korea; (M.C.S.); (J.H.C.); (M.-H.W.)
| | - Moo-Ho Won
- Department of Emergency Medicine, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon 24289, Republic of Korea; (M.C.S.); (J.H.C.); (M.-H.W.)
| | - Il Jun Kang
- Department of Food Science and Nutrition, Hallym University, Chuncheon 24252, Republic of Korea;
| | - Joon Ha Park
- Department of Anatomy, College of Korean Medicine, Dongguk University, 123 Dongdae-ro, Gyeongju 38066, Republic of Korea
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11
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Tian X, Yang W, Jiang W, Zhang Z, Liu J, Tu H. Multi-Omics Profiling Identifies Microglial Annexin A2 as a Key Mediator of NF-κB Pro-inflammatory Signaling in Ischemic Reperfusion Injury. Mol Cell Proteomics 2024; 23:100723. [PMID: 38253182 PMCID: PMC10879806 DOI: 10.1016/j.mcpro.2024.100723] [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: 06/01/2023] [Revised: 12/19/2023] [Accepted: 12/23/2023] [Indexed: 01/24/2024] Open
Abstract
Cerebral stroke is one of the leading causes of mortality and disability worldwide. Restoring the cerebral circulation following a period of occlusion and subsequent tissue oxygenation leads to reperfusion injury. Cerebral ischemic reperfusion (I/R) injury triggers immune and inflammatory responses, apoptosis, neuronal damage, and even death. However, the cellular function and molecular mechanisms underlying cerebral I/R-induced neuronal injury are incompletely understood. By integrating proteomic, phosphoproteomic, and transcriptomic profiling in mouse hippocampi after cerebral I/R, we revealed that the differentially expressed genes and proteins mainly fall into several immune inflammatory response-related pathways. We identified that Annexin 2 (Anxa2) was exclusively upregulated in microglial cells in response to cerebral I/R in vivo and oxygen-glucose deprivation and reoxygenation (OGD/R) in vitro. RNA-seq analysis revealed a critical role of Anxa2 in the expression of inflammation-related genes in microglia via the NF-κB signaling. Mechanistically, microglial Anxa2 is required for nuclear translocation of the p65 subunit of NF-κB and its transcriptional activity upon OGD/R in BV2 microglial cells. Anxa2 knockdown inhibited the OGD/R-induced microglia activation and markedly reduced the expression of pro-inflammatory factors, including TNF-α, IL-1β, and IL-6. Interestingly, conditional medium derived from Anxa2-depleted BV2 cell cultures with OGD/R treatment alleviated neuronal death in vitro. Altogether, our findings revealed that microglia Anxa2 plays a critical role in I/R injury by regulating NF-κB inflammatory responses in a non-cell-autonomous manner, which might be a potential target for the neuroprotection against cerebral I/R injury.
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Affiliation(s)
- Xibin Tian
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha, Hunan, China
| | - Wuyan Yang
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha, Hunan, China
| | - Wei Jiang
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha, Hunan, China
| | - Zhen Zhang
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha, Hunan, China
| | - Junqiang Liu
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha, Hunan, China
| | - Haijun Tu
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha, Hunan, China; Shenzhen Research Institute, Hunan University, Shenzhen, Guangdong, China.
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12
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Yi F, Xiao H, Song M, Huang L, Huang Q, Deng J, Yang H, Zheng L, Wang H, Gu W. BMSC-derived exosomal miR-148b-3p attenuates OGD/R-induced HMC3 cell activation by targeting DLL4 and Notch1. Neurosci Res 2024; 199:36-47. [PMID: 37741572 DOI: 10.1016/j.neures.2023.09.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 09/04/2023] [Accepted: 09/19/2023] [Indexed: 09/25/2023]
Abstract
Bone mesenchymal stem cell (BMSC)-derived exosome (BMSC-Exo) could be a treatment method for ischemic injury. In ischemic cerebrovascular disease (IC), microglia is pivotal in neuronal damage and remodeling. This study explores the mechanisms of BMSC-Exo miR-148b-3p in regulating oxygen-glucose deprivation/reoxygenation (OGD/R)-induced human microglial clone 3 (HMC3) cell activation. Transmission electron microscopy (TEM) and qNano were used to assess BMSC-Exo features. The functions of BMSC-Exo miR-148 b-3p in OGD/R-induced HMC3 cell activation were explored via MTT assay, flow cytometry, scratch, transwell, and enzyme-linked immunosorbent assay (ELISA) assays. A dual-luciferase reporter assay was performed to determine the relationship between miR-148b-3p and Delta-like ligand 4(DDL4) or neurogenic locus notch homolog protein 1 (Notch1). OGD/R decreased miR-148b-3p expression in HMC3 cells. After BMSC-Exo treatment, miR-148b-3p expression was upregulated, cell viability and migration were inhibited, cell cycles remained in the G0/G1 phase, and proinflammatory cytokines were decreased in OGD/R-induced HMC3 cells. More importantly, BMSC-Exo miR-148b-3p could further strengthen BMSC-Exo effects. DDL4 and Notch1 are direct targets of miR-148b-3p, respectively. Moreover, the knockdown of DLL4 or Notch1 could inhibit OGD/R-induced HMC3 cell activation. BMSC-Exo miR-148b-3p inhibited OGD/R-induced HMC3 cell activation via inhibiting DLL4 and Notch1 expression, which provided a new strategy for treating cerebral ischemia.
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Affiliation(s)
- Fang Yi
- Department of Geriatric Neurology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
| | - Hui Xiao
- Department of Neurology, Changsha Central Hospital, Changsha 410004, Hunan, PR China
| | - Mingyu Song
- Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; Clinical Research Center for Cerebrovascular Disease of Hunan Province, Central South University, Changsha, Hunan 410008, PR China
| | - Lei Huang
- Department of Neurological Rehabilitation, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410000, Hunan, PR China
| | - Qianyi Huang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China
| | - Jun Deng
- Department of Neurology, Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, Changsha 410000, Hunan, PR China
| | - Han Yang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China
| | - Lan Zheng
- Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China
| | - Hong Wang
- Department of Geriatric Neurology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China
| | - Wenping Gu
- Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; Clinical Research Center for Cerebrovascular Disease of Hunan Province, Central South University, Changsha, Hunan 410008, PR China.
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13
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Islam R, Ahlfors JE, Siu R, Noman H, Akbary R, Morshead CM. Inhibition of Apoptosis in a Model of Ischemic Stroke Leads to Enhanced Cell Survival, Endogenous Neural Precursor Cell Activation and Improved Functional Outcomes. Int J Mol Sci 2024; 25:1786. [PMID: 38339065 PMCID: PMC10855341 DOI: 10.3390/ijms25031786] [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: 12/13/2023] [Revised: 01/24/2024] [Accepted: 01/30/2024] [Indexed: 02/12/2024] Open
Abstract
Stroke results in neuronal cell death, which causes long-term disabilities in adults. Treatment options are limited and rely on a narrow window of opportunity. Apoptosis inhibitors demonstrate efficacy in improving neuronal cell survival in animal models of stroke. However, many inhibitors non-specifically target apoptosis pathways and high doses are needed for treatment. We explored the use of a novel caspase-3/7 inhibitor, New World Laboratories (NWL) 283, with a lower IC50 than current caspase-3/7 inhibitors. We performed in vitro and in vivo assays to determine the efficacy of NWL283 in modulating cell death in a preclinical model of stroke. In vitro and in vivo assays show that NWL283 enhances cell survival of neural precursor cells. Delivery of NWL283 following stroke enhances endogenous NPC migration and leads to increased neurogenesis in the stroke-injured cortex. Furthermore, acute NWL283 administration is neuroprotective at the stroke injury site, decreasing neuronal cell death and reducing microglia activation. Coincident with NWL283 delivery for 8 days, stroke-injured mice exhibited improved functional outcomes that persisted following cessation of the drug. Therefore, we propose that NWL283 is a promising therapeutic warranting further investigation to enhance stroke recovery.
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Affiliation(s)
- Rehnuma Islam
- Institute of Medical Science, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 3E1, Canada
| | - Jan-Eric Ahlfors
- New World Laboratories, 275 Boul. Armand-Frappier, Laval, QC H7V 4A7, Canada
| | - Ricky Siu
- Department of Surgery, University of Toronto, 149 College Street, Toronto, ON M5T 1P5, Canada
| | - Humna Noman
- Institute of Medical Science, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 3E1, Canada
| | - Roya Akbary
- Department of Surgery, University of Toronto, 149 College Street, Toronto, ON M5T 1P5, Canada
| | - Cindi M. Morshead
- Institute of Medical Science, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 3E1, Canada
- Department of Surgery, University of Toronto, 149 College Street, Toronto, ON M5T 1P5, Canada
- Institute of Biomedical Engineering, University of Toronto, 164 College Street, Toronto, ON M5S 3G9, Canada
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada
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14
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Huang CH, Yang TT, Lin KI. Mechanisms and functions of SUMOylation in health and disease: a review focusing on immune cells. J Biomed Sci 2024; 31:16. [PMID: 38280996 PMCID: PMC10821541 DOI: 10.1186/s12929-024-01003-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: 08/01/2023] [Accepted: 01/05/2024] [Indexed: 01/29/2024] Open
Abstract
SUMOylation, which is a type of post-translational modification that involves covalent conjugation of small ubiquitin-like modifier (SUMO) proteins to target substrates, regulates various important molecular and cellular processes, including transcription, the cell cycle, cell signaling, and DNA synthesis and repair. Newly synthesized SUMO is immature and cleaved by the SUMO-specific protease family, resulting in exposure of the C-terminal Gly-Gly motif to become the mature form. In the presence of ATP, mature SUMO is conjugated with the activating enzyme E1 through the cysteine residue of E1, followed by transfer to the cysteine residue of E2-conjugating enzyme Ubc9 in humans that recognizes and modifies the lysine residue of a substrate protein. E3 SUMO ligases promote SUMOylation. SUMOylation is a reversible modification and mediated by SUMO-specific proteases. Cumulative studies have indicated that SUMOylation affects the functions of protein substrates in various manners, including cellular localization and protein stability. Gene knockout studies in mice have revealed that several SUMO cycling machinery proteins are crucial for the development and differentiation of various cell lineages, including immune cells. Aberrant SUMOylation has been implicated in several types of diseases, including cancers, cardiovascular diseases, and autoimmune diseases. This review summarizes the biochemistry of SUMO modification and the general biological functions of proteins involved in SUMOylation. In particular, this review focuses on the molecular mechanisms by which SUMOylation regulates the development, maturation, and functions of immune cells, including T, B, dendritic, and myeloid cells. This review also discusses the underlying relevance of disruption of SUMO cycling and site-specific interruption of SUMOylation on target proteins in immune cells in diseases, including cancers and infectious diseases.
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Affiliation(s)
- Chien-Hsin Huang
- Genomics Research Center, Academia Sinica, 128 Academia Road, Sec. 2, Nankang District, Taipei, 115, Taiwan
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, 110, Taiwan
| | - Tsan-Tzu Yang
- Genomics Research Center, Academia Sinica, 128 Academia Road, Sec. 2, Nankang District, Taipei, 115, Taiwan
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, 110, Taiwan
| | - Kuo-I Lin
- Genomics Research Center, Academia Sinica, 128 Academia Road, Sec. 2, Nankang District, Taipei, 115, Taiwan.
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, 110, Taiwan.
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15
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Fleiss B, Gressens P. Role of Microglial Modulation in Therapies for Perinatal Brain Injuries Leading to Neurodevelopmental Disorders. ADVANCES IN NEUROBIOLOGY 2024; 37:591-606. [PMID: 39207715 DOI: 10.1007/978-3-031-55529-9_33] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Neurodevelopmental disorders (NDDs) encompass various conditions stemming from changes during brain development, typically diagnosed early in life. Examples include autism spectrum disorder, intellectual disability, cerebral palsy, seizures, dyslexia, and attention deficit hyperactivity disorder. Many NDDs are linked to perinatal events like infections, oxygen disturbances, or insults in combination. This chapter outlines the causes and effects of perinatal brain injury as they relate to microglia, along with efforts to prevent or treat such damage. We primarily discuss therapies targeting microglia modulation, focusing on those either clinically used or in advanced development, often tested in large animal models such as sheep, non-human primates, and piglets-standard translational models in perinatal medicine. Additionally, it touches on experimental studies showcasing advancements in the field.
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Affiliation(s)
- Bobbi Fleiss
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia
- Université de Paris, NeuroDiderot, Inserm, Paris, France
| | - Pierre Gressens
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia.
- Université de Paris, NeuroDiderot, Inserm, Paris, France.
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16
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Cao Y, Song Y, Ding Y, Ni J, Zhu B, Shen J, Miao L. The role of hormones in the pathogenesis and treatment mechanisms of delirium in ICU: The past, the present, and the future. J Steroid Biochem Mol Biol 2023; 233:106356. [PMID: 37385414 DOI: 10.1016/j.jsbmb.2023.106356] [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: 06/05/2023] [Revised: 06/18/2023] [Accepted: 06/26/2023] [Indexed: 07/01/2023]
Abstract
Delirium is an acute brain dysfunction. As one of the common psychiatric disorders in ICU, it can seriously affect the prognosis of patients. Hormones are important messenger substances found in the human body that help to regulate and maintain the function and metabolism of various tissues and organs. They are also one of the most commonly used drugs in clinical practice. Recent evidences suggest that aberrant swings in cortisol and non-cortisol hormones might induce severe cognitive impairment, eventually leading to delirium. However, the role of hormones in the pathogenesis of delirium still remains controversial. This article reviews the recent research on risk factors of delirium and the association between several types of hormones and cognitive dysfunction. These mechanisms are expected to offer novel ideas and clinical relevance for the treatment and prevention of delirium.
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Affiliation(s)
- Yuchun Cao
- Department of Critical Care Medicine, the Third Affiliated Hospital of Soochow University, Changzhou 213000, Jiangsu, China
| | - Yuwei Song
- Department of Critical Care Medicine, the Third Affiliated Hospital of Soochow University, Changzhou 213000, Jiangsu, China
| | - Yuan Ding
- Department of Critical Care Medicine, the Third Affiliated Hospital of Soochow University, Changzhou 213000, Jiangsu, China
| | - Jiayuan Ni
- Department of Critical Care Medicine, the Third Affiliated Hospital of Soochow University, Changzhou 213000, Jiangsu, China
| | - Bin Zhu
- Department of Critical Care Medicine, the Third Affiliated Hospital of Soochow University, Changzhou 213000, Jiangsu, China
| | - Jianqin Shen
- Department of Blood Purification Center, the Third Affiliated Hospital of Soochow University, Changzhou 213000, Jiangsu, China.
| | - Liying Miao
- Department of Nephrology, The Third Affiliated Hospital of Soochow University, Changzhou 213000, Jiangsu, China.
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17
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Mu Q, Yao K, Syeda MZ, Zhang M, Cheng Q, Zhang Y, Sun R, Lu Y, Zhang H, Luo Z, Huang H, Liu X, Luo C, Zhu X, Wu S, Cui L, Huang C, Chen X, Tang L. Ligustrazine Nanoparticle Hitchhiking on Neutrophils for Enhanced Therapy of Cerebral Ischemia-Reperfusion Injury. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2301348. [PMID: 37078794 PMCID: PMC10323616 DOI: 10.1002/advs.202301348] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/19/2023] [Indexed: 05/03/2023]
Abstract
Ischemic stroke is a refractory disease that endangers human health and safety owing to cerebral ischemia. Brain ischemia induces a series of inflammatory reactions. Neutrophils migrate from the circulatory system to the site of cerebral ischemia and accumulate in large numbers at the site of inflammation across the blood-brain barrier. Therefore, hitchhiking on neutrophils to deliver drugs to ischemic brain sites could be an optimal strategy. Since the surface of neutrophils has a formyl peptide receptor (FPR), this work modifies a nanoplatform surface by the peptide cinnamyl-F-(D)L-F-(D)L-F (CFLFLF), which can specifically bind to the FPR receptor. After intravenous injection, the fabricated nanoparticles effectively adhered to the surface of neutrophils in peripheral blood mediated by FPR, thereby hitchhiking with neutrophils to achieve higher accumulation at the inflammatory site of cerebral ischemia. In addition, the nanoparticle shell is composed of a polymer with reactive oxygen species (ROS)-responsive bond breaking and is encased in ligustrazine, a natural product with neuroprotective properties. In conclusion, the strategy of hitching the delivered drugs to neutrophils in this study could improve drug enrichment in the brain, thereby providing a general delivery platform for ischemic stroke or other inflammation-related diseases.
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Affiliation(s)
- Qingchun Mu
- The People's Hospital of GaozhouGuangdong Medical UniversityMaoming525200China
| | - Kai Yao
- Department of NeurosurgeryFirst Affiliated Hospital of Harbin Medical UniversityHarbin150001China
| | - Madiha Zahra Syeda
- The People's Hospital of GaozhouGuangdong Medical UniversityMaoming525200China
| | - Min Zhang
- International Institutes of MedicineThe Fourth Affiliated HospitalZhejiang University School of MedicineYiwu322000China
| | - Qian Cheng
- Basic Medical CollegeGuilin Medical UniversityGuilin541199China
| | - Yufei Zhang
- Basic Medical CollegeGuilin Medical UniversityGuilin541199China
| | - Rui Sun
- School of Pharmaceutical SciencesGuangdong Provincial Key Laboratory of New Drug ScreeningSouthern Medical UniversityGuangzhou510515China
| | - Yuting Lu
- International Institutes of MedicineThe Fourth Affiliated HospitalZhejiang University School of MedicineYiwu322000China
| | - Huamiao Zhang
- International Institutes of MedicineThe Fourth Affiliated HospitalZhejiang University School of MedicineYiwu322000China
| | - Zhicheng Luo
- The People's Hospital of GaozhouGuangdong Medical UniversityMaoming525200China
| | - Hanning Huang
- The People's Hospital of GaozhouGuangdong Medical UniversityMaoming525200China
| | - Xiaojing Liu
- The People's Hospital of GaozhouGuangdong Medical UniversityMaoming525200China
| | - Chunmei Luo
- The People's Hospital of GaozhouGuangdong Medical UniversityMaoming525200China
| | - Xiulong Zhu
- The People's Hospital of GaozhouGuangdong Medical UniversityMaoming525200China
| | - Shuyu Wu
- Department of NeurosurgeryHainan General HospicalHainan Affiliated Hospital of Hainan Medical UniversityHaikou570311China
| | - Liao Cui
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs and School of PharmacyGuangdong Medical UniversityDongguan523808China
| | - Chunming Huang
- The People's Hospital of GaozhouGuangdong Medical UniversityMaoming525200China
| | - Xiaoyuan Chen
- Departments of Diagnostic Radiologyand SurgeryClinical Imaging Research CentreCentre for Translational MedicineNanomedicine Translational Research ProgramNUS Center for NanomedicineYong Loo Lin School of MedicineDepartments of Chemical and Biomolecular Engineeringand Biomedical EngineeringFaculty of EngineeringNational University of SingaporeSingapore117597Singapore
| | - Longguang Tang
- The People's Hospital of GaozhouGuangdong Medical UniversityMaoming525200China
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18
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Owjfard M, Karimi F, Mallahzadeh A, Nabavizadeh SA, Namavar MR, Saadi MI, Hooshmandi E, Salehi MS, Zafarmand SS, Bayat M, Karimlou S, Borhani-Haghighi A. Mechanism of action and therapeutic potential of dimethyl fumarate in ischemic stroke. J Neurosci Res 2023. [PMID: 37183360 DOI: 10.1002/jnr.25202] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 04/09/2023] [Accepted: 04/21/2023] [Indexed: 05/16/2023]
Abstract
Dimethyl fumarate (DMF) is an immunomodulatory drug currently approved for the treatment of multiple sclerosis and psoriasis. Its benefits on ischemic stroke outcomes have recently come to attention. To date, only tissue plasminogen activators (tPAs) and clot retrieval methods have been approved by the FDA for the treatment of ischemic stroke. Ischemic conditions lead to inflammation through diverse mechanisms, and recanalization can worsen the state. DMF and the nuclear factor erythroid-derived 2-related factor 2 (Nrf2) pathway it regulates seem to be important in postischemic inflammation, and animal studies have demonstrated that the drug improves overall stroke outcomes. Although the exact mechanism is still unknown, studies indicate that these beneficial impacts are due to the modulation of immune responses, blood-brain barrier permeability, and hemodynamic adjustments. One major component evaluated before, during, and after tPA therapy in stroke patients is blood pressure (BP). Recent studies have found that DMF may impact BP. Both hypotension and hypertension need correction before treatment, which may delay the appropriate intervention. Since BP management is crucial in managing stroke patients, it is important to consider DMF's role in this matter. That being said, it seems further investigations on DMF may lead to an alternative approach for stroke patients. In this article, we discuss the mechanistic roles of DMF and its potential role in stroke based on previously published literature and laboratory findings.
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Affiliation(s)
- Maryam Owjfard
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Shiraz University of Applied Science and Technology (UAST), Shiraz, Iran
| | | | - Arashk Mallahzadeh
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Ali Nabavizadeh
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Reza Namavar
- Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Anatomical Sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Etrat Hooshmandi
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Saied Salehi
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Mahnaz Bayat
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sedigheh Karimlou
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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19
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Lee RD, Chen YJ, Singh L, Nguyen HM, Wulff H. Immunocytoprotection after reperfusion with Kv1.3 inhibitors has an extended treatment window for ischemic stroke. Front Pharmacol 2023; 14:1190476. [PMID: 37180699 PMCID: PMC10166874 DOI: 10.3389/fphar.2023.1190476] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 04/17/2023] [Indexed: 05/16/2023] Open
Abstract
Introduction: Mechanical thrombectomy has improved treatment options and outcomes for acute ischemic stroke with large artery occlusion. However, as the time window of endovascular thrombectomy is extended there is an increasing need to develop immunocytoprotective therapies that can reduce inflammation in the penumbra and prevent reperfusion injury. We previously demonstrated, that by reducing neuroinflammation, KV1.3 inhibitors can improve outcomes not only in young male rodents but also in female and aged animals. To further explore the therapeutic potential of KV1.3 inhibitors for stroke therapy, we here directly compared a peptidic and a small molecule KV1.3 blocker and asked whether KV1.3 inhibition would still be beneficial when started at 72 hours after reperfusion. Methods: Transient middle cerebral artery occlusion (tMCAO, 90-min) was induced in male Wistar rats and neurological deficit assessed daily. On day-8 infarction was determined by T2-weighted MRI and inflammatory marker expression in the brain by quantitative PCR. Potential interactions with tissue plasminogen activator (tPA) were evaluated in-vitro with a chromogenic assay. Results: In a direct comparison with administration started at 2 hours after reperfusion, the small molecule PAP-1 significantly improved outcomes on day-8, while the peptide ShK-223 failed to reduce infarction and neurological deficits despite reducing inflammatory marker expression. PAP-1 still provided benefits when started 72 hours after reperfusion. PAP-1 does not reduce the proteolytic activity of tPA. Discussion: Our studies suggest that KV1.3 inhibition for immunocytoprotection after ischemic stroke has a wide therapeutic window for salvaging the inflammatory penumbra and requires brain-penetrant small molecules.
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Affiliation(s)
- Ruth D. Lee
- Department of Pharmacology, School of Medicine, University of California, Davis, Davis, CA, United States
| | - Yi-Je Chen
- Department of Pharmacology, School of Medicine, University of California, Davis, Davis, CA, United States
- Animal Models Core, Department of Pharmacology, School of Medicine, University of California, Davis, Davis, CA, United States
| | - Latika Singh
- Department of Pharmacology, School of Medicine, University of California, Davis, Davis, CA, United States
| | - Hai M. Nguyen
- Department of Pharmacology, School of Medicine, University of California, Davis, Davis, CA, United States
| | - Heike Wulff
- Department of Pharmacology, School of Medicine, University of California, Davis, Davis, CA, United States
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20
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Jing X, Luo X, Fang C, Zhang B. N-acetylserotonin inhibits oxidized mitochondrial DNA-induced neuroinflammation by activating the AMPK/PGC-1α/TFAM pathway in neonatal hypoxic-ischemic brain injury model. Int Immunopharmacol 2023. [DOI: 10.1016/j.intimp.2023.109878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
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21
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Kim GS, Harmon E, Gutierrez M, Stephenson J, Chauhan A, Banerjee A, Wise Z, Doan A, Wu T, Lee J, Jung JE, McCullough L, Wythe J, Marrelli S. Single-cell analysis identifies Ifi27l2a as a novel gene regulator of microglial inflammation in the context of aging and stroke. RESEARCH SQUARE 2023:rs.3.rs-2557290. [PMID: 36824976 PMCID: PMC9949241 DOI: 10.21203/rs.3.rs-2557290/v1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Microglia are key mediators of inflammatory responses within the brain, as they regulate pro-inflammatory responses while also limiting neuroinflammation via reparative phagocytosis. Thus, identifying genes that modulate microglial function may reveal novel therapeutic interventions for promoting better outcomes in diseases featuring extensive inflammation, such as stroke. To facilitate identification of potential mediators of inflammation, we performed single-cell RNA sequencing of aged mouse brains following stroke and found that Ifi27l2a was significantly up-regulated, particularly in microglia. The increased Ifi27l2a expression was further validated in microglial culture, stroke models with microglial depletion, and human autopsy samples. Ifi27l2a is known to be induced by interferons for viral host defense, however the role of Ifi27l2a in neurodegeneration is unknown. In vitro studies in cultured microglia demonstrated that Ifi27l2a overexpression causes neuroinflammation via reactive oxygen species. Interestingly, hemizygous deletion of Ifi27l2a significantly reduced gliosis in the thalamus following stroke, while also reducing neuroinflammation, indicating Ifi27l2a gene dosage is a critical mediator of neuroinflammation in ischemic stroke. Collectively, this study demonstrates that a novel gene, Ifi27l2a, regulates microglial function and neuroinflammation in the aged brain and following stroke. These findings suggest that Ifi27l2a may be a novel target for conferring cerebral protection post-stroke.
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Affiliation(s)
- Gab Seok Kim
- The University of Texas Health Science Center at Houston
| | | | | | | | | | | | - Zachary Wise
- The University of Texas Health Science Center at Houston
| | - Andrea Doan
- The University of Texas Health Science Center at Houston
| | - Ting Wu
- The University of Texas Health Science Center at Houston
| | - Juneyoung Lee
- The University of Texas Health Science Center at Houston
| | | | - Louise McCullough
- McGovern Medical School/University of Texas Health Science Center at Houston
| | | | - Sean Marrelli
- The University of Texas McGovern Medical School at Houston, 77030, TX
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22
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Thapa K, Shivam K, Khan H, Kaur A, Dua K, Singh S, Singh TG. Emerging Targets for Modulation of Immune Response and Inflammation in Stroke. Neurochem Res 2023; 48:1663-1690. [PMID: 36763312 DOI: 10.1007/s11064-023-03875-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 01/18/2023] [Accepted: 01/24/2023] [Indexed: 02/11/2023]
Abstract
The inflammatory and immunological responses play a significant role after stroke. The innate immune activation stimulated by microglia during stroke results in the migration of macrophages and lymphocytes into the brain and are responsible for tissue damage. The immune response and inflammation following stroke have no defined targets, and the intricacies of the immunological and inflammatory processes are only partially understood. Innate immune cells enter the brain and meninges during the acute phase, which can cause ischemia damage. Activation of systemic immunity is caused by danger signals sent into the bloodstream by injured brain cells, which is followed by a significant immunodepression that encourages life-threatening infections. Neuropsychiatric sequelae, a major source of post-stroke morbidity, may be induced by an adaptive immune response that is initiated by antigen presentation during the chronic period and is directed against the brain. Thus, the current review discusses the role of immune response and inflammation in stroke pathogenesis, their role in the progression of injury during the stroke, and the emerging targets for the modulation of the mechanism of immune response and inflammation that may have possible therapeutic benefits against stroke.
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Affiliation(s)
- Komal Thapa
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India.,School of Pharmacy, Chitkara University, Rajpura, Himachal Pradesh, 174103, India
| | - Kumar Shivam
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
| | - Heena Khan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
| | - Amarjot Kaur
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW, 2007, Australia.,Faculty of Health, Australian Research Centre in Complementary & Integrative Medicine, University of Technology Sydney, Ultimo, 2007, Australia
| | - Sachin Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar - Delhi G.T. Road, Phagwara, Punjab, 144411, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India.
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23
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Roseborough AD, Myers SJ, Khazaee R, Zhu Y, Zhao L, Iorio E, Elahi FM, Pasternak SH, Whitehead SN. Plasma derived extracellular vesicle biomarkers of microglia activation in an experimental stroke model. J Neuroinflammation 2023; 20:20. [PMID: 36721258 PMCID: PMC9890769 DOI: 10.1186/s12974-023-02708-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 01/27/2023] [Indexed: 02/02/2023] Open
Abstract
Chronic microglia activation post-stroke is associated with worse neurological and cognitive outcomes. However, measurement of microglia activation in vivo is currently limited. Plasma derived extracellular vesicles (EVs) are cell-specific indicators that may allow for non-invasive measurement of microglia phenotype. The aim of this study was to identify activation-state specific microglia EVs (MEVs) in vitro followed by validation in an experimental stroke model. Following pro-inflammatory activation, MEVs contain the microglia protein TMEM119 alongside increased expression of the Toll-like receptor 4 co-receptor CD14. Immunoprecipitation followed by fluorescent nanoparticle tracking analysis (ONI Nanoimager) was used to confirm the isolation of TMEM119+/CD14+ EVs from rat plasma. Electron microscopy confirmed that TMEM119 and CD14 localize to the MEV membrane. To model ischemia, plasma was collected from 3-month wildtype Fischer344 rats prior to, 7 and 28 days after endothelin-1 or saline injection into the dorsal right striatum. Fluorescently labelled MEVs were directly measured in the plasma using nanoflow cytometry (Apogee A60 Microplus). We report a significant increase in circulating TMEM119+/CD14+ EVs 28-days post-stroke in comparison to baseline levels and saline-injected rats, which correlated weakly with stroke volume. TMEM119+/MHC-II+ EVs were also increased post-stroke in comparison to baseline and saline-injected animals. This study is the first to describe an EV biomarker of activated microglia detected directly in plasma following stroke and represents a future tool for the measurement of microglia activity in vivo.
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Affiliation(s)
- A. D. Roseborough
- grid.39381.300000 0004 1936 8884Vulnerable Brain Laboratory, Department of Anatomy and Cell Biology, The Schulich School of Medicine and Dentistry, The University of Western Ontario, 458 Medical Sciences Building, ON N6A 3K London, Canada
| | - S. J. Myers
- grid.39381.300000 0004 1936 8884Vulnerable Brain Laboratory, Department of Anatomy and Cell Biology, The Schulich School of Medicine and Dentistry, The University of Western Ontario, 458 Medical Sciences Building, ON N6A 3K London, Canada
| | - R. Khazaee
- grid.39381.300000 0004 1936 8884Biotron Integrated Microscopy Facility, The University of Western Ontario, London, ON Canada ,grid.39381.300000 0004 1936 8884Deparment of Biology, The University of Western Ontario, London, ON Canada
| | - Y. Zhu
- grid.39381.300000 0004 1936 8884Vulnerable Brain Laboratory, Department of Anatomy and Cell Biology, The Schulich School of Medicine and Dentistry, The University of Western Ontario, 458 Medical Sciences Building, ON N6A 3K London, Canada
| | - L. Zhao
- grid.39381.300000 0004 1936 8884Vulnerable Brain Laboratory, Department of Anatomy and Cell Biology, The Schulich School of Medicine and Dentistry, The University of Western Ontario, 458 Medical Sciences Building, ON N6A 3K London, Canada
| | - E. Iorio
- grid.266102.10000 0001 2297 6811Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA USA
| | - F. M. Elahi
- grid.266102.10000 0001 2297 6811Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA USA ,grid.59734.3c0000 0001 0670 2351Icahn School of Medicine at Mount Sinai, New York, USA ,grid.39381.300000 0004 1936 8884Department of Clinical Neurological Sciences, The Schulich School of Medicine and Dentistry, The University of Western Ontario, ON London, Canada
| | - S. H. Pasternak
- grid.59734.3c0000 0001 0670 2351Icahn School of Medicine at Mount Sinai, New York, USA ,grid.39381.300000 0004 1936 8884Department of Clinical Neurological Sciences, The Schulich School of Medicine and Dentistry, The University of Western Ontario, ON London, Canada ,grid.39381.300000 0004 1936 8884Robarts Research Institute, The Schulich School of Medicine and Dentistry, The University of Western Ontario, ON London, Canada
| | - S. N. Whitehead
- grid.39381.300000 0004 1936 8884Vulnerable Brain Laboratory, Department of Anatomy and Cell Biology, The Schulich School of Medicine and Dentistry, The University of Western Ontario, 458 Medical Sciences Building, ON N6A 3K London, Canada
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24
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Lee D, Nakai A, Miwa Y, Negishi K, Tomita Y, Kurihara T. Pemafibrate prevents choroidal neovascularization in a mouse model of neovascular age-related macular degeneration. PeerJ 2023; 11:e14611. [PMID: 36643635 PMCID: PMC9838199 DOI: 10.7717/peerj.14611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 11/30/2022] [Indexed: 01/12/2023] Open
Abstract
Background Pathological choroidal neovascularization (CNV) is one of the major causes of visual impairment in neovascular age-related macular degeneration (AMD). CNV has been suppressed by using anti-vascular endothelial growth factor (VEGF) antibodies. However, some clinical cases have demonstrated the failure of anti-VEGF therapies. Furthermore, anti-VEGF agents might induce the development of ocular atrophy. Recently, peroxisome proliferator-activated receptor alpha (PPARα) activation using pemafibrate treatment was suggested as one of the promising therapeutic targets in the prevention of ocular ischemia. However, the preventive role of pemafibrate remains unclear in CNV. We aimed to examine the preventive role of pemafibrate on laser-induced pathological CNV. Methods Adult male C57BL/6 mice were orally supplied pemafibrate (0.5 mg/kg) for four days, followed by laser irradiation. Then, pemafibrate was consecutively given to mice with the same condition. CNV was visualized with isolectin-IB4. The eye (retina and/or retinal pigment epithelium [RPE]-choroid), liver, and serum were used for biomolecular analyses. Results We found that pemafibrate administration suppressed CNV volumes. Pemafibrate administration activated PPARα downstream genes in the liver and eye (especially, RPE-choroid). Furthermore, pemafibrate administration elevated serum fibroblast growth factor 21 levels and reduced serum levels of triglycerides. Conclusions Our data suggest a promising pemafibrate therapy for suppressing CNV in AMD.
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Affiliation(s)
- Deokho Lee
- Laboratory of Photobiology, Keio University School of Medicine, Tokyo, Japan,Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Ayaka Nakai
- Laboratory of Photobiology, Keio University School of Medicine, Tokyo, Japan,Ophthalmology, Keio University School of Medicine, Tokyo, Japan,Ophthalmology, Nihon University School of Medicine, Tokyo, Japan
| | - Yukihiro Miwa
- Laboratory of Photobiology, Keio University School of Medicine, Tokyo, Japan,Ophthalmology, Keio University School of Medicine, Tokyo, Japan,Aichi Animal Eye Clinics, Aichi, Japan
| | - Kazuno Negishi
- Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Yohei Tomita
- Laboratory of Photobiology, Keio University School of Medicine, Tokyo, Japan,Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Toshihide Kurihara
- Laboratory of Photobiology, Keio University School of Medicine, Tokyo, Japan,Ophthalmology, Keio University School of Medicine, Tokyo, Japan
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25
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Liang Z, Lou Y, Hao Y, Li H, Feng J, Liu S. The Relationship of Astrocytes and Microglia with Different Stages of Ischemic Stroke. Curr Neuropharmacol 2023; 21:2465-2480. [PMID: 37464832 PMCID: PMC10616922 DOI: 10.2174/1570159x21666230718104634] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 01/31/2023] [Accepted: 02/04/2023] [Indexed: 07/20/2023] Open
Abstract
Ischemic stroke is the predominant cause of severe morbidity and mortality worldwide. Post-stroke neuroinflammation has recently received increasing attention with the aim of providing a new effective treatment strategy for ischemic stroke. Microglia and astrocytes are major components of the innate immune system of the central nervous system. They can be involved in all phases of ischemic stroke, from the early stage, contributing to the first wave of neuronal cell death, to the late stage involving phagocytosis and repair. In the early stage of ischemic stroke, a vicious cycle exists between the activation of microglia and astrocytes (through astrocytic connexin 43 hemichannels), aggravating neuroinflammatory injury post-stroke. However, in the late stage of ischemic stroke, repeatedly activated microglia can induce the formation of glial scars by triggering reactive astrogliosis in the peri-infarct regions, which may limit the movement of activated microglia in reverse and restrict the diffusion of inflammation to healthy brain tissues, alleviating the neuroinflammatory injury poststroke. In this review, we elucidated the various roles of astrocytes and microglia and summarized their relationship with neuroinflammation. We also examined how astrocytes and microglia influence each other at different stages of ischemic stroke. Several potential therapeutic approaches targeting astrocytes and microglia in ischemic stroke have been reviewed. Understanding the details of astrocytemicroglia interaction processes will contribute to a better understanding of the mechanisms underlying ischemic stroke, contributing to the identification of new therapeutic interventions.
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Affiliation(s)
- Zhen Liang
- Department of Neurology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Yingyue Lou
- Department of Rehabilitation, The Second Hospital of Jilin University, Changchun, China
| | - Yulei Hao
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| | - Hui Li
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| | - Jiachun Feng
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| | - Songyan Liu
- Department of Neurology, China-Japan Union Hospital, Jilin University, Changchun, China
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26
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Bui TA, Jickling GC, Winship IR. Neutrophil dynamics and inflammaging in acute ischemic stroke: A transcriptomic review. Front Aging Neurosci 2022; 14:1041333. [PMID: 36620775 PMCID: PMC9813499 DOI: 10.3389/fnagi.2022.1041333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 11/28/2022] [Indexed: 12/24/2022] Open
Abstract
Stroke is among the leading causes of death and disability worldwide. Restoring blood flow through recanalization is currently the only acute treatment for cerebral ischemia. Unfortunately, many patients that achieve a complete recanalization fail to regain functional independence. Recent studies indicate that activation of peripheral immune cells, particularly neutrophils, may contribute to microcirculatory failure and futile recanalization. Stroke primarily affects the elderly population, and mortality after endovascular therapies is associated with advanced age. Previous analyses of differential gene expression across injury status and age identify ischemic stroke as a complex age-related disease. It also suggests robust interactions between stroke injury, aging, and inflammation on a cellular and molecular level. Understanding such interactions is crucial in developing effective protective treatments. The global stroke burden will continue to increase with a rapidly aging human population. Unfortunately, the mechanisms of age-dependent vulnerability are poorly defined. In this review, we will discuss how neutrophil-specific gene expression patterns may contribute to poor treatment responses in stroke patients. We will also discuss age-related transcriptional changes that may contribute to poor clinical outcomes and greater susceptibility to cerebrovascular diseases.
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Affiliation(s)
- Truong An Bui
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
| | - Glen C. Jickling
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
- Department of Medicine, Division of Neurology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Ian R. Winship
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
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27
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Yilmazer-Hanke D, Ouali Alami N, Fang L, Klotz S, Kovacs GG, Pankratz H, Weis J, Katona I, Scheuerle A, Streit WJ, Del Tredici K. Differential Glial Chitotriosidase 1 and Chitinase 3-like Protein 1 Expression in the Human Primary Visual Cortex and Cerebellum after Global Hypoxia-Ischemia. Neuroscience 2022; 506:91-113. [PMID: 36332693 DOI: 10.1016/j.neuroscience.2022.10.018] [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: 03/14/2022] [Revised: 10/15/2022] [Accepted: 10/20/2022] [Indexed: 11/06/2022]
Abstract
Here, we studied the neuroinflammation- and ischemia-related glial markers chitotriosidase 1 (CHIT1) and chitinase-3-like protein 1 (CHI3L1, alias YKL-40) in the human striate cortex and cerebellum at different time points after global hypoxic-ischemic brain injury (HIBI). Both regions differ considerably in their glial cell population but are supplied by the posterior circulation. CHIT1 and CHI3L1 expression was compared to changes in microglial (IBA1, CD68), astrocytic (GFAP, S100β), and neuronal markers (H&E, neurofilament heavy chain, NfH; calretinin, CALR) using immunohistochemistry and multiple-label immunofluorescence. Initial striatal cortical and cerebellar Purkinje cell damage, detectable already 1/2 d after HIBI, led to delayed neuronal death, whereas loss of cerebellar NfH-positive stellate and CALR-positive granule cells was variable. During the first week post-HIBI, a transient reduction of IBA1-positive microglia was observed in both regions, and fragmented/clasmatodendritic cerebellar Bergmann glia appeared. In long-term survivors, both brain regions displayed high densities of activated IBA1-positive cells and CD68-positive macrophages, which showed CHIT1 co-localization in the striate cortex. Furthermore, enlarged GFAP- and S100β-positive astroglia emerged in both regions around 9-10 d post-HIBI, i.e., along with clearance of dead neurons from the neuropil, although GFAP-/S100β-positive gemistocytic astrocytes that co-expressed CHI3L1 were found only in the striate cortex. Thus, only GFAP-/S100β-positive astrocytes in the striate cortex, but not cerebellar Bergmann glia, differentiated into CHI3L1-positive gemistocytes. CHIT1 was co-expressed almost entirely in macrophages in the striate cortex and not cerebellum of long-term survivors, thereby indicating that CHIT1 and CHI3L1 could be valuable biomarkers for monitoring the outcome of global HIBI.
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Affiliation(s)
- Deniz Yilmazer-Hanke
- Clinical Neuroanatomy, Neurology, School of Medicine, Ulm University, Ulm, Germany.
| | - Najwa Ouali Alami
- Clinical Neuroanatomy, Neurology, School of Medicine, Ulm University, Ulm, Germany
| | - Lubin Fang
- Clinical Neuroanatomy, Neurology, School of Medicine, Ulm University, Ulm, Germany
| | - Sigried Klotz
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria
| | - Gabor G Kovacs
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria
| | - Helmut Pankratz
- Institute of Forensic Medicine, Medical Faculty, Ludwig-Maximilian University Munich, Germany
| | - Joachim Weis
- Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany
| | - Istvan Katona
- Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany
| | - Angelika Scheuerle
- Department of Pathology, Section Neuropathology, University Hospital, Ulm, Germany
| | - Wolfgang J Streit
- Department of Neuroscience, College of Medicine, University of Florida, FL, USA
| | - Kelly Del Tredici
- Clinical Neuroanatomy, Neurology, School of Medicine, Ulm University, Ulm, Germany
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28
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Pedroza-García KA, Calderón-Vallejo D, Quintanar JL. Neonatal Hypoxic-Ischemic Encephalopathy: Perspectives of Neuroprotective and Neuroregenerative Treatments. Neuropediatrics 2022; 53:402-417. [PMID: 36030792 DOI: 10.1055/s-0042-1755235] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
Hypoxic-ischemic encephalopathy (HIE) is a serious condition that could have deleterious neurological outcomes, such as cerebral palsy, neuromotor disability, developmental disability, epilepsy, and sensitive or cognitive problems, and increase the risk of death in severe cases. Once HIE occurs, molecular cascades are triggered favoring the oxidative stress, excitotoxicity, and inflammation damage that promote cell death via apoptosis or necrosis. Currently, the therapeutic hypothermia is the standard of care in HIE; however, it has a small window of action and only can be used in children of more than 36 gestational weeks; for this reason, it is very important to develop new therapies to prevent the progression of the hypoxic-ischemic injury or to develop neuroregenerative therapies in severe HIE cases. The objective of this revision is to describe the emerging treatments for HIE, either preventing cell death for oxidative stress, excitotoxicity, or exacerbated inflammation, as well as describing a new therapeutic approach for neuroregeneration, such as mesenchymal stem cells, brain-derived neurotrophic factor, and gonadotropin realizing hormone agonists.
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Affiliation(s)
- Karina A Pedroza-García
- Departamento de Fisiología y Farmacología, Laboratorio de Neurofisiología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, México
| | - Denisse Calderón-Vallejo
- Departamento de Fisiología y Farmacología, Laboratorio de Neurofisiología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, México.,Departamento de Morfología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, México
| | - J Luis Quintanar
- Departamento de Fisiología y Farmacología, Laboratorio de Neurofisiología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Aguascalientes, México
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Kurniawan VR, Islam AA, Adhimarta W, Zainuddin AA, Widodo D, Nasrullah, Ihwan A, Wahyudi, Faruk M. The role of diphenhydramine HCl on tumor necrosis factor-α levels in wistar rats with traumatic brain injury: An in vivo study. Ann Med Surg (Lond) 2022; 81:104399. [PMID: 36147062 PMCID: PMC9486624 DOI: 10.1016/j.amsu.2022.104399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/11/2022] [Accepted: 08/12/2022] [Indexed: 10/27/2022] Open
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Energy restriction induced SIRT6 inhibits microglia activation and promotes angiogenesis in cerebral ischemia via transcriptional inhibition of TXNIP. Cell Death Dis 2022; 13:449. [PMID: 35562171 PMCID: PMC9095711 DOI: 10.1038/s41419-022-04866-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 04/13/2022] [Accepted: 04/19/2022] [Indexed: 12/14/2022]
Abstract
Energy restriction (ER) protects against cerebral ischemic injury, but the underlying mechanism remains largely unclear. Here, rats were fed ad libitum (AL) or on an alternate-day food deprivation intermittent fasting (IF) diet for 3 months, followed by middle cerebral artery occlusion (MCAO) surgery. The body weight, infarct volume, and neurological deficit score were accessed at the designated time points. ELISA, qRT-PCR, and Western blotting were used to determine cytokine secretion and the expression of SIRT6, TXNIP, and signaling molecules, respectively. Immunofluorescence evaluated microglial activation and angiogenesis in vivo. For in vitro study, oxygen-glucose deprivation/reoxygenation (OGD/R)-treated cell model was generated. MTT and tube formation assays were employed to determine cell viability and tube formation capability. ChIP assay detected chromatin occupancy of SIRT6 and SIRT6-mediated H3 deacetylation. We found that IF or ER mimetics ameliorated cerebral ischemic brain damage and microglial activation, and potentiated angiogenesis in vivo. ER mimetics or SIRT6 overexpression alleviated cerebral ischemia and reperfusion (I/R)-induced injury in vitro. SIRT6 suppressed TXNIP via deacetylation of H3K9ac and H3K56ac in HAPI cells and BMVECs. Downregulation of SIRT6 reversed ER mimetics-mediated protection during cerebral I/R in vitro. Our study demonstrated that ER-mediated upregulation of SIRT6 inhibited microglia activation and potentiated angiogenesis in cerebral ischemia via suppressing TXNIP.
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Ma WY, Wang SS, Wu QL, Zhou X, Chu SF, Chen NH. The versatile role of TREM2 in regulating of microglia fate in the ischemic stroke. Int Immunopharmacol 2022; 109:108733. [PMID: 35525233 DOI: 10.1016/j.intimp.2022.108733] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 03/07/2022] [Accepted: 03/22/2022] [Indexed: 12/15/2022]
Abstract
Microglia are the earliest activated and the longest lasting immune cells after stroke, and they participate in almost all the pathological reactions after stroke. However, their regulatory mechanism has not been fully elucidated. Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor that is mainly expressed in microglia of the central nervous system. The receptor plays an important role in regulating microglia energy metabolism and phenotypic transformation. At present, TREM2 has been developed as a potential target for AD, coronary atherosclerosis and other diseases. However, TREM2 does not provide a systematic summary of the functional transformation and intrinsic molecular mechanisms of microglia after stroke. In this paper, we have summarized the functional changes of TREM2 in microglia after stroke in recent years, and found that TREM2 has important effects on energy metabolism, phagocytosis and anti-inflammatory function of microglia after stroke, suggesting that TREM2 is a potential therapeutic target for the treatment of stroke.
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Affiliation(s)
- Wen-Yu Ma
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Sha-Sha Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Qing-Lin Wu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Xin Zhou
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medical & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Shi-Feng Chu
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medical & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
| | - Nai-Hong Chen
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medical & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
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Zhao B, Jiang X. hsa-miR-518-5p/hsa-miR-3135b Regulates the REL/SOD2 Pathway in Ischemic Cerebral Infarction. Front Neurol 2022; 13:852013. [PMID: 35481271 PMCID: PMC9038098 DOI: 10.3389/fneur.2022.852013] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 02/24/2022] [Indexed: 12/12/2022] Open
Abstract
ObjectivesIschemic cerebral infarction (ICI) is a fatal neurovascular disorder. A bioinformatics approach based on single-cell and bulk RNA-seq analyses was applied to investigate the pathways and genes involved in ICI and study the expression profile of these genes.MethodsFirst, the aberrantly regulated “small-molecule ribonucleic acids” [microRNA (miRNAs)] and messenger RNAs (mRNAs) were analyzed using transcriptome data from the ischemic brain infarction dataset of the Gene Expression Omnibus (GEO) database. In mouse cerebrovascular monocytes, the single-cell regulatory network inference and clustering (SCENIC) workflow was used to identify key transcription factors (TFs). Then, the two miRNA-TF-mRNA interaction networks were constructed. Moreover, the molecular complex detection (MCODE) extracted the core sub-networks and identified the important TFs within these sub-networks. Finally, whole blood samples were collected for validation of the expression of critical molecules in ICI.ResultsWe identified four cell types and 266 regulons in mouse cerebrovascular monocytes using SCENIC analysis. Moreover, 112 differently expressed miRNAs and 3,780 differentially expressed mRNAs were identified. We discovered potential biomarkers in ICI by building a miRNA-TF-mRNA interaction network. The hsa-miR-518-5p/hsa-miR-3135b/REL/SOD2 was found to play a potential role in ICI progression. The expression of REL and superoxide dismutase 2 (SOD2) was significantly elevated in the ICI group in the clinical cohort (P < 0.05). Furthermore, a REL expression was elevated in endothelial cells and fibroblasts at the single-cell level, indicating that REL is a cell-specific regulon. Functional enrichment analyses revealed that REL is primarily engaged in neurotransmitter activity and oxidative phosphorylation.ConclusionsOur research uncovered novel biomarkers for ICI of neurovascular disease. The hsa-miR-518-5p/hsa-miR-3135b may regulate the REL/SOD2 pathway in ICI progression.
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Markwell SM, Ross JL, Olson CL, Brat DJ. Necrotic reshaping of the glioma microenvironment drives disease progression. Acta Neuropathol 2022; 143:291-310. [PMID: 35039931 DOI: 10.1007/s00401-021-02401-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 12/13/2022]
Abstract
Glioblastoma is the most common primary brain tumor and has a dismal prognosis. The development of central necrosis represents a tipping point in the evolution of these tumors that foreshadows aggressive expansion, swiftly leading to mortality. The onset of necrosis, severe hypoxia and associated radial glioma expansion correlates with dramatic tumor microenvironment (TME) alterations that accelerate tumor growth. In the past, most have concluded that hypoxia and necrosis must arise due to "cancer outgrowing its blood supply" when rapid tumor growth outpaces metabolic supply, leading to diffusion-limited hypoxia. However, growing evidence suggests that microscopic intravascular thrombosis driven by the neoplastic overexpression of pro-coagulants attenuates glioma blood supply (perfusion-limited hypoxia), leading to TME restructuring that includes breakdown of the blood-brain barrier, immunosuppressive immune cell accumulation, microvascular hyperproliferation, glioma stem cell enrichment and tumor cell migration outward. Cumulatively, these adaptations result in rapid tumor expansion, resistance to therapeutic interventions and clinical progression. To inform future translational investigations, the complex interplay among environmental cues and myriad cell types that contribute to this aggressive phenotype requires better understanding. This review focuses on contributions from intratumoral thrombosis, the effects of hypoxia and necrosis, the adaptive and innate immune responses, and the current state of targeted therapeutic interventions.
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Affiliation(s)
- Steven M Markwell
- Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave. Ward 3-140, Chicago, IL, USA
| | - James L Ross
- Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA
| | - Cheryl L Olson
- Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave. Ward 3-140, Chicago, IL, USA
| | - Daniel J Brat
- Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave. Ward 3-140, Chicago, IL, USA.
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MacKenzie JL, Ivanova N, Nell HJ, Giordano CR, Terlecky SR, Agca C, Agca Y, Walton PA, Whitehead SN, Cechetto DF. Microglial inflammation and cognitive dysfunction in comorbid rat models of striatal ischemic stroke and alzheimer’s disease: effects of antioxidant catalase-SKL on behavioral and cellular pathology. Neuroscience 2022; 487:47-65. [DOI: 10.1016/j.neuroscience.2022.01.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 01/26/2022] [Accepted: 01/28/2022] [Indexed: 12/25/2022]
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35
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Gao H, Ju F, Ti R, Zhang Y, Zhang S. Differential Regulation of Microglial Activation in Response to Different Degree of Ischemia. Front Immunol 2022; 13:792638. [PMID: 35154109 PMCID: PMC8831277 DOI: 10.3389/fimmu.2022.792638] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 01/11/2022] [Indexed: 11/13/2022] Open
Abstract
Microglia are primary immune cells within the brain and are rapidly activated after cerebral ischemia. The degree of microglial activation is closely associated with the severity of ischemia. However, it remains largely unclear how microglial activation is differentially regulated in response to a different degree of ischemia. In this study, we used a bilateral common carotid artery ligation (BCAL) model and induced different degrees of ischemia by varying the duration of ligation to investigate the microglial response in CX3CR1GFP/+ mice. Confocal microscopy, immunofluorescence staining, RNA sequencing, and qRT-PCR were used to evaluate the de-ramification, proliferation, and differential gene expression associated with microglial activation. Our results showed that 30 min of ischemia induced rapid de-ramification of microglia but did not have significant influence on the microglial density. In contrast, 60 min of ischemia led to a significant decrease in microglial density and more pronounced de-ramification of microglial processes. Importantly, 30 min of ischemia did not induce proliferation of microglia, but 60 min of ischemia led to a marked increase in the density of proliferative microglia. Further analysis utilized transcriptome sequencing showed that microglial activation is differentially regulated in response to different degrees of ischemia. A total of 1,097 genes were differentially regulated after 60 min of ischemia, but only 68 genes were differentially regulated after 30 min of ischemia. Pathway enrichment analysis showed that apoptosis, cell mitosis, immune receptor activity and inflammatory-related pathways were highly regulated after 60 min of ischemia compared to 30 min of ischemia. Multiple microglia-related genes such as Cxcl10, Tlr7, Cd86, Tnfrsf1a, Nfkbia, Tgfb1, Ccl2 and Il-6, were upregulated with prolonged ischemia. Pharmacological inhibition of CSF1 receptor demonstrated that CSF1R signaling pathway contributed to microglial proliferation. Together, these results suggest that the proliferation of microglia is gated by the duration of ischemia and microglia were differentially activated in responding to different degrees of ischemia.
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36
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Hamner MA, McDonough A, Gong DC, Todd LJ, Rojas G, Hodecker S, Ransom CB, Reh TA, Ransom BR, Weinstein JR. Microglial depletion abolishes ischemic preconditioning in white matter. Glia 2021; 70:661-674. [PMID: 34939240 DOI: 10.1002/glia.24132] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 12/10/2021] [Accepted: 12/10/2021] [Indexed: 01/17/2023]
Abstract
Ischemic preconditioning (IPC) is a phenomenon whereby a brief, non-injurious ischemic exposure enhances tolerance to a subsequent ischemic challenge. The mechanism of IPC has mainly been studied in rodent stroke models where gray matter (GM) constitutes about 85% of the cerebrum. In humans, white matter (WM) is 50% of cerebral volume and is a critical component of stroke damage. We developed a novel CNS WM IPC model using the mouse optic nerve (MON) and identified the involved immune signaling pathways. Here we tested the hypothesis that microglia are necessary for WM IPC. Microglia were depleted by treatment with the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX5622. MONs were exposed to transient ischemia in vivo, acutely isolated 72 h later, and subjected to oxygen-glucose deprivation (OGD) to simulate a severe ischemic injury (i.e., stroke). Functional and structural axonal recovery was assessed by recording compound action potentials (CAPs) and by microscopy using quantitative stereology. Microglia depletion eliminated IPC-mediated protection. In control mice, CAP recovery was improved in preconditioned MONs compared with non-preconditioned MONs, however, in PLX5622-treated mice, we observed no difference in CAP recovery between preconditioned and non-preconditioned MONs. Microgliadepletion also abolished IPC protective effects on axonal integrity and survival of mature (APC+ ) oligodendrocytes after OGD. IPC-mediated protection was independent of retinal injury suggesting it results from mechanistic processes intrinsic to ischemia-exposed WM. We conclude that preconditioned microglia are critical for IPC in WM. The "preconditioned microglia" phenotype might protect against other CNS pathologies and is a neurotherapeutic horizon worth exploring.
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Affiliation(s)
- Margaret A Hamner
- Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, USA
| | - Ashley McDonough
- Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, USA
| | - Davin C Gong
- Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, USA
| | - Levi J Todd
- Department of Biological Structure, School of Medicine, University of Washington, Seattle, Washington, USA
| | - German Rojas
- Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, USA
| | - Sibylle Hodecker
- Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, USA
| | - Christopher B Ransom
- Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, USA
| | - Thomas A Reh
- Department of Biological Structure, School of Medicine, University of Washington, Seattle, Washington, USA
| | - Bruce R Ransom
- Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, USA.,Neuroscience Department, City University of Hong Kong, Kowloon, Hong Kong
| | - Jonathan R Weinstein
- Department of Neurology, School of Medicine, University of Washington, Seattle, Washington, USA.,Department of Neurological Surgery, School of Medicine, University of Washington, Seattle, Washington, USA
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Jurcau A, Simion A. Neuroinflammation in Cerebral Ischemia and Ischemia/Reperfusion Injuries: From Pathophysiology to Therapeutic Strategies. Int J Mol Sci 2021; 23:14. [PMID: 35008440 PMCID: PMC8744548 DOI: 10.3390/ijms23010014] [Citation(s) in RCA: 223] [Impact Index Per Article: 55.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 12/18/2021] [Accepted: 12/18/2021] [Indexed: 02/07/2023] Open
Abstract
Its increasing incidence has led stroke to be the second leading cause of death worldwide. Despite significant advances in recanalization strategies, patients are still at risk for ischemia/reperfusion injuries in this pathophysiology, in which neuroinflammation is significantly involved. Research has shown that in the acute phase, neuroinflammatory cascades lead to apoptosis, disruption of the blood-brain barrier, cerebral edema, and hemorrhagic transformation, while in later stages, these pathways support tissue repair and functional recovery. The present review discusses the various cell types and the mechanisms through which neuroinflammation contributes to parenchymal injury and tissue repair, as well as therapeutic attempts made in vitro, in animal experiments, and in clinical trials which target neuroinflammation, highlighting future therapeutic perspectives.
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Affiliation(s)
- Anamaria Jurcau
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania;
- Neurology Ward, Clinical Municipal Hospital “dr. G. Curteanu” Oradea, 410154 Oradea, Romania
| | - Aurel Simion
- Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania;
- Neurorehabilitation Ward, Clinical Municipal Hospital “dr. G. Curteanu” Oradea, 410154 Oradea, Romania
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Wang L, Deng Z, Zhao Y, Yuan R, Yang M, Zhang Y, Li Y, Liu Y, Zhou F, Kang H. Mesenchymal stem cells regulate activation of microglia cells to improve hippocampal injury of heat stroke rats. J Therm Biol 2021; 101:103081. [PMID: 34879909 DOI: 10.1016/j.jtherbio.2021.103081] [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: 05/12/2021] [Revised: 08/05/2021] [Accepted: 08/12/2021] [Indexed: 10/20/2022]
Abstract
Heat stroke is a severe systemic inflammatory response disease caused by high fever, mainly with nervous system damage. Mesenchymal stem cells (MSCs) are currently believed to have anti-inflammation and immunomodulatory effects. Therefore, we aimed to explore the protective effect and mechanism of MSCs on heat stroke-induced excessive inflammation and neurological dysfunction. We established a heat stroke model in rats under conditions of continuous high temperature and high humidity. After modeling, rats were randomly divided into heat stroke model group, MSCs treatment group and normal temperature control group without any treatment. We performed survival analysis, neurological deficit score, histological staining of hippocampus and cerebellum, immunofluorescence staining of microglia, detection of inflammatory and chemokine levels in the hippocampus and cerebellum in each group. We found that MSCs treatment not only significantly reduced early (day 3) and late (day 28) mortality, but also prominently reduced nerve injury in heat stroke rats, and improved pathology and neuronal cell damage in the hippocampus and cerebellum. In addition, MSCs treatment can significantly inhibit the over-activation of hippocampal microglia in heat stroke rats and the levels of pro-inflammatory factors and chemokines in the hippocampus. Early treatment of MSCs can greatly promote the activation of cerebellar microglia in heat stroke rats. Meanwhile, MSCs treatment has an inhibitory effect on the level of chemokine in the cerebellum of rats in the early stage of heat stroke. In conclusion, the application of MSCs in the treatment of heat stroke in rats can significantly reduce mortality and neurological deficits and improve hippocampal damage, possibly by inhibiting the excessive activation of hippocampal microglia in heat stroke rats.
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Affiliation(s)
- Lu Wang
- Medical School of Chinese PLA, Beijing, China; Department of Critical Care Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China.
| | - Zihui Deng
- Department of Biochemistry, Graduate School, Chinese PLA General Hospital, Beijing, China.
| | - Yan Zhao
- Department of Critical Care Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China.
| | - Rui Yuan
- Medical School of Chinese PLA, Beijing, China; Department of Critical Care Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China.
| | - Mengmeng Yang
- Department of Critical Care Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China.
| | - Yu Zhang
- Department of Critical Care Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China.
| | - Yun Li
- Medical School of Chinese PLA, Beijing, China; Department of Critical Care Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China.
| | - Yuyan Liu
- Medical School of Chinese PLA, Beijing, China; Department of Critical Care Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China.
| | - Feihu Zhou
- Department of Critical Care Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China.
| | - Hongjun Kang
- Department of Critical Care Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China.
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Soares NL, Vieira HLA. Microglia at the Centre of Brain Research: Accomplishments and Challenges for the Future. Neurochem Res 2021; 47:218-233. [PMID: 34586585 DOI: 10.1007/s11064-021-03456-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/17/2021] [Accepted: 09/20/2021] [Indexed: 02/08/2023]
Abstract
Microglia are the immune guardians of the central nervous system (CNS), with critical functions in development, maintenance of homeostatic tissue balance, injury and repair. For a long time considered a forgotten 'third element' with basic phagocytic functions, a recent surge in interest, accompanied by technological progress, has demonstrated that these distinct myeloid cells have a wide-ranging importance for brain function. This review reports microglial origins, development, and function in the healthy brain. Moreover, it also targets microglia dysfunction and how it contributes to the progression of several neurological disorders, focusing on particular molecular mechanisms and whether these may present themselves as opportunities for novel, microglia-targeted therapeutic approaches, an ever-enticing prospect. Finally, as it has been recently celebrated 100 years of microglia research, the review highlights key landmarks from the past century and looked into the future. Many challenging problems have arisen, thus it points out some of the most pressing questions and experimental challenges for the ensuing century.
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Affiliation(s)
- Nuno L Soares
- Chronic Diseases Research Center (CEDOC) - Faculdade de Ciências Médicas/NOVA Medical School, Universidade Nova de Lisboa, Campo dos Mártires da Pátria 130, 1169-056, Lisboa, Portugal.
| | - Helena L A Vieira
- Chronic Diseases Research Center (CEDOC) - Faculdade de Ciências Médicas/NOVA Medical School, Universidade Nova de Lisboa, Campo dos Mártires da Pátria 130, 1169-056, Lisboa, Portugal.,Department of Chemistry, UCIBIO, Applied Molecular Biosciences Unit, NOVA School of Science and Technology, Universidade Nova de Lisboa, Lisboa, Portugal.,Associate Laboratory i4HB - Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, Lisboa, Portugal
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40
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Klichkhanov NK, Dzhafarova AM. Effect of Mild Hypothermia on the Catalytic Characteristics of Synaptic Acetylcholinesterase during Subtotal Global Cerebral Ischemia in Rats. NEUROCHEM J+ 2021. [DOI: 10.1134/s1819712421030077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Salminen A, Kaarniranta K, Kauppinen A. Hypoxia/ischemia impairs CD33 (Siglec-3)/TREM2 signaling: Potential role in Alzheimer's pathogenesis. Neurochem Int 2021; 150:105186. [PMID: 34530055 DOI: 10.1016/j.neuint.2021.105186] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/10/2021] [Accepted: 09/12/2021] [Indexed: 12/22/2022]
Abstract
Recent genetic and molecular studies have indicated that the innate immune system, especially microglia, have a crucial role in the accumulation of β-amyloid plaques in Alzheimer's disease (AD). In particular, the CD33 receptor, also called Siglec-3, inhibits the TREM2 receptor-induced phagocytic activity of microglia. CD33 receptors recognize the α2,3 and α2,6-linked sialic groups in tissue glycocalyx, especially sialylated gangliosides in human brain. The CD33 receptor triggers cell-type specific responses, e.g., in microglia, CD33 inhibits phagocytosis, whereas in natural killer cells, it inhibits the cytotoxic activity of the NKG2D receptor. Nonetheless, the regulation of the activity of CD33 receptor needs to be clarified. For example, it seems that hypoxia/ischemia, a potential cause of AD pathology, increases the expression of CD33 and its downstream target SHP-1, a tyrosine phosphatase which suppresses the phagocytosis driven by TREM2. Moreover, hypoxia/ischemia increases the deposition of sialylated gangliosides, e.g., GM1, GM2, GM3, and GD1, which are ligands for inhibitory CD33/Siglec-3 receptors. In addition, β-amyloid peptides bind to the sialylated gangliosides in raft-like clusters and subsequently these gangliosides act as seeds for the formation of β-amyloid plaques in AD pathology. It is known that senile plaques contain sialylated GM1, GM2, and GM3 gangliosides, i.e., the same species induced by hypoxia/ischemia treatment. Sialylated gangliosides in plaques might stimulate the CD33/Siglec-3 receptors of microglia and thus impede TREM2-driven phagocytosis. We propose that hypoxia/ischemia, e.g., via the accumulation of sialylated gangliosides, prevents the phagocytosis of β-amyloid deposits by inhibiting CD33/TREM2 signaling.
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Affiliation(s)
- Antero Salminen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
| | - Kai Kaarniranta
- Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, P.O. Box 100, FI-70029, KYS, Finland
| | - Anu Kauppinen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
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Mao Y, Qu Y, Wang Q. Cryptotanshinone reduces neurotoxicity induced by cerebral ischemia-reperfusion injury involving modulation of microglial polarization. Restor Neurol Neurosci 2021; 39:209-220. [PMID: 34219678 DOI: 10.3233/rnn-201070] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND The diterpenoid cryptotanshinone (CTS) has wide biological functions, including inhibition of tumor growth, inflammation and apoptosis. The present study aimed to explore the possible effect of CTS on cerebral ischemia/reperfusion (I/R) injury and the underlying mechanisms. METHODS Male C57BL/6J mice underwent transient middle cerebral artery occlusion (tMCAO) and murine microglia BV2 cells were challenged by Oxygen/glucose deprivation, to mimic I/R and ischemic/hypoxic and reperfusion (H/R) injury, respectively. CTS was administered 0.5 h (10 mg/kg) after the onset of MCAO or 2 h (20μM) post OGD. Infarct volume and neurological deficit were measured. Immunofluorescence, qPCR, and western blot, were performed to detect the expression of cytokines, apoptotic marker, and M1/M2 phenotype-specific genes. Flow cytometry was applied for M1/M2 subpopulation or Annexin V/PI apoptosis assessment. RESULTS CTS significantly reduced cerebral infarct volume, neurologic deficit scores, pro-inflammatory cytokine production (IL-6, TNF-α, and IL-1β), apoptotic protein expression (cleaved caspase-3) of mice after tMCAO challenge. Furthermore, CTS attenuated CD16+ M1-type and elevated CD206+ M2-type microglia in vivo or in vitro. CONCLUSIONS We propose that the neuroprotective effect of CTS in the I/R or H/R context are explained modulation of microglial polarization, suggesting therapeutic potential for cerebral ischemic stroke.
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Affiliation(s)
- Yanfang Mao
- Department of Neurology, Liaocheng People's Hospital, Liaocheng, Shandong, China
| | - Yang Qu
- Department of Neurology, Liaocheng People's Hospital, Liaocheng, Shandong, China
| | - Qingdong Wang
- Department of Neurology, Liaocheng People's Hospital, Liaocheng, Shandong, China
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Wang J, Zhang Q, Lu Y, Dong Y, Dhandapani KM, Brann DW, Yu RK. Ganglioside GD3 is up-regulated in microglia and regulates phagocytosis following global cerebral ischemia. J Neurochem 2021; 158:737-752. [PMID: 34133773 DOI: 10.1111/jnc.15455] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/24/2021] [Accepted: 06/09/2021] [Indexed: 01/03/2023]
Abstract
Gangliosides, the major sialic-acid containing glycosphingolipids in the mammalian brain, play important roles in brain development and neural functions. Here, we show that the b-series ganglioside GD3 and its biosynthetic enzyme, GD3-synthase (GD3S), were up-regulated predominantly in the microglia of mouse hippocampus from 2 to 7 days following global cerebral ischemia (GCI). Interestingly, GD3S knockout (GD3S-KO) mice exhibited decreased hippocampal neuronal loss following GCI, as compared to wild-type (WT) mice. While comparable levels of astrogliosis and microglial proliferation were observed between WT and GD3S-KO mice, the phagocytic capacity of the GD3S-KO microglia was significantly compromised after GCI. At 2 and 4 days following GCI, the GD3S-KO microglia demonstrated decreased amoebic morphology, reduced neuronal material engulfment, and lower expression of the phagolysosome marker CD68, as compared to the WT microglia. Finally, by using a microglia-primary neuron co-culture model, we demonstrated that the GD3S-KO microglia isolated from mouse brains at 2 days after GCI are less neurotoxic to co-cultured hippocampal neurons than the WT-GCI microglia. Moreover, the percentage of microglia with engulfed neuronal elements in the co-cultured wells was also significantly decreased in the GD3S-KO mice after GCI. Interestingly, the impaired phagocytic capacity of GD3S-KO microglia could be partially restored by pre-treatment with exogenous ganglioside GD3. Altogether, this study provides functional evidence that ganglioside GD3 regulates phagocytosis by microglia in an ischemic stroke model. Our data also suggest that the GD3-linked microglial phagocytosis may contribute to the mechanism of delayed neuronal death following ischemic brain injury.
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Affiliation(s)
- Jing Wang
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Quanguang Zhang
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Yujiao Lu
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Yan Dong
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Krishnan M Dhandapani
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Darrell W Brann
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Robert K Yu
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
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Kim GS, Stephenson JM, Al Mamun A, Wu T, Goss MG, Min JW, Li J, Liu F, Marrelli SP. Determining the effect of aging, recovery time, and post-stroke memantine treatment on delayed thalamic gliosis after cortical infarct. Sci Rep 2021; 11:12613. [PMID: 34131204 PMCID: PMC8206333 DOI: 10.1038/s41598-021-91998-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 06/03/2021] [Indexed: 12/18/2022] Open
Abstract
Secondary injury following cortical stroke includes delayed gliosis and eventual neuronal loss in the thalamus. However, the effects of aging and the potential to ameliorate this gliosis with NMDA receptor (NMDAR) antagonism are not established. We used the permanent distal middle cerebral artery stroke model (pdMCAO) to examine secondary thalamic injury in young and aged mice. At 3 days post-stroke (PSD3), slight microgliosis (IBA-1) and astrogliosis (GFAP) was evident in thalamus, but no infarct. Gliosis increased dramatically through PSD14, at which point degenerating neurons were detected. Flow cytometry demonstrated a significant increase in CD11b+/CD45int microglia (MG) in the ipsilateral thalamus at PSD14. CCR2-RFP reporter mouse further demonstrated that influx of peripheral monocytes contributed to the MG/Mϕ population. Aged mice demonstrated reduced microgliosis and astrogliosis compared with young mice. Interestingly, astrogliosis demonstrated glial scar-like characteristics at two years post-stroke, but not by 6 weeks. Lastly, treatment with memantine (NMDAR antagonist) at 4 and 24 h after stroke significantly reduced gliosis at PSD14. These findings expand our understanding of gliosis in the thalamus following cortical stroke and demonstrate age-dependency of this secondary injury. Additionally, these findings indicate that delayed treatment with memantine (an FDA approved drug) provides significant reduction in thalamic gliosis.
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Affiliation(s)
- Gab Seok Kim
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin St, Houston, TX, 77030, USA
| | - Jessica M Stephenson
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin St, Houston, TX, 77030, USA
| | - Abdullah Al Mamun
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin St, Houston, TX, 77030, USA
| | - Ting Wu
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin St, Houston, TX, 77030, USA
| | - Monica G Goss
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin St, Houston, TX, 77030, USA
| | - Jia-Wei Min
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin St, Houston, TX, 77030, USA
| | - Jun Li
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin St, Houston, TX, 77030, USA
| | - Fudong Liu
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin St, Houston, TX, 77030, USA
| | - Sean P Marrelli
- Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin St, Houston, TX, 77030, USA.
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Naseh M, Vatanparast J, Rafati A, Bayat M, Haghani M. The emerging role of FTY720 as a sphingosine 1-phosphate analog for the treatment of ischemic stroke: The cellular and molecular mechanisms. Brain Behav 2021; 11:e02179. [PMID: 33969931 PMCID: PMC8213944 DOI: 10.1002/brb3.2179] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 04/23/2021] [Accepted: 04/25/2021] [Indexed: 12/28/2022] Open
Abstract
Finding novel and effective drugs for the treatment of ischemic stroke is warranted because there is not a definitive treatment for this prevalent disease. Due to the relevance between the sphingosine 1-phosphate (S1P) receptor and several neurological diseases including ischemic stroke, it seems that fingolimod (FTY720), as an agonist of S1P receptor, can be a useful therapeutic strategy in these patients. FTY720 is the first oral drug approved by the US food and drug administration for the treatment of multiple sclerosis. Three important mechanisms for neuroprotective effects of FTY720 have been described. First, the functional antagonistic mechanism that is associated with lymphopenia and reduced lymphocytic inflammation. This effect results from the down-regulation and degradation of lymphocytes' S1P receptors, which inhibits lymph node lymphocytes from entering the bloodstream. Second, a functional agonistic activity that is mediated through direct effects via targeting S1P receptors on the membrane of various cells including neurons, microglia, oligodendrocytes, astrocytes, and endothelial cells of blood vessels in the central nervous system (CNS), and the third, receptor-independent mechanisms that are displayed by binding to specific cellular proteins that modulate intracellular signaling pathways or affect epigenetic transcriptions. Therefore, we review these mechanisms in more detail and describe the animal model and in clinical trial studies that support these three mechanisms for the neuroprotective action of FTY720 in ischemic stroke.
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Affiliation(s)
- Maryam Naseh
- Histomorphometry and Stereology Research CentreShiraz University of Medical SciencesShirazIran
| | | | - Ali Rafati
- Histomorphometry and Stereology Research CentreShiraz University of Medical SciencesShirazIran
- Department of PhysiologyShiraz University of Medical SciencesShirazIran
| | - Mahnaz Bayat
- Clinical Neurology Research CenterShiraz University of Medical SciencesShirazIran
| | - Masoud Haghani
- Histomorphometry and Stereology Research CentreShiraz University of Medical SciencesShirazIran
- Department of PhysiologyShiraz University of Medical SciencesShirazIran
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New epigenetic players in stroke pathogenesis: From non-coding RNAs to exosomal non-coding RNAs. Biomed Pharmacother 2021; 140:111753. [PMID: 34044272 PMCID: PMC8222190 DOI: 10.1016/j.biopha.2021.111753] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/22/2021] [Accepted: 05/19/2021] [Indexed: 12/17/2022] Open
Abstract
Non-coding RNAs (ncRNAs) have critical role in the pathophysiology as well as recovery after ischemic stroke. ncRNAs, particularly microRNAs, and the long non-coding RNAs (lncRNAs) are critical for angiogenesis and neuroprotection, and they have been suggested to be therapeutic, diagnostic and prognostic tools in cerebrovascular diseases, including stroke. Moreover, exosomes have been considered as nanocarriers capable of transferring various cargos, such as lncRNAs and miRNAs to recipient cells, with prominent inter-cellular roles in the mediation of neuro-restorative events following strokes and neural injuries. In this review, we summarize the pathogenic role of ncRNAs and exosomal ncRNAs in the stroke.
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Li C, Li J, Loreno EG, Miriyala S, Panchatcharam M, Lu X, Sun H. Chronic Low-Dose Alcohol Consumption Attenuates Post-Ischemic Inflammation via PPARγ in Mice. Int J Mol Sci 2021; 22:ijms22105121. [PMID: 34066125 PMCID: PMC8150922 DOI: 10.3390/ijms22105121] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/04/2021] [Accepted: 05/07/2021] [Indexed: 01/17/2023] Open
Abstract
Ischemic stroke is one of the leading causes of death and permanent disability in adults. Recently, we found that light alcohol consumption (LAC) suppresses post-ischemic inflammatory response, which plays an important role in ischemic brain damage. Our goal was to determine the role of peroxisome proliferator-activated receptor-gamma (PPARγ) in the anti-inflammatory effect of LAC against transient focal cerebral ischemia. In in vivo study, male C57BL/6J wild type (WT) and endothelial-specific conditional PPARγ knockout mice were gavage fed with 0.7 g/kg/day ethanol or volume-matched water daily for 8 weeks. From the 7th week, 3 mg/kg/day GW9662 (a selective PPARγ antagonist) was intraperitoneally given for two weeks. Cerebral ischemia/reperfusion (I/R) injury and expression of manganese superoxide dismutase (MnSOD) and adhesion molecules, neutrophil infiltration, and microglial activation in the cerebral cortex before and following a 90 min unilateral middle cerebral artery occlusion (MCAO)/24 h reperfusion were evaluated. In in vitro study, the impact of chronic alcohol exposure on expression of PPARγ and MnSOD in C57BL/6J mouse brain microvascular endothelial cells (MBMVECs) was measured. PPARγ and MnSOD were significantly upregulated in the cerebral cortex of ethanol-fed WT mice and low-concentration ethanol-exposed C57BL/6J MBMVECs. GW9662 significantly inhibited alcohol-induced upregulation of MnSOD. Eight-week ethanol feeding significantly reduced cerebral I/R injury and alleviated the post-ischemic inflammatory response (upregulation of intercellular adhesion molecule-1 (ICAM-1) and E-selectin, microglial activation, and neutrophil infiltration). Treatment with GW9662 and endothelial-specific conditional knockout of PPARγ did not alter cerebral I/R injury and the inflammatory response in the control mice but abolish the neuroprotective effect in ethanol-fed mice. In addition, GW9662 and endothelial-specific conditional knockout of PPARγ diminished the inhibitory effect of LAC on the post-ischemic expression of adhesion molecules and neutrophil infiltration. Our findings suggest that LAC may protect against cerebral I/R injury by suppressing the post-ischemic inflammation via activation of PPARγ.
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Affiliation(s)
- Chun Li
- Department of Cellular Biology and Anatomy, LSUHSC-Shreveport, Shreveport, LA 71130, USA; (C.L.); (J.L.); (E.G.L.); (S.M.); (M.P.)
| | - Jiyu Li
- Department of Cellular Biology and Anatomy, LSUHSC-Shreveport, Shreveport, LA 71130, USA; (C.L.); (J.L.); (E.G.L.); (S.M.); (M.P.)
| | - Ethyn G. Loreno
- Department of Cellular Biology and Anatomy, LSUHSC-Shreveport, Shreveport, LA 71130, USA; (C.L.); (J.L.); (E.G.L.); (S.M.); (M.P.)
| | - Sumitra Miriyala
- Department of Cellular Biology and Anatomy, LSUHSC-Shreveport, Shreveport, LA 71130, USA; (C.L.); (J.L.); (E.G.L.); (S.M.); (M.P.)
| | - Manikandan Panchatcharam
- Department of Cellular Biology and Anatomy, LSUHSC-Shreveport, Shreveport, LA 71130, USA; (C.L.); (J.L.); (E.G.L.); (S.M.); (M.P.)
| | - Xiaohong Lu
- Department of Pharmacology, Toxicology & Neuroscience, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71130, USA;
| | - Hong Sun
- Department of Cellular Biology and Anatomy, LSUHSC-Shreveport, Shreveport, LA 71130, USA; (C.L.); (J.L.); (E.G.L.); (S.M.); (M.P.)
- Correspondence: ; Tel.: +1-(318)-675-4566; Fax: +1-(318)-675-5889
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Yu H, Xu Z, Qu G, Wang H, Lin L, Li X, Xie X, Lei Y, He X, Chen Y, Li Y. Hypoxic Preconditioning Enhances the Efficacy of Mesenchymal Stem Cells-Derived Conditioned Medium in Switching Microglia toward Anti-inflammatory Polarization in Ischemia/Reperfusion. Cell Mol Neurobiol 2021; 41:505-524. [PMID: 32424775 PMCID: PMC11448619 DOI: 10.1007/s10571-020-00868-5] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 05/05/2020] [Indexed: 02/07/2023]
Abstract
Activation of pro-inflammatory microglia is an important mechanism of the cerebral ischemia-reperfusion (I/R)-induced neuronal injury and dysfunction. Mesenchymal stem cells (MSCs) together with their paracrine factors demonstrated curative potential in immune disorders and inflammatory diseases, as well as in ischemic diseases. However, it remains unclear whether conditioned medium from MSCs could effectively regulate the activation and polarization of microglia exposed to I/R stimulation. In this study, we investigated the effects of conditioned medium from bone marrow MSCs (BMSCs-CM) on I/R-stimulated microglia and the potential mechanism involved, as well as the way to obtain more effective BMSCs-CM. First, cell model of oxygen-glucose deprivation/reoxygenation (OGD/R) was established in microglia to mimic the I/R. BMSCs-CM from different culture conditions (normoxic: 21% O2; hypoxic: 1% O2; hypoxia preconditioning: preconditioning with 1% O2 for 24 h) was used to treat the microglia. Our results showed that BMSCs-CM effectively promoted the survival and alleviated the injury of microglia. Moreover, in microglia exposed to OGD/R, BMSCs-CM inhibited significantly the expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), CD86 and inducible nitric oxide synthase, whereas upregulated the levels of anti-inflammatory cytokine (IL-10), CD206 and Arginase-1. These results suggested that BMSCs-CM promoted the polarization of anti-inflammatory microglia. In particular, BMSCs-CM from cultures with hypoxia preconditioning was more effective in alleviating cell injury and promoting anti-inflammatory microglia polarization than BMSCs-CM from normoxic cultures and from hypoxic cultures. Furthermore, inhibition of exosomes secretion could largely mitigate these effects of BMSCs-CM. In conclusion, our results suggested that hypoxia preconditioning of BMSCs could enhance the efficacy of BMSCs-CM in alleviating OGD/R-induced injury and in promoting the anti-inflammatory polarization of microglia, and these beneficial effects of BMSCs-CM owed substantially to exosomes.
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Affiliation(s)
- Han Yu
- Department of Pathophysiology & Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
- Department of Pathology, The Affiliated Hospital of Hubei University of Medicine, The First People's Hospital of Xiangyang, Xiangyang, 441000, China
| | - Zhihong Xu
- Department of Pathophysiology & Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Gaojing Qu
- Department of Pathophysiology & Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Huimin Wang
- Department of Pathophysiology & Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Lulu Lin
- Department of Pathophysiology & Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Xianyu Li
- Department of Pathophysiology & Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Xiaolin Xie
- Department of Pathophysiology & Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Yifeng Lei
- The Institute of Technological Sciences & School of Power and Mechanical Engineering, Wuhan University, Wuhan, 430072, China
| | - Xiaohua He
- Department of Pathophysiology & Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Yun Chen
- Department of Biomedical Engineering, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Yinping Li
- Department of Pathophysiology & Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
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Li T, Zhao J, Xie W, Yuan W, Guo J, Pang S, Gan WB, Gómez-Nicola D, Zhang S. Specific depletion of resident microglia in the early stage of stroke reduces cerebral ischemic damage. J Neuroinflammation 2021; 18:81. [PMID: 33757565 PMCID: PMC7986495 DOI: 10.1186/s12974-021-02127-w] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 03/11/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Ischemia can induce rapid activation of microglia in the brain. As key immunocompetent cells, reactive microglia play an important role in pathological development of ischemic stroke. However, the role of activated microglia during the development of ischemia remains controversial. Thus, we aimed to investigate the function of reactive microglia in the early stage of ischemic stroke. METHODS A Rose Bengal photothrombosis model was applied to induce targeted ischemic stroke in mice. CX3CR1CreER:R26iDTR mice were used to specifically deplete resident microglia through intragastric administration of tamoxifen (Ta) and intraperitoneal injection of diphtheria toxin (DT). At day 3 after ischemic stroke, behavioral tests were performed. After that, mouse brains were collected for further histological analysis and detection of mRNA expression of inflammatory factors. RESULTS The results showed that specific depletion of microglia resulted in a significant decrease in ischemic infarct volume and improved performance in motor ability 3 days after stroke. Microglial depletion caused a remarkable reduction in the densities of degenerating neurons and inducible nitric oxide synthase positive (iNOS+) cells. Importantly, depleting microglia induced a significant increase in the mRNA expression level of anti-inflammatory factors TGF-β1, Arg1, IL-10, IL-4, and Ym1 as well as a significant decline of pro-inflammatory factors TNF-α, iNOS, and IL-1β 3 days after stroke. CONCLUSIONS These results suggest that activated microglia is an important modulator of the brain's inflammatory response in stroke, contributing to neurological deficit and infarct expansion. Modulation of the inflammatory response through the elimination of microglia at a precise time point may be a promising therapeutic approach for the treatment of cerebral ischemia.
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Affiliation(s)
- Ting Li
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, No. 222 South Tianshui Road, Lanzhou, Gansu, 730000, People's Republic of China
| | - Jin Zhao
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, No. 222 South Tianshui Road, Lanzhou, Gansu, 730000, People's Republic of China
| | - Wenguang Xie
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, No. 222 South Tianshui Road, Lanzhou, Gansu, 730000, People's Republic of China
| | - Wanru Yuan
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, No. 222 South Tianshui Road, Lanzhou, Gansu, 730000, People's Republic of China
| | - Jing Guo
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, No. 222 South Tianshui Road, Lanzhou, Gansu, 730000, People's Republic of China
| | - Shengru Pang
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, No. 222 South Tianshui Road, Lanzhou, Gansu, 730000, People's Republic of China
| | - Wen-Biao Gan
- Molecular Neurobiology Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY, 10016, USA.
| | - Diego Gómez-Nicola
- Centre for Biological Sciences, University of Southampton, South Lab and Path Block, Mail Point 840 LD80C, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK.
| | - Shengxiang Zhang
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, No. 222 South Tianshui Road, Lanzhou, Gansu, 730000, People's Republic of China.
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Shah TA, Pallera HK, Kaszowski CL, Bass WT, Lattanzio FA. Therapeutic Hypothermia Inhibits the Classical Complement Pathway in a Rat Model of Neonatal Hypoxic-Ischemic Encephalopathy. Front Neurosci 2021; 15:616734. [PMID: 33642979 PMCID: PMC7907466 DOI: 10.3389/fnins.2021.616734] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 01/25/2021] [Indexed: 01/17/2023] Open
Abstract
OBJECTIVE Complement activation is instrumental in the pathogenesis of Hypoxic-ischemic encephalopathy (HIE), a significant cause of neonatal mortality and disability worldwide. Therapeutic hypothermia (HT), the only available treatment for HIE, only modestly improves outcomes. Complement modulation as a therapeutic adjunct to HT has been considered, but is challenging due to the wide-ranging role of the complement system in neuroinflammation, homeostasis and neurogenesis in the developing brain. We sought to identify potential therapeutic targets by measuring the impact of treatment with HT on complement effector expression in neurons and glia in neonatal HIE, with particular emphasis on the interactions between microglia and C1q. METHODS The Vannucci model was used to induce HIE in term-equivalent rat pups. At P10-12, pups were randomly assigned to three different treatment groups: Sham (control), normothermia (NT), and hypothermia (HT) treatment. Local and systemic complement expression and neuronal apoptosis were measured by ELISA, TUNEL and immunofluorescence labeling, and differences compared between groups. RESULTS Treatment with HT is associated with decreased systemic and microglial expression of C1q, decreased systemic C5a levels, and decreased microglial and neuronal deposition of C3 and C9. The effect of HT on cytokines was variable with decreased expression of pro and anti-inflammatory effectors. HT treatment was associated with decreased C1q binding on cells undergoing apoptosis. CONCLUSION Our data demonstrate the extreme complexity of the immune response in neonatal HIE. We propose modulation of downstream effectors C3a and C5a as a therapeutic adjunct to HT to enhance neuroprotection in the developing brain.
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Affiliation(s)
- Tushar A. Shah
- Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, United States
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, United States
- Children’s Specialty Group, Norfolk, VA, United States
- Children’s Hospital of The King’s Daughters, Norfolk, VA, United States
| | - Haree K. Pallera
- Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, United States
| | | | - William Thomas Bass
- Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, United States
- Children’s Specialty Group, Norfolk, VA, United States
- Children’s Hospital of The King’s Daughters, Norfolk, VA, United States
| | - Frank A. Lattanzio
- Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, United States
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