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Vu TH, Kim C, Truong AD, Lillehoj HS, Hong YH. Unveiling the immunomodulatory role of soluble chicken fractalkine: Insights from functional characterization and pathway activation analyses. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2025; 162:105279. [PMID: 39396691 DOI: 10.1016/j.dci.2024.105279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 10/10/2024] [Accepted: 10/10/2024] [Indexed: 10/15/2024]
Abstract
This study describes the first successful cloning and functional characterization of chicken CX3CL1, a chemokine involved in immune cell migration and inflammatory responses. Evolutionary analyses revealed its close relation to CX3CL1 from other avian species, particularly duck, turkey, and quail. Structurally, chicken CX3CL1 includes a signal peptide and a chemokine interleukin-8-like domain characterized by unique alpha-helices and disulfide bonds. Additionally, we produced and purified recombinant CX3CL1 protein and assessed its endotoxin levels. Chemotaxis assays revealed that CX3CL1 significantly enhances the migration of HD11 macrophages and CU91 T cells. Furthermore, recombinant CX3CL1 induced the expression of pro-inflammatory cytokines (TNF-α, IFN-β, IFN-γ, IL-6, and CCL20) in a time-dependent manner, while exerting differential effects on anti-inflammatory cytokines (IL-4, IL-10). Conversely, transfection with siCX3CL1 or siCX3CR1 led to the downregulation of these responses. We also observed activation of the MAPK, NF-κB, and JAK/STAT pathways, evidenced by increased phosphorylation of key signaling molecules. These findings underscore the crucial role of chicken CX3CL1 in regulating immune responses, cell migration, and the activation of key signaling pathways. This study provides valuable insights into the immunomodulatory functions of soluble CX3CL1, highlighting its potential as a therapeutic target for inflammatory conditions and enhancing our understanding of immune cell dynamics.
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Affiliation(s)
- Thi Hao Vu
- Department of Animal Science and Technology, Chung-Ang University, 17546, Anseong, Republic of Korea.
| | - Chaeeun Kim
- Department of Animal Science and Technology, Chung-Ang University, 17546, Anseong, Republic of Korea.
| | - Anh Duc Truong
- Department of Biochemistry and Immunology, National Institute of Veterinary Research, 100000, Hanoi, Viet Nam.
| | - Hyun S Lillehoj
- Animal Biosciences and Biotechnology Laboratory, Agricultural Research Services, United States Department of Agriculture, 20705, Beltsville, MD, USA.
| | - Yeong Ho Hong
- Department of Animal Science and Technology, Chung-Ang University, 17546, Anseong, Republic of Korea.
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Pezeshkian F, Shahriarirad R, Mahram H. An overview of the role of chemokine CX3CL1 (Fractalkine) and CX3C chemokine receptor 1 in systemic sclerosis. Immun Inflamm Dis 2024; 12:e70034. [PMID: 39392260 PMCID: PMC11467895 DOI: 10.1002/iid3.70034] [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: 02/02/2024] [Revised: 09/13/2024] [Accepted: 09/19/2024] [Indexed: 10/12/2024] Open
Abstract
INTRODUCTION Systemic sclerosis (SSc) is a complex autoimmune disease characterized by fibrosis, vascular damage, and immune dysregulation. Fractalkine or chemokine (C-X3-C motif) ligand 1 (CX3CL1), a chemokine and adhesion molecule, along with its receptor CX3CR1, have been implicated in the inflammatory processes of SSc. CX3CL1 functions as both a chemoattractant and an adhesion molecule, guiding immune cell trafficking. This systematic review examines the role of CX3CL1 and its receptor CX3CR1 in the pathogenesis of SSc, with a focus on pulmonary and vascular complications. METHODS A systematic literature search was conducted across databases including PubMed, Scopus, and Web of Science from inception to November 2020. The search focused on studies investigating the CX3CL1/CX3CR1 axis in the context of SSc. RESULTS The review identified elevated CX3CL1 expression in SSc patients, particularly in the skin and lungs, where CX3CR1 is expressed on infiltrating immune cells. Higher levels of CX3CL1 were correlated with the severity of interstitial lung disease in SSc patients, indicating a potential predictive marker for disease progression. CX3CR1-positive monocytes and NK cells were recruited to inflamed tissues, contributing to fibrosis and tissue damage. Animal studies showed that inhibition of the CX3CL1/CX3CR1 axis reduced fibrosis and improved vascular function. CONCLUSION The CX3CL1/CX3CR1 axis plays a key role in immune cell recruitment and fibrosis in SSc. Elevated CX3CL1 levels are associated with lung and vascular complications, making it a potential biomarker for disease progression and a promising therapeutic target.
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Affiliation(s)
| | - Reza Shahriarirad
- Thoracic and Vascular Surgery Research CenterShiraz University of Medical SciencesShirazIran
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Zhan L, Qiu M, Zheng J, Lai M, Lin K, Dai J, Sun W, Xu E. Fractalkine/CX3CR1 axis is critical for neuroprotection induced by hypoxic postconditioning against cerebral ischemic injury. Cell Commun Signal 2024; 22:457. [PMID: 39327578 PMCID: PMC11426015 DOI: 10.1186/s12964-024-01830-4] [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: 04/29/2024] [Accepted: 09/15/2024] [Indexed: 09/28/2024] Open
Abstract
Microglial activation-mediated neuroinflammation is a major contributor to neuronal damage after cerebral ischemia. The Fractalkine (FKN)/CX3C chemokine receptor 1 (CX3CR1) axis plays a critical role in regulating microglial activation and neuroinflammation. The aim of this study is to ascertain the role and mechanism of FKN/CX3CR1 axis in hypoxic postconditioning (HPC)-induced anti-inflammatory and neuroprotective effects on transient global cerebral ischemia (tGCI). We found that HPC suppressed microglial activation and alleviated neuroinflammation in hippocampal CA1 after tGCI. Meanwhile, HPC upregulated the expression of FKN and CX3CR1 in neurons, but it downregulated the expression of CX3CR1 in glial cells after tGCI. In addition, the overexpression of FKN induced by the administration of FKN-carried lentivirus reduced microglial activation and inhibited neuroinflammation in CA1 after tGCI. Furthermore, silencing CX3CR1 with CX3CRi-carried lentivirus in CA1 after tGCI suppressed microglial activation and neuroinflammation and exerted neuroprotective effects. Finally, the overexpression of FKN caused a marked increase of neuronal CX3CR1 receptors, upregulated the phosphorylation of Akt, and reduced neuronal loss of rats in CA1 after tGCI. These findings demonstrated that HPC protected against neuronal damage in CA1 of tGCI rats through inhibiting microglial activation and activating Akt signaling pathway via FKN/CX3CR1 axis.
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Affiliation(s)
- Lixuan Zhan
- Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, 250 Changgang Dong RD, Guangzhou, 510260, P. R. China
| | - Meiqian Qiu
- Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, 250 Changgang Dong RD, Guangzhou, 510260, P. R. China
| | - Jianhua Zheng
- Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, 250 Changgang Dong RD, Guangzhou, 510260, P. R. China
| | - Meijing Lai
- Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, 250 Changgang Dong RD, Guangzhou, 510260, P. R. China
| | - Kunqin Lin
- Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, 250 Changgang Dong RD, Guangzhou, 510260, P. R. China
| | - Jiahua Dai
- Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, 250 Changgang Dong RD, Guangzhou, 510260, P. R. China
| | - Weiwen Sun
- Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, 250 Changgang Dong RD, Guangzhou, 510260, P. R. China
| | - En Xu
- Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, 250 Changgang Dong RD, Guangzhou, 510260, P. R. China.
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Rodriguez C, Chocarro L, Echaide M, Ausin K, Escors D, Kochan G. Fractalkine in Health and Disease. Int J Mol Sci 2024; 25:8007. [PMID: 39125578 PMCID: PMC11311528 DOI: 10.3390/ijms25158007] [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: 06/18/2024] [Revised: 07/18/2024] [Accepted: 07/20/2024] [Indexed: 08/12/2024] Open
Abstract
CX3CL1 is one of the 50 up-to-date identified and characterized chemokines. While other chemokines are produced as small, secreted proteins, CX3CL1 (fractalkine) is synthetized as a transmembrane protein which also leads to a soluble form produced as a result of proteolytic cleavage. The membrane-bound protein and the soluble forms exhibit different biological functions. While the role of the fractalkine/CX3CR1 signaling axis was described in the nervous system and was also related to the migration of leukocytes to sites of inflammation, its actions are controversial in cancer progression and anti-tumor immunity. In the present review, we first describe the known biology of fractalkine concerning its action through its cognate receptor, but also its role in the activation of different integrins. The second part of this review is dedicated to its role in cancer where we discuss its role in anti-cancer or procarcinogenic activities.
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Grants
- FIS PI23/00196 Instituto de Salud Carlos III-FEDER
- FIS PI20/00010 Instituto de Salud Carlos III-FEDER
- BMED 036-2023 Departamento de Salud del Gobierno de Navarra-FEDER, Spain
- LINTERNA, Ref. 0011-1411-2020-000033 Departamento de Industria, Gobierno de Navarra, Spain
- ARNMUNE, 0011-1411-2023-000111 Departamento de Industria, Gobierno de Navarra, Spain
- ISOLDA project, under grant agreement ID: 848166. Horizon 2020, European Union
- PFIS, FI21/00080 Instituto de Salud Carlos III-FEDER
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Affiliation(s)
| | | | | | | | - David Escors
- Oncoimmunology Unit, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Navarrabiomed-Fundación Miguel Servet, Universidad Pública de Navarra (UPNA), Hospital Universitario de Navarra (HUN), 31008 Pamplona, Spain; (C.R.); (L.C.); (M.E.); (K.A.)
| | - Grazyna Kochan
- Oncoimmunology Unit, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Navarrabiomed-Fundación Miguel Servet, Universidad Pública de Navarra (UPNA), Hospital Universitario de Navarra (HUN), 31008 Pamplona, Spain; (C.R.); (L.C.); (M.E.); (K.A.)
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Wątroba M, Grabowska AD, Szukiewicz D. Chemokine CX3CL1 (Fractalkine) Signaling and Diabetic Encephalopathy. Int J Mol Sci 2024; 25:7527. [PMID: 39062768 PMCID: PMC11277241 DOI: 10.3390/ijms25147527] [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: 05/31/2024] [Revised: 07/04/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
Diabetes mellitus (DM) is the most common metabolic disease in humans, and its prevalence is increasing worldwide in parallel with the obesity pandemic. A lack of insulin or insulin resistance, and consequently hyperglycemia, leads to many systemic disorders, among which diabetic encephalopathy (DE) is a long-term complication of the central nervous system (CNS), characterized by cognitive impairment and motor dysfunctions. The role of oxidative stress and neuroinflammation in the pathomechanism of DE has been proven. Fractalkine (CX3CL1) has unique properties as an adhesion molecule and chemoattractant, and by acting on its only receptor, CX3CR1, it regulates the activity of microglia in physiological states and neuroinflammation. Depending on the clinical context, CX3CL1-CX3CR1 signaling may have neuroprotective effects by inhibiting the inflammatory process in microglia or, conversely, maintaining/intensifying inflammation and neurotoxicity. This review discusses the evidence supporting that the CX3CL1-CX3CR1 pair is neuroprotective and other evidence that it is neurotoxic. Therefore, interrupting the vicious cycle within neuron-microglia interactions by promoting neuroprotective effects or inhibiting the neurotoxic effects of the CX3CL1-CX3CR1 signaling axis may be a therapeutic goal in DE by limiting the inflammatory response. However, the optimal approach to prevent DE is simply tight glycemic control, because the elimination of dysglycemic states in the CNS abolishes the fundamental mechanisms that induce this vicious cycle.
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Affiliation(s)
| | | | - Dariusz Szukiewicz
- Laboratory of the Blood-Brain Barrier, Department of Biophysics, Physiology & Pathophysiology, Medical University of Warsaw, Chałubińskiego 5, 02-400 Warsaw, Poland; (M.W.); (A.D.G.)
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6
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Akdeniz YS, Özkan S. New markers in chronic obstructive pulmonary disease. Adv Clin Chem 2024; 123:1-63. [PMID: 39181619 DOI: 10.1016/bs.acc.2024.06.001] [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] [Indexed: 08/27/2024]
Abstract
Chronic obstructive pulmonary disease (COPD), a global healthcare and socioeconomic burden, is a multifaceted respiratory disorder that results in substantial decline in health status and life quality. Acute exacerbations of the disease contribute significantly to increased morbidity and mortality. Consequently, the identification of reliable and effective biomarkers for rapid diagnosis, prediction, and prognosis of exacerbations is imperative. In addition, biomarkers play a crucial role in monitoring responses to therapeutic interventions and exploring innovative treatment strategies. Although established markers such as CRP, fibrinogen and neutrophil count are routinely used, a universal marker is lacking. Fortunately, an increasing number of studies based on next generation analytics have explored potential biomarkers in COPD. Here we review those advances and the need for standardized validation studies in the appropriate clinical setting.
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Affiliation(s)
- Yonca Senem Akdeniz
- Department of Emergency Medicine, Cerrahpaşa Faculty of Medicine, İstanbul University-Cerrahpaşa, İstanbul, Türkiye.
| | - Seda Özkan
- Department of Emergency Medicine, Cerrahpaşa Faculty of Medicine, İstanbul University-Cerrahpaşa, İstanbul, Türkiye
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Wang C, Wang J, Zhu Z, Hu J, Lin Y. Spotlight on pro-inflammatory chemokines: regulators of cellular communication in cognitive impairment. Front Immunol 2024; 15:1421076. [PMID: 39011039 PMCID: PMC11247373 DOI: 10.3389/fimmu.2024.1421076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Accepted: 06/12/2024] [Indexed: 07/17/2024] Open
Abstract
Cognitive impairment is a decline in people's ability to think, learn, and remember, and so forth. Cognitive impairment is a global health challenge that affects the quality of life of thousands of people. The condition covers a wide range from mild cognitive impairment to severe dementia, which includes Alzheimer's disease (AD) and Parkinson's disease (PD), among others. While the etiology of cognitive impairment is diverse, the role of chemokines is increasingly evident, especially in the presence of chronic inflammation and neuroinflammation. Although inflammatory chemokines have been linked to cognitive impairment, cognitive impairment is usually multifactorial. Researchers are exploring the role of chemokines and other inflammatory mediators in cognitive dysfunction and trying to develop therapeutic strategies to mitigate their effects. The pathogenesis of cognitive disorders is very complex, their underlying causative mechanisms have not been clarified, and their treatment is always one of the challenges in the field of medicine. Therefore, exploring its pathogenesis and treatment has important socioeconomic value. Chemokines are a growing family of structurally and functionally related small (8-10 kDa) proteins, and there is growing evidence that pro-inflammatory chemokines are associated with many neurobiological processes that may be relevant to neurological disorders beyond their classical chemotactic function and play a crucial role in the pathogenesis and progression of cognitive disorders. In this paper, we review the roles and regulatory mechanisms of pro-inflammatory chemokines (CCL2, CCL3, CCL4, CCL5, CCL11, CCL20, and CXCL8) in cognitive impairment. We also discuss the intrinsic relationship between the two, hoping to provide some valuable references for the treatment of cognitive impairment.
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Affiliation(s)
- Chenxu Wang
- Department of Anesthesiology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Department of Endocrinology and Metabolism, The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Jiayi Wang
- Department of Anesthesiology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Department of Endocrinology and Metabolism, The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Zhichao Zhu
- Department of Anesthesiology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Department of Endocrinology and Metabolism, The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Jialing Hu
- Department of Emergency Medicine, The Second Affiliated Hospital of Nanchang University, Jiangxi Medical College, Nanchang, China
| | - Yong Lin
- Department of Anesthesiology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Ganzhou Key Laboratory of Anesthesia, The First Affiliated Hospital of GanNan Medical University, Ganzhou, China
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Naessens F, Demuynck R, Vershinina O, Efimova I, Saviuk M, De Smet G, Mishchenko TA, Vedunova MV, Krysko O, Catanzaro E, Krysko DV. CX3CL1 release during immunogenic apoptosis is associated with enhanced anti-tumour immunity. Front Immunol 2024; 15:1396349. [PMID: 39011040 PMCID: PMC11246865 DOI: 10.3389/fimmu.2024.1396349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 06/19/2024] [Indexed: 07/17/2024] Open
Abstract
Introduction Immunogenic cell death (ICD) has emerged as a novel option for cancer immunotherapy. The key determinants of ICD encompass antigenicity (the presence of antigens) and adjuvanticity, which involves the release of damage-associated molecular patterns (DAMPs) and various cytokines and chemokines. CX3CL1, also known as neurotactin or fractalkine, is a chemokine involved in cellular signalling and immune cell interactions. CX3CL1 has been denoted as a "find me" signal that stimulates chemotaxis of immune cells towards dying cells, facilitating efferocytosis and antigen presentation. However, in the context of ICD, it is uncertain whether CX3CL1 is an important mediator of the effects of ICD. Methods In this study, we investigated the intricate role of CX3CL1 in immunogenic apoptosis induced by mitoxantrone (MTX) in cancer cells. The Luminex xMAP technology was used to quantify murine cytokines, chemokines and growth factors to identify pivotal regulatory cytokines released by murine fibrosarcoma MCA205 and melanoma B16-F10 cells undergoing ICD. Moreover, a murine tumour prophylactic vaccination model was employed to analyse the effect of CX3CL1 on the activation of an adaptive immune response against MCA205 cells undergoing ICD. Furthermore, thorough analysis of the TCGA-SKCM public dataset from 98 melanoma patients revealed the role of CX3CL1 and its receptor CX3CR1 in melanoma patients. Results Our findings demonstrate enhanced CX3CL1 release from apoptotic MCA205 and B16-F10 cells (regardless of the cell type) but not if they are undergoing ferroptosis or accidental necrosis. Moreover, the addition of recombinant CX3CL1 to non-immunogenic doses of MTX-treated, apoptotically dying cancer cells in the murine prophylactic tumour vaccination model induced a robust immunogenic response, effectively increasing the survival of the mice. Furthermore, analysis of melanoma patient data revealed enhanced survival rates in individuals exhibiting elevated levels of CD8+ T cells expressing CX3CR1. Conclusion These data collectively underscore the importance of the release of CX3CL1 in eliciting an immunogenic response against dying cancer cells and suggest that CX3CL1 may serve as a key switch in conferring immunogenicity to apoptosis.
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Affiliation(s)
- Faye Naessens
- Cell Death Investigation and Therapy Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent, Belgium
| | - Robin Demuynck
- Cell Death Investigation and Therapy Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent, Belgium
| | - Olga Vershinina
- Institute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - Iuliia Efimova
- Cell Death Investigation and Therapy Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent, Belgium
| | - Mariia Saviuk
- Cell Death Investigation and Therapy Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent, Belgium
| | - Greet De Smet
- Cell Death Investigation and Therapy Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Tatiana A. Mishchenko
- Institute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - Maria V. Vedunova
- Institute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - Olga Krysko
- Cell Death Investigation and Therapy Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Elena Catanzaro
- Cell Death Investigation and Therapy Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent, Belgium
| | - Dmitri V. Krysko
- Cell Death Investigation and Therapy Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent, Belgium
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Yu H, Shen B, Han R, Zhang Y, Xu S, Zhang Y, Guo Y, Huang P, Huang S, Zhong Y. CX3CL1-CX3CR1 axis protects retinal ganglion cells by inhibiting microglia activation in a distal optic nerve trauma model. Inflamm Regen 2024; 44:30. [PMID: 38844990 PMCID: PMC11154987 DOI: 10.1186/s41232-024-00343-4] [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: 02/22/2024] [Accepted: 05/28/2024] [Indexed: 06/09/2024] Open
Abstract
BACKGROUND The chemokine CX3CL1 has been reported to play an important role in optic nerve protection, but the underlying mechanism is still unclear. CX3CR1, the only receptor of CX3CL1, is specifically expressed on retinal microglia, whose activation plays a role in the pathological process of optic nerve injury. This study aimed to evaluate whether CX3CL1 exerts optic neuroprotection by affecting the activation of microglia by combining with CX3CR1. METHODS A mouse model of distal optic nerve trauma (ONT) was used to evaluate the effects of the CX3CL1-CX3CR1 axis on the activation of microglia and survival or axonal regeneration of retinal ganglion cells (RGCs). The activation of microglia, loss of RGCs, and damage to visual function were detected weekly till 4 weeks after modeling. CX3CL1 was injected intravitreally immediately or delayed after injury and the status of microglia and RGCs were examined. RESULTS Increases in microglia activation and optic nerve damage were accompanied by a reduced production of the CX3CL1-CX3CR1 axis after the distal ONT modeling. Both immediate and delayed intravitreal injection of CX3CL1 inhibited microglia activation, promoted survival of RGCs, and improved axonal regenerative capacity. Injection with CX3CL1 was no longer effective after 48 h post ONT. The CX3CL1-CX3CR1 axis promotes survival and axonal regeneration, as indicated by GAP43 protein and gene expression, of RGCs by inhibiting the microglial activation after ONT. CONCLUSIONS The CX3CL1-CX3CR1 axis could promote survival and axonal regeneration of RGCs by inhibiting the microglial activation after optic nerve injury. The CX3CL1-CX3CR1 axis may become a potential target for the treatment of optic nerve injury. Forty-eight hours is the longest time window for effective treatment after injury. The study is expected to provide new ideas for the development of targeted drugs for the repair of optic nerve.
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Affiliation(s)
- Huan Yu
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin Er Road, Shanghai, 200025, China
| | - Bingqiao Shen
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin Er Road, Shanghai, 200025, China
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, Shanghai, 200080, China
| | - Ruiqi Han
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin Er Road, Shanghai, 200025, China
| | - Yang Zhang
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin Er Road, Shanghai, 200025, China
| | - Shushu Xu
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin Er Road, Shanghai, 200025, China
| | - Yumeng Zhang
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin Er Road, Shanghai, 200025, China
| | - Yanzhi Guo
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin Er Road, Shanghai, 200025, China
| | - Ping Huang
- Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin Er Road, Shanghai, 200025, China.
| | - Shouyue Huang
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin Er Road, Shanghai, 200025, China.
| | - Yisheng Zhong
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin Er Road, Shanghai, 200025, China.
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Szukiewicz D. CX3CL1 (Fractalkine)-CX3CR1 Axis in Inflammation-Induced Angiogenesis and Tumorigenesis. Int J Mol Sci 2024; 25:4679. [PMID: 38731899 PMCID: PMC11083509 DOI: 10.3390/ijms25094679] [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: 03/28/2024] [Revised: 04/19/2024] [Accepted: 04/24/2024] [Indexed: 05/13/2024] Open
Abstract
The chemotactic cytokine fractalkine (FKN, chemokine CX3CL1) has unique properties resulting from the combination of chemoattractants and adhesion molecules. The soluble form (sFKN) has chemotactic properties and strongly attracts T cells and monocytes. The membrane-bound form (mFKN) facilitates diapedesis and is responsible for cell-to-cell adhesion, especially by promoting the strong adhesion of leukocytes (monocytes) to activated endothelial cells with the subsequent formation of an extracellular matrix and angiogenesis. FKN signaling occurs via CX3CR1, which is the only known member of the CX3C chemokine receptor subfamily. Signaling within the FKN-CX3CR1 axis plays an important role in many processes related to inflammation and the immune response, which often occur simultaneously and overlap. FKN is strongly upregulated by hypoxia and/or inflammation-induced inflammatory cytokine release, and it may act locally as a key angiogenic factor in the highly hypoxic tumor microenvironment. The importance of the FKN/CX3CR1 signaling pathway in tumorigenesis and cancer metastasis results from its influence on cell adhesion, apoptosis, and cell migration. This review presents the role of the FKN signaling pathway in the context of angiogenesis in inflammation and cancer. The mechanisms determining the pro- or anti-tumor effects are presented, which are the cause of the seemingly contradictory results that create confusion regarding the therapeutic goals.
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Affiliation(s)
- Dariusz Szukiewicz
- Department of Biophysics, Physiology & Pathophysiology, Faculty of Health Sciences, Medical University of Warsaw, 02-004 Warsaw, Poland
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11
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Zhang C, Zhang Y, Zhuang R, Yang K, Chen L, Jin B, Ma Y, Zhang Y, Tang K. Alterations in CX3CL1 Levels and Its Role in Viral Pathogenesis. Int J Mol Sci 2024; 25:4451. [PMID: 38674036 PMCID: PMC11050295 DOI: 10.3390/ijms25084451] [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: 03/18/2024] [Revised: 04/12/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024] Open
Abstract
CX3CL1, also named fractalkine or neurotactin, is the only known member of the CX3C chemokine family that can chemoattract several immune cells. CX3CL1 exists in both membrane-anchored and soluble forms, with each mediating distinct biological activities. CX3CL1 signals are transmitted through its unique receptor, CX3CR1, primarily expressed in the microglia of the central nervous system (CNS). In the CNS, CX3CL1 acts as a regulator of microglia activation in response to brain disorders or inflammation. Recently, there has been a growing interest in the role of CX3CL1 in regulating cell adhesion, chemotaxis, and host immune response in viral infection. Here, we provide a comprehensive review of the changes and function of CX3CL1 in various viral infections, such as human immunodeficiency virus (HIV), SARS-CoV-2, influenza virus, and cytomegalovirus (CMV) infection, to highlight the emerging roles of CX3CL1 in viral infection and associated diseases.
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Affiliation(s)
| | | | | | | | | | | | | | - Yun Zhang
- Department of Immunology, The Fourth Military Medical University, Xi’an 710032, China; (C.Z.); (Y.Z.); (R.Z.); (K.Y.); (L.C.); (B.J.); (Y.M.)
| | - Kang Tang
- Department of Immunology, The Fourth Military Medical University, Xi’an 710032, China; (C.Z.); (Y.Z.); (R.Z.); (K.Y.); (L.C.); (B.J.); (Y.M.)
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12
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Kim W, Kim M, Kim B. Unraveling the enigma: housekeeping gene Ugt1a7c as a universal biomarker for microglia. Front Psychiatry 2024; 15:1364201. [PMID: 38666091 PMCID: PMC11043603 DOI: 10.3389/fpsyt.2024.1364201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Accepted: 03/26/2024] [Indexed: 04/28/2024] Open
Abstract
Background Microglia, brain resident macrophages, play multiple roles in maintaining homeostasis, including immunity, surveillance, and protecting the central nervous system through their distinct activation processes. Identifying all types of microglia-driven populations is crucial due to the presence of various phenotypes that differ based on developmental stages or activation states. During embryonic development, the E8.5 yolk sac contains erythromyeloid progenitors that go through different growth phases, eventually resulting in the formation of microglia. In addition, microglia are present in neurological diseases as a diverse population. So far, no individual biomarker for microglia has been discovered that can accurately identify and monitor their development and attributes. Summary Here, we highlight the newly defined biomarker of mouse microglia, UGT1A7C, which exhibits superior stability in expression during microglia development and activation compared to other known microglia biomarkers. The UGT1A7C sensing chemical probe labels all microglia in the 3xTG AD mouse model. The expression of Ugt1a7c is stable during development, with only a 4-fold variation, while other microglia biomarkers, such as Csf1r and Cx3cr1, exhibit at least a 10-fold difference. The UGT1A7C expression remains constant throughout its lifespan. In addition, the expression and activity of UGT1A7C are the same in response to different types of inflammatory activators' treatment in vitro. Conclusion We propose employing UGT1A7C as the representative biomarker for microglia, irrespective of their developmental state, age, or activation status. Using UGT1A7C can reduce the requirement for using multiple biomarkers, enhance the precision of microglia analysis, and even be utilized as a standard for gene/protein expression.
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Affiliation(s)
| | | | - Beomsue Kim
- Neural Circuit Research Group, Korea Brain Research Institute, Daegu, Republic of Korea
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13
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Dadwal S, Heneka MT. Microglia heterogeneity in health and disease. FEBS Open Bio 2024; 14:217-229. [PMID: 37945346 PMCID: PMC10839410 DOI: 10.1002/2211-5463.13735] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 10/12/2023] [Accepted: 11/08/2023] [Indexed: 11/12/2023] Open
Abstract
Microglia, the resident immune cells of the central nervous system (CNS), have received significant attention due to their critical roles in maintaining brain homeostasis and mediating cerebral immune responses. Understanding the origin of microglia has been a subject of great interest, and emerging evidence suggests that microglia consist of multiple subpopulations with unique molecular and functional characteristics. These subpopulations of microglia may exhibit specialized roles in response to different environmental cues as in disease conditions. The newfound understanding of microglial heterogeneity has significant implications for elucidating their roles in both physiological and pathological conditions. In the context of disease, microglia have been studied rigorously as they play a very important role in neuroinflammation. Dysregulated microglial activation and function contribute to chronic inflammation. Further exploration of microglial heterogeneity and their interactions with other cell types in the CNS will undoubtedly pave the way to novel therapeutic strategies targeting microglia-mediated pathologies. In this review, we discuss the latest advances in the field of microglia research, focusing specifically on the origin and subpopulations of microglia, the populations of microglia types in the brains of patients with neurodegenerative diseases, and how microglia are regulated in the healthy CNS.
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Affiliation(s)
- Shilauni Dadwal
- Luxembourg Centre for Systems BiomedicineUniversity of LuxembourgBelvalLuxembourg
| | - Michael T. Heneka
- Luxembourg Centre for Systems BiomedicineUniversity of LuxembourgBelvalLuxembourg
- Division of Infectious Diseases and ImmunologyUniversity of Massachusetts Medical SchoolWorcesterMAUSA
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14
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Pokharel J, Shryki I, Zwijnenburg AJ, Sandu I, Krumm L, Bekiari C, Avramov V, Heinbäck R, Lysell J, Eidsmo L, Harris HE, Gerlach C. The cellular microenvironment regulates CX3CR1 expression on CD8 + T cells and the maintenance of CX3CR1 + CD8 + T cells. Eur J Immunol 2024; 54:e2350658. [PMID: 37816219 DOI: 10.1002/eji.202350658] [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: 07/10/2023] [Revised: 10/06/2023] [Accepted: 10/09/2023] [Indexed: 10/12/2023]
Abstract
Expression levels of the chemokine receptor CX3CR1 serve as high-resolution marker delineating functionally distinct antigen-experienced T-cell states. The factors that influence CX3CR1 expression in T cells are, however, incompletely understood. Here, we show that in vitro priming of naïve CD8+ T cells failed to robustly induce CX3CR1, which highlights the shortcomings of in vitro priming settings in recapitulating in vivo T-cell differentiation. Nevertheless, in vivo generated memory CD8+ T cells maintained CX3CR1 expression during culture. This allowed us to investigate whether T-cell receptor ligation, cell death, and CX3CL1 binding influence CX3CR1 expression. T-cell receptor stimulation led to downregulation of CX3CR1. Without stimulation, CX3CR1+ CD8+ T cells had a selective survival disadvantage, which was enhanced by factors released from necrotic but not apoptotic cells. Exposure to CX3CL1 did not rescue their survival and resulted in a dose-dependent loss of CX3CR1 surface expression. At physiological concentrations of CX3CL1, CX3CR1 surface expression was only minimally reduced, which did not hamper the interpretability of T-cell differentiation states delineated by CX3CR1. Our data further support the broad utility of CX3CR1 surface levels as T-cell differentiation marker and identify factors that influence CX3CR1 expression and the maintenance of CX3CR1 expressing CD8+ T cells.
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Affiliation(s)
- Jyoti Pokharel
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden
| | - Iman Shryki
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden
| | - Anthonie J Zwijnenburg
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden
| | - Ioana Sandu
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden
| | - Laura Krumm
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden
| | - Christina Bekiari
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden
| | - Victor Avramov
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden
| | - Rebecka Heinbäck
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden
| | - Josefin Lysell
- Dermatology and Venereology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Liv Eidsmo
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden
- Leo Foundation Skin Immunology Center, University of Copenhagen, Kobenhavn, Denmark
| | - Helena E Harris
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden
| | - Carmen Gerlach
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden
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15
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Ullah A, Zhao J, Li J, Singla RK, Shen B. Involvement of CXC chemokines (CXCL1-CXCL17) in gastric cancer: Prognosis and therapeutic molecules. Life Sci 2024; 336:122277. [PMID: 37995936 DOI: 10.1016/j.lfs.2023.122277] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 11/15/2023] [Indexed: 11/25/2023]
Abstract
Gastric cancer (GC) is the fifth-most prevalent and second-most deadly cancer worldwide. Due to the late onset of symptoms, GC is frequently treated at a mature stage. In order to improve the diagnostic and clinical decision-making processes, it is necessary to establish more specific and sensitive indicators valuable in the early detection of the disease whenever a cancer is asymptomatic. In this work, we gathered information about CXC chemokines and GC by using scientific search engines including Google Scholar, PubMed, SciFinder, and Web of Science. Researchers believe that GC chemokines, small proteins, class CXC chemokines, and chemokine receptors promote GC inflammation, initiation, and progression by facilitating angiogenesis, tumor transformation, invasion, survival, metastatic spread, host response safeguards, and inter-cell interaction. With our absolute best professionalism, the role of CXC chemokines and their respective receptors in GC diagnosis and prognosis has not been fully explained. This review article updates the general characteristics of CXC chemokines, their unique receptors, their function in the pathological process of GC, and their potential application as possible indicators for GC. Although there have only recently been a few studies focusing on the therapeutic efficacy of CXC chemokine inhibitors in GC, growing experimental evidence points to the inhibition of CXC chemokines as a promising targeted therapy. Therefore, further translational studies are warranted to determine whether specific antagonists or antibodies designed to target CXC chemokines alone or in combination with chemotherapy are useful for diagnosing advanced GC.
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Affiliation(s)
- Amin Ullah
- Department of Urology and Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jing Zhao
- Department of Urology and Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jiakun Li
- Department of Urology and Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Rajeev K Singla
- Department of Urology and Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Bairong Shen
- Department of Urology and Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu 610041, China.
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16
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von Bernhardi R, Eugenín J. Aging Microglia and Their Impact in the Nervous System. ADVANCES IN NEUROBIOLOGY 2024; 37:379-395. [PMID: 39207703 DOI: 10.1007/978-3-031-55529-9_21] [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
Aging is the greatest risk factor for neurodegenerative diseases. Microglia are the resident immune cells in the central nervous system (CNS), playing key roles in its normal functioning, and as mediators for age-dependent changes of the CNS, condition at which they generate a hostile environment for neurons. Transforming Growth Factor β1 (TGFβ1) is a regulatory cytokine involved in immuneregulation and neuroprotection, affecting glial cell inflammatory activation, neuronal survival, and function. TGFβ1 signaling undergoes age-dependent changes affecting the regulation of microglial cells and can contribute to the pathophysiology of neurodegenerative diseases. This chapter focuses on assessing the role of age-related changes on the regulation of microglial cells and their impact on neuroinflammation and neuronal function, for understanding age-dependent changes of the nervous system.
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Affiliation(s)
- Rommy von Bernhardi
- Faculty of Odontology and Rehabilitation Sciences, Universidad San Sebastian, Santiago, Chile.
| | - Jaime Eugenín
- Faculty of Chemistry and Biology, Universidad de Santiago de Chile, Santiago, Chile
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17
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Edderkaoui B. Chemokines in Cartilage Regeneration and Degradation: New Insights. Int J Mol Sci 2023; 25:381. [PMID: 38203552 PMCID: PMC10779035 DOI: 10.3390/ijms25010381] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 12/24/2023] [Accepted: 12/25/2023] [Indexed: 01/12/2024] Open
Abstract
Cartilage plays a crucial role in the human body by forming long bones during development and growth to bear loads on joints and intervertebral discs. However, the increasing prevalence of cartilage degenerative disorders is a growing public health concern, especially due to the poor innate regenerative capacity of cartilage. Chondrocytes are a source of several inflammatory mediators that play vital roles in the pathogenesis of cartilage disorders. Among these mediators, chemokines have been explored as potential contributors to cartilage degeneration and regeneration. Our review focuses on the progress made during the last ten years in identifying the regulators and roles of chemokines and their receptors in different mechanisms related to chondrocytes and cartilage. Recent findings have demonstrated that chemokines influence cartilage both positively and negatively. Their induction and involvement in either process depends on the local molecular environment and is both site- and time-dependent. One of the challenges in defining the role of chemokines in cartilage pathology or regeneration is the apparent redundancy in the interaction of chemokines with their receptors. Hence, it is crucial to determine, for each situation, whether targeting specific chemokines or their receptors will help in developing effective therapeutic strategies for cartilage repair.
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Affiliation(s)
- Bouchra Edderkaoui
- Musculoskeletal Disease Center, Research Service, VA Loma Linda Healthcare Systems, Loma Linda, CA 92357, USA;
- Department of Medicine, Loma Linda University, Loma Linda, CA 92354, USA
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18
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Ullah A, Zhao J, Singla RK, Shen B. Pathophysiological impact of CXC and CX3CL1 chemokines in preeclampsia and gestational diabetes mellitus. Front Cell Dev Biol 2023; 11:1272536. [PMID: 37928902 PMCID: PMC10620730 DOI: 10.3389/fcell.2023.1272536] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 10/09/2023] [Indexed: 11/07/2023] Open
Abstract
Diabetes-related pathophysiological alterations and various female reproductive difficulties were common in pregnant women with gestational diabetes mellitus (GDM), who had 21.1 million live births. Preeclampsia (PE), which increases maternal and fetal morbidity and mortality, affects approximately 3%-5% of pregnancies worldwide. Nevertheless, it is unclear what triggers PE and GDM to develop. Therefore, the development of novel moderator therapy approaches is a crucial advancement. Chemokines regulate physiological defenses and maternal-fetal interaction during healthy and disturbed pregnancies. Chemokines regulate immunity, stem cell trafficking, anti-angiogenesis, and cell attraction. CXC chemokines are usually inflammatory and contribute to numerous reproductive disorders. Fractalkine (CX3CL1) may be membrane-bound or soluble. CX3CL1 aids cell survival during homeostasis and inflammation. Evidence reveals that CXC and CX3CL1 chemokines and their receptors have been the focus of therapeutic discoveries for clinical intervention due to their considerable participation in numerous biological processes. This review aims to give an overview of the functions of CXC and CX3CL1 chemokines and their receptors in the pathophysiology of PE and GDM. Finally, we examined stimulus specificity for CXC and CX3CL1 chemokine expression and synthesis in PE and GDM and preclinical and clinical trials of CXC-based PE and GDM therapies.
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Affiliation(s)
- Amin Ullah
- Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine, Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Jing Zhao
- Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine, Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Rajeev K. Singla
- Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine, Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Bairong Shen
- Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine, Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
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19
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Cabana-Puig X, Lu R, Geng S, Michaelis JS, Oakes V, Armstrong C, Testerman JC, Liao X, Alajoleen R, Appiah M, Zhang Y, Reilly CM, Li L, Luo XM. CX 3CR1 modulates SLE-associated glomerulonephritis and cardiovascular disease in MRL/lpr mice. Inflamm Res 2023; 72:1083-1097. [PMID: 37060359 PMCID: PMC10748465 DOI: 10.1007/s00011-023-01731-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 03/31/2023] [Accepted: 04/05/2023] [Indexed: 04/16/2023] Open
Abstract
OBJECTIVE Patients with systemic lupus erythematosus (SLE) often develop multi-organ damages including heart and kidney complications. We sought to better define the underlying mechanisms with a focus on the chemokine receptor CX3CR1. METHODS We generated Cx3cr1-deficient MRL/lpr lupus-prone mice through backcrossing. We then employed heterozygous intercross to generate MRL/lpr littermates that were either sufficient or deficient of CX3CR1. The mice were also treated with either Lactobacillus spp. or a high-fat diet (HFD) followed by assessments of the kidney and heart, respectively. RESULTS Cx3cr1-/- MRL/lpr mice exhibited a distinct phenotype of exacerbated glomerulonephritis compared to Cx3cr1+/+ littermates, which was associated with a decrease of spleen tolerogenic marginal zone macrophages and an increase of double-negative T cells. Interestingly, upon correction of the gut microbiota with Lactobacillus administration, the phenotype of exacerbated glomerulonephritis was reversed, suggesting that CX3CR1 controls glomerulonephritis in MRL/lpr mice through a gut microbiota-dependent mechanism. Upon treatment with HFD, Cx3cr1-/- MRL/lpr mice developed significantly more atherosclerotic plaques that were promoted by Ly6C+ monocytes. Activated monocytes expressed ICOS-L that interacted with ICOS-expressing follicular T-helper cells, which in turn facilitated a germinal center reaction to produce more autoantibodies. Through a positive feedback mechanism, the increased circulatory autoantibodies further promoted the activation of Ly6C+ monocytes and their display of ICOS-L. CONCLUSIONS We uncovered novel, Cx3cr1 deficiency-mediated pathogenic mechanisms contributing to SLE-associated glomerulonephritis and cardiovascular disease.
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Affiliation(s)
- Xavier Cabana-Puig
- Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA, USA
| | - Ran Lu
- Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA, USA
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA, USA
| | - Shuo Geng
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA, USA
| | - Jacquelyn S Michaelis
- Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, USA
| | - Vanessa Oakes
- Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA, USA
| | - Caitlin Armstrong
- Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA, USA
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA, USA
| | - James C Testerman
- Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA, USA
| | - Xiaofeng Liao
- Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA, USA
| | - Razan Alajoleen
- Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA, USA
| | - Michael Appiah
- Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA, USA
| | - Yao Zhang
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA, USA
| | | | - Liwu Li
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA, USA.
| | - Xin M Luo
- Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA, USA.
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20
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Finneran D, Li Q, Subbarayan MS, Joly-Amado A, Kamath S, Dengler DG, Gordon MN, Jackson MR, Morgan D, Bickford PC, Smith LH, Nash KR. Concentration and proteolysis of CX3CL1 may regulate the microglial response to CX3CL1. Glia 2023; 71:245-258. [PMID: 36106533 PMCID: PMC9772123 DOI: 10.1002/glia.24269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 08/25/2022] [Accepted: 08/26/2022] [Indexed: 12/24/2022]
Abstract
Fractalkine (FKN) is a membrane-bound chemokine that can be cleaved by proteases such as ADAM 10, ADAM 17, and cathepsin S to generate soluble fragments. Studies using different forms of the soluble FKN yield conflicting results in vivo. These observations prompted us to investigate the function and pharmacology of two commonly used isoforms of FKN, a human full-length soluble FKN (sFKN), and a human chemokine domain only FKN (cdFKN). Both are prevalent in the literature and are often assumed to be functionally equivalent. We observed that recombinant sFKN and cdFKN exhibit similar potencies in a cell-based cAMP assay, but binding affinity for CX3CR1 was modestly different. There was a 10-fold difference in potency between sFKN and cdFKN when assessing their ability to stimulate β-arrestin recruitment. Interestingly, high concentrations of FKN, regardless of cleavage variant, were ineffective at reducing pro-inflammatory microglial activation and may induce a pro-inflammatory response. This effect was observed in mouse and rat primary microglial cells as well as microglial cell lines. The inflammatory response was exacerbated in aged microglia, which is known to exhibit age-related inflammatory phenotypes. We observed the same effects in Cx3cr1-/- primary microglia and therefore speculate that an alternative FKN receptor may exist. Collectively, these data provide greater insights into the function and pharmacology of these common FKN reagents, which may clarify conflicting reports and urge greater caution in the selection of FKN peptides for use in in vitro and in vivo studies and the interpretation of results obtained using these differing peptides.
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Affiliation(s)
- Dylan Finneran
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa FL-33612, USA
- Michigan State University, Department of Translational Neuroscience, 400 Monroe Ave. NW, Grand Rapids, MI, United States
| | - Qingyou Li
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa FL-33612, USA
| | - Meena S. Subbarayan
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa FL-33612, USA
- Center for Excellence in Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa FL-33612, USA
- Gladstone Institute of Neurological Disease, Gladstone Institutes, 1650 Owens St, San Francisco, CA 94158
| | - Aurelie Joly-Amado
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa FL-33612, USA
| | - Siddharth Kamath
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa FL-33612, USA
| | - Daniela G. Dengler
- Conrad Prebys Center for Chemical Genomics, Sandford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037
| | - Marcia N. Gordon
- Michigan State University, Department of Translational Neuroscience, 400 Monroe Ave. NW, Grand Rapids, MI, United States
| | - Michael R. Jackson
- Conrad Prebys Center for Chemical Genomics, Sandford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037
| | - Dave Morgan
- Michigan State University, Department of Translational Neuroscience, 400 Monroe Ave. NW, Grand Rapids, MI, United States
| | - Paula C. Bickford
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa FL-33612, USA
- Center for Excellence in Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa FL-33612, USA
- Research Service, James A Haley Veterans Hospital, 13000 Bruce B Downs Blvd, Tampa FL-33612, USA
| | - Layton H. Smith
- Conrad Prebys Center for Chemical Genomics, Sandford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037
| | - Kevin R. Nash
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa FL-33612, USA
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21
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Potential Impact of Prosthetic Biomaterials on the Periodontium: A Comprehensive Review. Molecules 2023; 28:molecules28031075. [PMID: 36770741 PMCID: PMC9921997 DOI: 10.3390/molecules28031075] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/14/2023] [Accepted: 01/17/2023] [Indexed: 01/24/2023] Open
Abstract
The success of a prosthetic treatment is closely related to the periodontal health of the individual. The aim of this article was to review and present the importance of prosthetic restorative materials on the condition of the periodontium, the changes that occur in the composition of the subgingival microbiota and the levels of inflammatory markers in gingival crevicular fluid. Articles on the influence of different prosthetic restorative materials on subgingival microbiota and proinflammatory cytokines were searched for using the keywords "prosthetic biomaterials", "fixed prosthesis", "periodontal health", "subgingival microbiota", "periodontal biomarkers" and "gingival crevicular fluid" in PubMed/Medline, Science Direct, Scopus and Google Scholar. The type of material used for prosthesis fabrication together with poor marginal and internal fit can result in changes in the composition of the subgingival microbiota, as well as increased accumulation and retention of dentobacterial plaque, thus favoring the development of periodontal disease and prosthetic treatment failure. Biological markers have helped to understand the inflammatory response of different prosthetic materials on periodontal tissues with the main purpose of improving their clinical application in patients who need them. Metal-free ceramic prostheses induce a lower inflammatory response regardless of the fabrication method; however, the use of CAD/CAM systems is recommended for their fabrication. In addition, it is presumed that metal-ceramic prostheses cause changes in the composition of the subgingival microbiota producing a more dysbiotic biofilm with a higher prevalence of periodontopathogenic bacteria, which may further favor periodontal deterioration.
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Fractalkine/CX3CR1-Dependent Modulation of Synaptic and Network Plasticity in Health and Disease. Neural Plast 2023; 2023:4637073. [PMID: 36644710 PMCID: PMC9833910 DOI: 10.1155/2023/4637073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 10/14/2022] [Accepted: 10/18/2022] [Indexed: 01/06/2023] Open
Abstract
CX3CR1 is a G protein-coupled receptor that is expressed exclusively by microglia within the brain parenchyma. The only known physiological CX3CR1 ligand is the chemokine fractalkine (FKN), which is constitutively expressed in neuronal cell membranes and tonically released by them. Through its key role in microglia-neuron communication, the FKN/CX3CR1 axis regulates microglial state, neuronal survival, synaptic plasticity, and a variety of synaptic functions, as well as neuronal excitability via cytokine release modulation, chemotaxis, and phagocytosis. Thus, the absence of CX3CR1 or any failure in the FKN/CX3CR1 axis has been linked to alterations in different brain functions, including changes in synaptic and network plasticity in structures such as the hippocampus, cortex, brainstem, and spinal cord. Since synaptic plasticity is a basic phenomenon in neural circuit integration and adjustment, here, we will review its modulation by the FKN/CX3CR1 axis in diverse brain circuits and its impact on brain function and adaptation in health and disease.
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23
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Goode-Romero G, Dominguez L. Computational study of the conformational ensemble of CX3C chemokine receptor 1 (CX3CR1) and its interactions with antagonist and agonist ligands. J Mol Graph Model 2022; 117:108278. [PMID: 35988439 DOI: 10.1016/j.jmgm.2022.108278] [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: 12/05/2021] [Revised: 07/14/2022] [Accepted: 07/15/2022] [Indexed: 01/14/2023]
Abstract
The CX3C chemokine receptor 1 (CX3CR1), a member of the class A of G Protein-Coupled Receptors (GPCR) superfamily, and its ligand fractalkine constitute an important biochemical axis that influence many cellular pathways involving homeostatic and inflammatory processes. They participate in the activation, chemotaxis and recruitment of multiple immunological cells such as microglia, macrophages and monocytes, and play a critical role in neuroinflammatory conditions such as Alzheimer's disease and multiple sclerosis, in the recovery from central nervous system injuries, in several chronic, peripheral inflammatory entities and in some infective processes including HIV-AIDS. In this work we present the study of the CX3CR1 receptor employing extensive atomistic Molecular Dynamics (MD) simulations with the aim to characterize the conformational ensemble of the receptor in the presence of its antagonist and agonist ligands. We analyzed the receptor conformational changes and described interactions within its key regions and the bounded ligands to identify their notable differences. Finally, we classify the features that would allow the identification of patterns that characterize a functional state to contribute to the understanding of the complexity of the GPCR superfamily.
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Affiliation(s)
- Guillermo Goode-Romero
- Facultad de Química, Departamento de Fisicoquímica, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
| | - Laura Dominguez
- Facultad de Química, Departamento de Fisicoquímica, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico.
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24
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Increment of CSF fractalkine-positive microvesicles preceded the spatial memory impairment in amyloid beta neurotoxicity. Cytokine 2022; 160:156050. [PMID: 36179535 DOI: 10.1016/j.cyto.2022.156050] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 09/03/2022] [Accepted: 09/09/2022] [Indexed: 11/23/2022]
Abstract
BACKGROUND Fractalkine (CX3CL1) is a key chemokine, affects neuronal cell communication and involves in Alzheimer's disease pathogenesis. Microvesicles (MVs) participate in neuronal cells' cross-talk in physiological and pathological states. Microvesicles released in cerebrospinal fluid (CSF) may provide a valuable footprint of brain changes. Little information is available regarding the release of fractalkine-positive MVs (CX3CL1+ -MVs) in the nervous system. METHODS We induced cognitive impairment by bilateral injection of amyloid-beta (Aβ) into the cerebral ventricles. We analyzed the CSF by flow cytometry in two experiments (trained and untrained) to elucidate the presence of CX3CL1+ -MVs. The hippocampal TNF-α as an inflammatory factor was assessed by immunohistochemistry. RESULTS The Aβ induced spatial memory impairment after two weeks, verified by a decrease in the escape latency in Morris water maze test. It caused an increase in the anxiety-like behaviors demonstrated by a decrease in entries into the open arms of elevated plus maze test. The Aβ increased the percent of the positive area for TNF-α staining. Histological evaluation of the hippocampus confirmed the tissue injuries. The CSF levels of CX3CL1+ -MVs, increased 2 and 7 days after Aβ injection. The Aβ increased the TNF-α staining and provided an inflammatory context to facilitate the MVs release. The rise of CX3CL1+ -MVs was transient and subsided after two weeks. Both trained and untrained experiments showed a similar rise pattern of CX3CL1+ -MVs. CONCLUSION Increase of fractalkine-positive microvesicles preceded the cognitive impairment, more studies are required to approve the CX3CL1+ -MVs as a potential biomarker in the early diagnosis of Alzheimer's disease.
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25
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Smith JB, Herbert JJ, Truong NR, Cunningham AL. Cytokines and chemokines: The vital role they play in herpes simplex virus mucosal immunology. Front Immunol 2022; 13:936235. [PMID: 36211447 PMCID: PMC9538770 DOI: 10.3389/fimmu.2022.936235] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 09/08/2022] [Indexed: 11/17/2022] Open
Abstract
Herpes simplex viruses (HSV) types 1 and 2 are ubiquitous infections in humans. They cause orofacial and genital herpes with occasional severe complications. HSV2 also predisposes individuals to infection with HIV. There is currently no vaccine or immunotherapy for these diseases. Understanding the immunopathogenesis of HSV infections is essential to progress towards these goals. Both HSV viruses result in initial infections in two major sites - in the skin or mucosa, either after initial infection or recurrence, and in the dorsal root or trigeminal ganglia where the viruses establish latency. HSV1 can also cause recurrent infection in the eye. At all of these sites immune cells respond to control infection. T cells and resident dendritic cells (DCs) in the skin/mucosa and around reactivating neurones in the ganglia, as well as keratinocytes in the skin and mucosa, are major sources of cytokines and chemokines. Cytokines such as the Type I and II interferons synergise in their local antiviral effects. Chemokines such as CCL2, 3 and 4 are found in lesion vesicle fluid, but their exact role in determining the interactions between epidermal and dermal DCs and with resident memory and infiltrating CD4 and CD8 T cells in the skin/mucosa is unclear. Even less is known about these mechanisms in the ganglia. Here we review the data on known sources and actions of these cytokines and chemokines at cellular and tissue level and indicate their potential for preventative and therapeutic interventions.
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Affiliation(s)
- Jacinta B. Smith
- Centre for Virus Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Jason J. Herbert
- Centre for Virus Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Naomi R. Truong
- Centre for Virus Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Anthony L. Cunningham
- Centre for Virus Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- *Correspondence: Anthony L. Cunningham,
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26
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Role of Chemokines in the Development and Progression of Alzheimer's Disease. J Mol Neurosci 2022; 72:1929-1951. [PMID: 35821178 PMCID: PMC9392685 DOI: 10.1007/s12031-022-02047-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/04/2022] [Indexed: 11/24/2022]
Abstract
Alzheimer’s disease (AD) is a progressive neurogenerative disorder manifested by gradual memory loss and cognitive decline due to profound damage of cholinergic neurons. The neuropathological hallmarks of AD are intracellular deposits of neurofibrillary tangles (NFTs) and extracellular aggregates of amyloid β (Aβ). Mounting evidence indicates that intensified neuroinflammatory processes play a pivotal role in the pathogenesis of AD. Chemokines serve as signaling molecules in immune cells but also in nerve cells. Under normal conditions, neuroinflammation plays a neuroprotective role against various harmful factors. However, overexpression of chemokines initiates disruption of the integrity of the blood–brain barrier, facilitating immune cells infiltration into the brain. Then activated adjacent glial cells–astrocytes and microglia, release massive amounts of chemokines. Prolonged inflammation loses its protective role and drives an increase in Aβ production and aggregation, impairment of its clearance, or enhancement of tau hyperphosphorylation, contributing to neuronal loss and exacerbation of AD. Moreover, chemokines can be further released in response to growing deposits of toxic forms of Aβ. On the other hand, chemokines seem to exert multidimensional effects on brain functioning, including regulation of neurogenesis and synaptic plasticity in regions responsible for memory and cognitive abilities. Therefore, underexpression or complete genetic ablation of some chemokines can worsen the course of AD. This review covers the current state of knowledge on the role of particular chemokines and their receptors in the development and progression of AD. Special emphasis is given to their impact on forming Aβ and NFTs in humans and in transgenic murine models of AD.
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27
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Pinelli F, Pizzetti F, Veneruso V, Petillo E, Raghunath M, Perale G, Veglianese P, Rossi F. Biomaterial-Mediated Factor Delivery for Spinal Cord Injury Treatment. Biomedicines 2022; 10:biomedicines10071673. [PMID: 35884981 PMCID: PMC9313204 DOI: 10.3390/biomedicines10071673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/24/2022] [Accepted: 07/05/2022] [Indexed: 11/19/2022] Open
Abstract
Spinal cord injury (SCI) is an injurious process that begins with immediate physical damage to the spinal cord and associated tissues during an acute traumatic event. However, the tissue damage expands in both intensity and volume in the subsequent subacute phase. At this stage, numerous events exacerbate the pathological condition, and therein lies the main cause of post-traumatic neural degeneration, which then ends with the chronic phase. In recent years, therapeutic interventions addressing different neurodegenerative mechanisms have been proposed, but have met with limited success when translated into clinical settings. The underlying reasons for this are that the pathogenesis of SCI is a continued multifactorial disease, and the treatment of only one factor is not sufficient to curb neural degeneration and resulting paralysis. Recent advances have led to the development of biomaterials aiming to promote in situ combinatorial strategies using drugs/biomolecules to achieve a maximized multitarget approach. This review provides an overview of single and combinatorial regenerative-factor-based treatments as well as potential delivery options to treat SCIs.
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Affiliation(s)
- Filippo Pinelli
- Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”, Politecnico di Milano, Via Mancinelli 7, 20131 Milan, Italy; (F.P.); (F.P.); (E.P.)
| | - Fabio Pizzetti
- Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”, Politecnico di Milano, Via Mancinelli 7, 20131 Milan, Italy; (F.P.); (F.P.); (E.P.)
| | - Valeria Veneruso
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milan, Italy;
| | - Emilia Petillo
- Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”, Politecnico di Milano, Via Mancinelli 7, 20131 Milan, Italy; (F.P.); (F.P.); (E.P.)
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milan, Italy;
| | - Michael Raghunath
- Center for Cell Biology and Tissue Engineering, Institute for Chemistry and Biotechnology (ICBT), Zurich University of Applied Sciences (ZHAW), 8820 Wädenswil, Switzerland;
| | - Giuseppe Perale
- Faculty of Biomedical Sciences, University of Southern Switzerland (USI), Via Buffi 13, 6900 Lugano, Switzerland;
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Donaueschingenstrasse 13, 1200 Vienna, Austria
| | - Pietro Veglianese
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milan, Italy;
- Correspondence: (P.V.); (F.R.); Tel.: +39-02-3901-4205 (P.V.); +39-02-2399-3145 (F.R.)
| | - Filippo Rossi
- Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”, Politecnico di Milano, Via Mancinelli 7, 20131 Milan, Italy; (F.P.); (F.P.); (E.P.)
- Correspondence: (P.V.); (F.R.); Tel.: +39-02-3901-4205 (P.V.); +39-02-2399-3145 (F.R.)
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Silva R, Malcangio M. Fractalkine/CX 3CR 1 Pathway in Neuropathic Pain: An Update. FRONTIERS IN PAIN RESEARCH 2022; 2:684684. [PMID: 35295489 PMCID: PMC8915718 DOI: 10.3389/fpain.2021.684684] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 06/30/2021] [Indexed: 01/23/2023] Open
Abstract
Injuries to the nervous system can result in a debilitating neuropathic pain state that is often resistant to treatment with available analgesics, which are commonly associated with several side-effects. Growing pre-clinical and clinical evidence over the last two decades indicates that immune cell-mediated mechanisms both in the periphery and in the Central Nervous System (CNS) play significant roles in the establishment and maintenance of neuropathic pain. Specifically, following peripheral nerve injury, microglia, which are CNS resident immune cells, respond to the activity of the first pain synapse in the dorsal horn of spinal cord and also to neuronal activity in higher centres in the brain. This microglial response leads to the production and release of several proinflammatory mediators which contribute to neuronal sensitisation under neuropathic pain states. In this review, we collect evidence demonstrating the critical role played by the Fractalkine/CX3CR1 signalling pathway in neuron-to-microglia communication in neuropathic pain states and explore how strategies that include components of this pathway offer opportunities for innovative targets for neuropathic pain.
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Affiliation(s)
- Rita Silva
- Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom
| | - Marzia Malcangio
- Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom
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29
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Kanzawa T, Tokita D, Saiga K, Yamakawa T, Ishigooka H, Fukuda H, Katsumata H, Miyairi S, Ishii R, Hirai T, Imai T, Okumi M, Tanabe K. Role of Fractalkine-CX3CR1 Axis in Acute Rejection of Mouse Heart Allografts Subjected to Ischemia Reperfusion Injury. Transpl Int 2022; 35:10157. [PMID: 35185378 PMCID: PMC8842273 DOI: 10.3389/ti.2022.10157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 01/10/2022] [Indexed: 11/24/2022]
Abstract
Transplantation outcomes are affected by the increase in rejection associated with ischemia reperfusion injury (IRI). Fractalkine (FKN), a chemokine for recruitment of CX3CR1+ leukocytes, contributes to the pathogenesis of various inflammatory diseases. Herein, we evaluated the importance of the FKN-CX3CR1 axis during IRI-related rejections using a mouse heterotopic heart transplantation model. FKN expression and graft survival was compared between wild-type C57BL/6 recipients transplanted with BALB/c hearts preserved for 8 (WT-IRI) and 0.5 h (WT-control) at 4°C. Graft survival of WT-IRI was shorter than that of WT-control. FKN was expressed on the vascular endothelium in WT-IRI allografts, but minimally in WT-control. The role of the FKN-CX3CR1 axis in IRI-related rejection was directly investigated using the transplant model with CX3CR1-deficient recipients (CX3CR1 KO-IRI) or treatment with anti-mouse FKN monoclonal antibodies. Graft survival of CX3CR1 KO-IRI was longer than that of WT-IRI; antibody treatment prolonged graft survival. The contribution of CX3CR1+ monocytes to IRI-related rejection was evaluated by adoptive transfer to CX3CR1 KO-IRI. Adoptive transfer of CX3CR1+ monocytes attenuated the effect of prolonged graft survival in CX3CR1 KO-IRI. Overall, the FKN-CX3CR1 axis plays a major role during IRI-related rejection; its blockade has the potential to improve the outcomes of deceased donor transplantation.
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Affiliation(s)
- Taichi Kanzawa
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | - Daisuke Tokita
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
- Clinical and Academic Research Promotion Center, Tokyo Women’s Medical University, Tokyo, Japan
- *Correspondence: Daisuke Tokita, ; Kan Saiga,
| | - Kan Saiga
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
- Department of Urology, Jyoban Hospital of Tokiwa Foundation, Fukushima, Japan
- *Correspondence: Daisuke Tokita, ; Kan Saiga,
| | - Takafumi Yamakawa
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | | | - Hironori Fukuda
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | - Haruki Katsumata
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | - Satoshi Miyairi
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | - Rumi Ishii
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | - Toshihito Hirai
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | | | - Masayoshi Okumi
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | - Kazunari Tanabe
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
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30
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Jiang G, Wang H, Huang D, Wu Y, Ding W, Zhou Q, Ding Q, Zhang N, Na R, Xu K. The Clinical Implications and Molecular Mechanism of CX3CL1 Expression in Urothelial Bladder Cancer. Front Oncol 2021; 11:752860. [PMID: 34671562 PMCID: PMC8521074 DOI: 10.3389/fonc.2021.752860] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 09/14/2021] [Indexed: 02/05/2023] Open
Abstract
Background CX3CL1 is a chemokine that may play important roles in cancer immune regulation. Its mechanism in bladder cancer (BCa) is poorly understood. The objective of the current study was to evaluate the association between CX3CL1 and BCa and the related biological mechanisms. Methods A total of 277 patients with BCa were enrolled in the present study. The association between CX3CL1 expression and disease outcome was evaluated. In vitro and in vivo experiments were performed using the TCCSUP cell line to investigate the function of CX3CL1 in BCa. Results Compared with low expression, high expression of CX3CL1 was significantly associated with poorer progression-free survival (hazard ratio [HR]=2.03, 95% confidence interval [95% CI]: 1.26-3.27, P=0.006), cancer-specific survival (HR=2.16, 95% CI: 1.59-2.93, P<0.001), and overall survival (HR=1.55, 95% CI: 1.08-2.24, P=0.039). Multivariable Cox regression analysis suggested that CX3CL1 was an independent prognostic factor for BCa outcomes. In vitro and in vivo experiments indicated that high expression of CX3CL1 was significantly associated with cell proliferation (P<0.001) and invasion (P<0.001). Gene expression profiling results showed that after CX3CL1 knockdown, CDH1 was significantly upregulated, while ETS1, RAF1, and EIF4E were significantly downregulated. Pathway enrichment analysis suggested that the ERK/MAPK signaling pathway was significantly inhibited (P<0.001). Conclusions CX3CL1 is an independent predictor of a poor prognosis in BCa and can promote the proliferation and invasion of BCa cells.
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Affiliation(s)
- Guangliang Jiang
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Wang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.,Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.,Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Da Huang
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yishuo Wu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.,Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Weihong Ding
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.,Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Qidong Zhou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.,Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Qiang Ding
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.,Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Ning Zhang
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rong Na
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ke Xu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.,Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
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31
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Impact of Age on Plasma Inflammatory Biomarkers in the 6 Months Following Mild Traumatic Brain Injury. J Head Trauma Rehabil 2021; 35:324-331. [PMID: 32881766 DOI: 10.1097/htr.0000000000000606] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE To compare plasma inflammatory biomarker concentrations to 6 months in young and older adults with and without mild traumatic brain injury (TBI). SETTING Level 1 trauma center. PARTICIPANTS Younger (21-54 years) and older (55+) adults diagnosed with mild TBI along with age-/sex-matched noninjured controls (n = 313). DESIGN Prospective cohort study. MAIN MEASURES Multiplex assays were used to quantify concentrations of selected plasma inflammatory markers at day 0, months 1 and 6. RESULTS Persistent aging-related differences were found between control groups in concentrations of 4 cytokines up to 6 months. At day 0, interleukin-6 (IL-6), IL-8, and fractalkine were higher in the older TBI compared with older control as well as the younger TBI groups, while IL-10 was higher in older TBI compared with controls. At month 1, significantly higher concentrations of IL-8, fractalkine, and tumor necrosis factor-α (TNF-α) were seen. At 6 months postinjury, significantly higher concentrations of IL-6 and IL-8 were seen, while a lower concentration of IL-7 was found in older versus younger TBI groups. CONCLUSION The neuroinflammatory signature that accompanies mild TBI in older adults differs from that of younger adults. The differences seen are notable for their roles in neutrophil attraction (IL-8), neuronal-microglial-immune cell interactions (fractalkine), and chronic inflammation (IL-6).
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32
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Stothert AR, Kaur T. Innate Immunity to Spiral Ganglion Neuron Loss: A Neuroprotective Role of Fractalkine Signaling in Injured Cochlea. Front Cell Neurosci 2021; 15:694292. [PMID: 34408629 PMCID: PMC8365835 DOI: 10.3389/fncel.2021.694292] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 07/14/2021] [Indexed: 12/20/2022] Open
Abstract
Immune system dysregulation is increasingly being attributed to the development of a multitude of neurodegenerative diseases. This, in large part, is due to the delicate relationship that exists between neurons in the central nervous system (CNS) and peripheral nervous system (PNS), and the resident immune cells that aid in homeostasis and immune surveillance within a tissue. Classically, the inner ear was thought to be immune privileged due to the presence of a blood-labyrinth barrier. However, it is now well-established that both vestibular and auditory end organs in the inner ear contain a resident (local) population of macrophages which are the phagocytic cells of the innate-immune system. Upon cochlear sterile injury or infection, there is robust activation of these resident macrophages and a predominant increase in the numbers of macrophages as well as other types of leukocytes. Despite this, the source, nature, fate, and functions of these immune cells during cochlear physiology and pathology remains unclear. Migration of local macrophages and infiltration of bone-marrow-derived peripheral blood macrophages into the damaged cochlea occur through various signaling cascades, mediated by the release of specific chemical signals from damaged sensory and non-sensory cells of the cochlea. One such signaling pathway is CX3CL1-CX3CR1, or fractalkine (FKN) signaling, a direct line of communication between macrophages and sensory inner hair cells (IHCs) and spiral ganglion neurons (SGNs) of the cochlea. Despite the known importance of this neuron-immune axis in CNS function and pathology, until recently it was not clear whether this signaling axis played a role in macrophage chemotaxis and SGN survival following cochlear injury. In this review, we will explore the importance of innate immunity in neurodegenerative disease development, specifically focusing on the regulation of the CX3CL1-CX3CR1 axis, and present evidence for a role of FKN signaling in cochlear neuroprotection.
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Affiliation(s)
- Andrew Rigel Stothert
- Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE, United States
| | - Tejbeer Kaur
- Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE, United States
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33
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Hamdan D, Robinson LA. Role of the CX 3CL1-CX 3CR1 axis in renal disease. Am J Physiol Renal Physiol 2021; 321:F121-F134. [PMID: 34121453 DOI: 10.1152/ajprenal.00059.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 06/08/2021] [Indexed: 12/12/2022] Open
Abstract
Excessive infiltration of immune cells into the kidney is a key feature of acute and chronic kidney diseases. The family of chemokines comprises key drivers of this process. Fractalkine [chemokine (C-X3-C motif) ligand 1 (CX3CL1)] is one of two unique chemokines synthesized as a transmembrane protein that undergoes proteolytic cleavage to generate a soluble species. Through interacting with its cognate receptor, chemokine (C-X3-C motif) receptor 1 (CX3CR1), CX3CL1 was originally shown to act as a conventional chemoattractant in the soluble form and as an adhesion molecule in the transmembrane form. Since then, other functions of CX3CL1 beyond leukocyte recruitment have been described, including cell survival, immunosurveillance, and cell-mediated cytotoxicity. This review summarizes diverse roles of CX3CL1 in kidney disease and potential uses as a therapeutic target and novel biomarker. As the CX3CL1-CX3CR1 axis has been shown to contribute to both detrimental and protective effects in various kidney diseases, a thorough understanding of how the expression and function of CX3CL1 are regulated is needed to unlock its therapeutic potential.
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Affiliation(s)
- Diana Hamdan
- Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Lisa A Robinson
- Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
- Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
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34
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Urban J, Suchankova M, Ganovska M, Leksa V, Sandor F, Tedlova E, Konig B, Bucova M. The Role of CX3CL1 and ADAM17 in Pathogenesis of Diffuse Parenchymal Lung Diseases. Diagnostics (Basel) 2021; 11:diagnostics11061074. [PMID: 34208027 PMCID: PMC8230701 DOI: 10.3390/diagnostics11061074] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 06/04/2021] [Accepted: 06/09/2021] [Indexed: 11/16/2022] Open
Abstract
Fractalkine (CX3CL1) is a unique chemokine that functions as a chemoattractant for effector cytotoxic lymphocytes and macrophages expressing fractalkine receptor CX3CR1. CX3CL1 exists in two forms—a soluble and a membrane-bound form. The soluble CX3CL1 is released from cell membranes by proteolysis by the TNF-α-converting enzyme/disintegrin-like metalloproteinase 17 (TACE/ADAM17) and ADAM10. In this study, we evaluated the diagnostic relevance and potential roles of CX3CL1 and ADAM17 in the pathogenesis of diffuse parenchymal lung diseases (DPLDs) in the human population. The concentration of CX3CL1 and ADAM17 was measured by the enzyme-linked immunosorbent assay (ELISA) test in bronchoalveolar lavage fluids of patients suffering from different DPLDs. The concentration of CX3CL1 was significantly higher in patients suffering from idiopathic pulmonary fibrosis (IPF) and hypersensitivity pneumonitis patients compared to the control group. A significantly higher concentration of CX3CL1 was measured in fibrotic DPLDs compared to non-fibrotic DLPD patients. We found a positive correlation of CX3CL1 levels with the number of CD8+ T cells, and a negative correlation with CD4+ T cells in BALF and diffusion capacity for carbon monoxide. The concentration of ADAM17 was significantly lower in the IPF group compared to the other DPLD groups. We noticed a significantly higher CX3CL1/ADAM17 ratio in the IPF group compared to the other DPLD groups. We suggest that CX3CL1 has a distinctive role in the pathogenesis of DPLDs. The level of CX3CL1 strongly correlates with the severity of lung parenchyma impairment. The results suggest that high values of CX3CL1/ADAM17 could be diagnostic markers for IPF.
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Affiliation(s)
- Jan Urban
- 4th Department of Pneumology and Phthisiology, National Institute for Tuberculosis, Respiratory Diseases and Thoracic Surgery, 059 84 Vysne Hagy, Slovakia
- Institute of Immunology, Faculty of Medicine Comenius University, 811 08 Bratislava, Slovakia; (M.S.); (M.B.)
- Correspondence: ; Tel.: +421-524-414-252
| | - Magda Suchankova
- Institute of Immunology, Faculty of Medicine Comenius University, 811 08 Bratislava, Slovakia; (M.S.); (M.B.)
| | - Martina Ganovska
- Department of Clinical Laboratories, National Institute for Tuberculosis, Respiratory Diseases and Thoracic Surgery, 059 84 Vysne Hagy, Slovakia;
| | - Vladimir Leksa
- Institute of Molecular Biology, Slovak Academy of Sciences, 845 51 Bratislava, Slovakia;
- Centre for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical University of Vienna, A-9010 Vienna, Austria
| | - Frantisek Sandor
- Department of Pneumology and Phthisiology, Faculty of Medicine Comenius University and University Hospital, 821 01 Bratislava, Slovakia; (F.S.); (E.T.)
| | - Eva Tedlova
- Department of Pneumology and Phthisiology, Faculty of Medicine Comenius University and University Hospital, 821 01 Bratislava, Slovakia; (F.S.); (E.T.)
| | - Brian Konig
- Department of Operations Research and Econometrics, Faculty of Economic Informatics, University of Economics in Bratislava, 852 35 Bratislava, Slovakia;
- Institute of Economic Research of Slovak Academy of Sciences, 811 05 Bratislava, Slovakia
| | - Maria Bucova
- Institute of Immunology, Faculty of Medicine Comenius University, 811 08 Bratislava, Slovakia; (M.S.); (M.B.)
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Cormican S, Griffin MD. Fractalkine (CX3CL1) and Its Receptor CX3CR1: A Promising Therapeutic Target in Chronic Kidney Disease? Front Immunol 2021; 12:664202. [PMID: 34163473 PMCID: PMC8215706 DOI: 10.3389/fimmu.2021.664202] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 05/11/2021] [Indexed: 12/19/2022] Open
Abstract
Innate immune cells are key contributors to kidney inflammation and fibrosis. Infiltration of the renal parenchyma by innate immune cells is governed by multiple signalling pathways. Since the discovery of the chemokine fractalkine (CX3CL1) and its receptor, CX3CR1 over twenty years ago, a wealth of evidence has emerged linking CX3CL1-CX3CR1 signalling to renal pathologies in both acute and chronic kidney diseases (CKD). However, despite the extent of data indicating a pathogenic role for this pathway in kidney disease and its complications, no human trials of targeted therapeutic agents have been reported. Although acute autoimmune kidney disease is often successfully treated with immunomodulatory medications, there is a notable lack of treatment options for patients with progressive fibrotic CKD. In this article we revisit the CX3CL1-CX3CR1 axis and its functional roles. Furthermore we review the accumulating evidence that CX3CL1-CX3CR1 interactions mediate important events in the intra-renal pathophysiology of CKD progression, particularly via recruitment of innate immune cells into the kidney. We also consider the role that systemic activation of the CX3CL1-CX3CR1 axis in renal disease contributes to CKD-associated cardiovascular disease. Based on this evidence, we highlight the potential for therapies targeting CX3CL1 or CX3CR1 to benefit people living with CKD.
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Affiliation(s)
- Sarah Cormican
- Regenerative Medical Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland
- Nephrology Services, Galway University Hospitals, Saolta University Health Group, Galway, Ireland
| | - Matthew D. Griffin
- Regenerative Medical Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland
- Nephrology Services, Galway University Hospitals, Saolta University Health Group, Galway, Ireland
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36
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Landscape of Exhausted Virus-Specific CD8 T Cells in Chronic LCMV Infection. Cell Rep 2021; 32:108078. [PMID: 32846135 DOI: 10.1016/j.celrep.2020.108078] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 01/31/2020] [Accepted: 08/05/2020] [Indexed: 01/14/2023] Open
Abstract
A hallmark of chronic infections is the presence of exhausted CD8 T cells, characterized by a distinct transcriptional program compared with functional effector or memory cells, co-expression of multiple inhibitory receptors, and impaired effector function, mainly driven by recurrent T cell receptor engagement. In the context of chronic lymphocytic choriomeningitis virus (LCMV) infection in mice, most studies focused on studying splenic virus-specific CD8 T cells. Here, we provide a detailed characterization of exhausted CD8 T cells isolated from six different tissues during established LCMV infection, using single-cell RNA sequencing. Our data reveal that exhausted cells are heterogeneous, adopt organ-specific transcriptomic profiles, and can be divided into five main functional subpopulations: advanced exhaustion, effector-like, intermediate, proliferating, or memory-like. Adoptive transfer experiments showed that these phenotypes are plastic, suggesting that the tissue microenvironment has a major impact in shaping the phenotype and function of virus-specific CD8 T cells during chronic infection.
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Saxena S, Singh RK. Chemokines orchestrate tumor cells and the microenvironment to achieve metastatic heterogeneity. Cancer Metastasis Rev 2021; 40:447-476. [PMID: 33959849 PMCID: PMC9863248 DOI: 10.1007/s10555-021-09970-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 04/22/2021] [Indexed: 01/26/2023]
Abstract
Chemokines, a subfamily of the cell cytokines, are low molecular weight proteins known to induce chemotaxis in leukocytes in response to inflammatory and pathogenic signals. A plethora of literature demonstrates that chemokines and their receptors regulate tumor progression and metastasis. With these diverse functionalities, chemokines act as a fundamental link between the tumor cells and their microenvironment. Recent studies demonstrate that the biology of chemokines and their receptor in metastasis is complex as numerous chemokines are involved in regulating site-specific tumor growth and metastasis. Successful treatment of disseminated cancer is a significant challenge. The most crucial problem for treating metastatic cancer is developing therapy regimes capable of overcoming heterogeneity problems within primary tumors and among metastases and within metastases (intralesional). This heterogeneity of malignant tumor cells can be related to metastatic potential, response to chemotherapy or specific immunotherapy, and many other factors. In this review, we have emphasized the role of chemokines in the process of metastasis and metastatic heterogeneity. Individual chemokines may not express the full potential to address metastatic heterogeneity, but chemokine networks need exploration. Understanding the interplay between chemokine-chemokine receptor networks between the tumor cells and their microenvironment is a novel approach to overcome the problem of metastatic heterogeneity. Recent advances in the understanding of chemokine networks pave the way for developing a potential targeted therapeutic strategy to treat metastatic cancer.
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Affiliation(s)
- Sugandha Saxena
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 Nebraska Medical Center, Omaha, NE, 68198-5900, USA
| | - Rakesh K Singh
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 Nebraska Medical Center, Omaha, NE, 68198-5900, USA.
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Lee B, Shin M, Park Y, Won SY, Cho KS. Physical Exercise-Induced Myokines in Neurodegenerative Diseases. Int J Mol Sci 2021; 22:ijms22115795. [PMID: 34071457 PMCID: PMC8198301 DOI: 10.3390/ijms22115795] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/24/2021] [Accepted: 05/25/2021] [Indexed: 12/18/2022] Open
Abstract
Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are disorders characterized by progressive degeneration of the nervous system. Currently, there is no disease-modifying treatments for most NDs. Meanwhile, numerous studies conducted on human and animal models over the past decades have showed that exercises had beneficial effects on NDs. Inter-tissue communication by myokine, a peptide produced and secreted by skeletal muscles during exercise, is thought to be an important underlying mechanism for the advantages. Here, we reviewed studies about the effects of myokines regulated by exercise on NDs and their mechanisms. Myokines could exert beneficial effects on NDs through a variety of regulatory mechanisms, including cell survival, neurogenesis, neuroinflammation, proteostasis, oxidative stress, and protein modification. Studies on exercise-induced myokines are expected to provide a novel strategy for treating NDs, for which there are no adequate treatments nowadays. To date, only a few myokines have been investigated for their effects on NDs and studies on mechanisms involved in them are in their infancy. Therefore, future studies are needed to discover more myokines and test their effects on NDs.
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Affiliation(s)
- Banseok Lee
- Department of Biological Sciences, Konkuk University, Seoul 05029, Korea; (B.L.); (M.S.); (Y.P.)
| | - Myeongcheol Shin
- Department of Biological Sciences, Konkuk University, Seoul 05029, Korea; (B.L.); (M.S.); (Y.P.)
| | - Youngjae Park
- Department of Biological Sciences, Konkuk University, Seoul 05029, Korea; (B.L.); (M.S.); (Y.P.)
| | - So-Yoon Won
- Department of Biological Sciences, Konkuk University, Seoul 05029, Korea; (B.L.); (M.S.); (Y.P.)
- Korea Hemp Institute, Konkuk University, Seoul 05029, Korea
- Correspondence: (S.-Y.W.); (K.S.C.); Tel.: +82-10-3688-5474 (S.-Y.W.); Tel.: +82-2-450-3424 (K.S.C.)
| | - Kyoung Sang Cho
- Department of Biological Sciences, Konkuk University, Seoul 05029, Korea; (B.L.); (M.S.); (Y.P.)
- Korea Hemp Institute, Konkuk University, Seoul 05029, Korea
- Correspondence: (S.-Y.W.); (K.S.C.); Tel.: +82-10-3688-5474 (S.-Y.W.); Tel.: +82-2-450-3424 (K.S.C.)
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Nash WT, Okusa MD. Chess Not Checkers: Complexities Within the Myeloid Response to the Acute Kidney Injury Syndrome. Front Med (Lausanne) 2021; 8:676688. [PMID: 34124107 PMCID: PMC8187556 DOI: 10.3389/fmed.2021.676688] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 04/26/2021] [Indexed: 12/23/2022] Open
Abstract
Immune dysregulation in acute kidney injury (AKI) is an area of intense interest which promises to enhance our understanding of the disease and how to manage it. Macrophages are a heterogeneous and dynamic population of immune cells that carry out multiple functions in tissue, ranging from maintenance to inflammation. As key sentinels of their environment and the major immune population in the uninjured kidney, macrophages are poised to play an important role in the establishment and pathogenesis of AKI. These cells have a profound capacity to orchestrate downstream immune responses and likely participate in skewing the kidney environment toward either pathogenic inflammation or injury resolution. A clear understanding of macrophage and myeloid cell dynamics in the development of AKI will provide valuable insight into disease pathogenesis and options for intervention. This review considers evidence in the literature that speaks to the role and regulation of macrophages and myeloid cells in AKI. We also highlight barriers or knowledge gaps that need to be addressed as the field advances.
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Affiliation(s)
- William T Nash
- Division of Nephrology, Department of Medicine, Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, VA, United States
| | - Mark D Okusa
- Division of Nephrology, Department of Medicine, Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, VA, United States
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40
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Chamera K, Szuster-Głuszczak M, Basta-Kaim A. Shedding light on the role of CX3CR1 in the pathogenesis of schizophrenia. Pharmacol Rep 2021; 73:1063-1078. [PMID: 34021899 PMCID: PMC8413165 DOI: 10.1007/s43440-021-00269-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 04/22/2021] [Accepted: 04/26/2021] [Indexed: 11/24/2022]
Abstract
Schizophrenia has a complex and heterogeneous molecular and clinical picture. Over the years of research on this disease, many factors have been suggested to contribute to its pathogenesis. Recently, the inflammatory processes have gained particular interest in the context of schizophrenia due to the increasing evidence from epidemiological, clinical and experimental studies. Within the immunological component, special attention has been brought to chemokines and their receptors. Among them, CX3C chemokine receptor 1 (CX3CR1), which belongs to the family of seven-transmembrane G protein-coupled receptors, and its cognate ligand (CX3CL1) constitute a unique system in the central nervous system. In the view of regulation of the brain homeostasis through immune response, as well as control of microglia reactivity, the CX3CL1–CX3CR1 system may represent an attractive target for further research and schizophrenia treatment. In the review, we described the general characteristics of the CX3CL1–CX3CR1 axis and the involvement of this signaling pathway in the physiological processes whose disruptions are reported to participate in mechanisms underlying schizophrenia. Furthermore, based on the available clinical and experimental data, we presented a guide to understanding the implication of the CX3CL1–CX3CR1 dysfunctions in the course of schizophrenia.
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Affiliation(s)
- Katarzyna Chamera
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343, Kraków, Poland.
| | - Magdalena Szuster-Głuszczak
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343, Kraków, Poland
| | - Agnieszka Basta-Kaim
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343, Kraków, Poland
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Xu C, Wang YN, Wu H. Glutaminyl Cyclase, Diseases, and Development of Glutaminyl Cyclase Inhibitors. J Med Chem 2021; 64:6549-6565. [PMID: 34000808 DOI: 10.1021/acs.jmedchem.1c00325] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Pyroglutamate (pE) modification, catalyzed mainly by glutaminyl cyclase (QC), is prevalent throughout nature and is particularly important in mammals including humans for the maturation of hormones, peptides, and proteins. In humans, the upregulation of QC is involved in multiple diseases and conditions including Alzheimer's disease, Huntington's disease, melanomas, thyroid carcinomas, accelerated atherosclerosis, septic arthritics, etc. This upregulation catalyzes the generation of modified mediators such as pE-amyloid beta (Aß) and pE-chemokine ligand 2 (CCL2) peptides. Not surprisingly, QC has emerged as a reasonable target for the development of therapeutics to combat these diseases and conditions. In this manuscript the deleterious effects of upregulated QC resulting in disease manifestation are reviewed, along with progress on the development of QC inhibitors.
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Affiliation(s)
- Chenshu Xu
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
| | - Yi-Nan Wang
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
| | - Haiqiang Wu
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
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42
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Ayub M, Jin HK, Bae JS. The blood cerebrospinal fluid barrier orchestrates immunosurveillance, immunoprotection, and immunopathology in the central nervous system. BMB Rep 2021. [PMID: 33298242 PMCID: PMC8093941 DOI: 10.5483/bmbrep.2021.54.4.205] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Once characterized as an immune privileged area, recent scientific advances have demonstrated that the central nervous system (CNS) is both immunologically active and a specialized site. The anatomical and cellular features of the brain barriers, the glia limitans, and other superficial coverings of the CNS endow the brain with specificity for immune cell entry and other macro- and micro-elements to the brain. Cellular trafficking via barriers comprised of tightly junctioned non-fenestrated endothelium or tightly regulated fenestrated epithelium results in different phenotypic and cellular changes in the brain, that is, inflammatory versus regulatory changes. Based on emerging evidence, we described the unique ability of the blood cerebrospinal fluid barrier (BCSFB) to recruit, skew, and suppress immune cells. Additionally, we sum up the current knowledge on both cellular and molecular mechanisms governed by the choroid plexus and the cerebrospinal fluid at the BCSFB for immunosurveillance, immunoprotection, and immunopathology.
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Affiliation(s)
- Maria Ayub
- KNU Alzheimer’s disease Research Institute, Kyungpook National University, Daegu 41566, Korea
- Department of Physiology, School of Medicine, Kyungpook National University, Daegu 41944, Korea
- Department of Biomedical Science, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu 41944, Korea
| | - Hee Kyung Jin
- KNU Alzheimer’s disease Research Institute, Kyungpook National University, Daegu 41566, Korea
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Korea
| | - Jae-sung Bae
- KNU Alzheimer’s disease Research Institute, Kyungpook National University, Daegu 41566, Korea
- Department of Physiology, School of Medicine, Kyungpook National University, Daegu 41944, Korea
- Department of Biomedical Science, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu 41944, Korea
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43
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In Sickness and in Health: The Immunological Roles of the Lymphatic System. Int J Mol Sci 2021; 22:ijms22094458. [PMID: 33923289 PMCID: PMC8123157 DOI: 10.3390/ijms22094458] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/15/2021] [Accepted: 04/18/2021] [Indexed: 02/06/2023] Open
Abstract
The lymphatic system plays crucial roles in immunity far beyond those of simply providing conduits for leukocytes and antigens in lymph fluid. Endothelial cells within this vasculature are distinct and highly specialized to perform roles based upon their location. Afferent lymphatic capillaries have unique intercellular junctions for efficient uptake of fluid and macromolecules, while expressing chemotactic and adhesion molecules that permit selective trafficking of specific immune cell subsets. Moreover, in response to events within peripheral tissue such as inflammation or infection, soluble factors from lymphatic endothelial cells exert “remote control” to modulate leukocyte migration across high endothelial venules from the blood to lymph nodes draining the tissue. These immune hubs are highly organized and perfectly arrayed to survey antigens from peripheral tissue while optimizing encounters between antigen-presenting cells and cognate lymphocytes. Furthermore, subsets of lymphatic endothelial cells exhibit differences in gene expression relating to specific functions and locality within the lymph node, facilitating both innate and acquired immune responses through antigen presentation, lymph node remodeling and regulation of leukocyte entry and exit. This review details the immune cell subsets in afferent and efferent lymph, and explores the mechanisms by which endothelial cells of the lymphatic system regulate such trafficking, for immune surveillance and tolerance during steady-state conditions, and in response to infection, acute and chronic inflammation, and subsequent resolution.
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Cho I, Kim JM, Kim EJ, Kim SY, Kam EH, Cheong E, Suh M, Koo BN. Orthopedic surgery-induced cognitive dysfunction is mediated by CX3CL1/R1 signaling. J Neuroinflammation 2021; 18:93. [PMID: 33858422 PMCID: PMC8048361 DOI: 10.1186/s12974-021-02150-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 04/05/2021] [Indexed: 12/31/2022] Open
Abstract
Background Postoperative pain is a common phenomenon after surgery and is closely associated with the development of postoperative cognitive dysfunction (POCD). Persistent pain and systemic inflammation caused by surgery have been suggested as key factors for the development of POCD. Fractalkine (CX3CL1) and its receptor, the CX3C chemokine receptor 1 (CX3CR1), are known to play a key role in pain and inflammation signaling pathways. Recent studies have shown that the regulation of CX3CR1/L1 signaling influences the development of various diseases including neuronal diseases. We determined whether CX3CR1/L1 signaling is a putative therapeutic target for POCD in a mouse model. Methods Adult (9–11 weeks) male mice were treated with neutralizing antibody to block CX3CR1/L1 signaling both before and after surgery. Inflammatory and behavioral responses including pain were assessed postoperatively. Also, CX3CR1 mRNA level was assessed. Hippocampal astrocyte activation, Mao B expression, and GABA expression were assessed at 2 days after surgery following neutralizing antibody administration. Results The behavioral response indicated cognitive dysfunction and development of pain in the surgery group compared with the control group. Also, increased levels of pro-inflammatory cytokines and CX3CR1 mRNA were observed in the surgery group. In addition, increased levels of GABA and increased Mao B expression were observed in reactive astrocytes in the surgery group; these responses were attenuated by neutralizing antibody administration. Conclusions Increased CX3CR1 after surgery is both necessary and sufficient to induce cognitive dysfunction. CX3CR1 could be an important target for therapeutic strategies to prevent the development of POCD. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-021-02150-x.
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Affiliation(s)
- Inja Cho
- Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Jeong Min Kim
- Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Eun Jung Kim
- Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - So Yeon Kim
- Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Eun Hee Kam
- Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Eunji Cheong
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Minah Suh
- Department of Biomedical Engineering, Sungkyunkwan University, 2066, Seobu-ro, Jangan-gu, Suwon-si, Gyeong gi-do, 16419, Republic of Korea.,Center for Neuroscience Imaging Research (CNIR), Institute for Basic Science (IBS), Sungkyunkwan University, Suwon, Korea.,Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon, 16419, South Korea.,Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Suwon, 16419, South Korea
| | - Bon-Nyeo Koo
- Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. .,Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Korea.
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Rappl P, Rösser S, Maul P, Bauer R, Huard A, Schreiber Y, Thomas D, Geisslinger G, Jakobsson PJ, Weigert A, Brüne B, Schmid T. Inhibition of mPGES-1 attenuates efficient resolution of acute inflammation by enhancing CX3CL1 expression. Cell Death Dis 2021; 12:135. [PMID: 33542207 PMCID: PMC7862376 DOI: 10.1038/s41419-021-03423-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 01/09/2021] [Accepted: 01/11/2021] [Indexed: 02/07/2023]
Abstract
Despite the progress to understand inflammatory reactions, mechanisms causing their resolution remain poorly understood. Prostanoids, especially prostaglandin E2 (PGE2), are well-characterized mediators of inflammation. PGE2 is produced in an inducible manner in macrophages (Mϕ) by microsomal PGE2-synthase-1 (mPGES-1), with the notion that it also conveys pro-resolving properties. We aimed to characterize the role of mPGES-1 during resolution of acute, zymosan-induced peritonitis. Experimentally, we applied the mPGES-1 inhibitor compound III (CIII) once the inflammatory response was established and confirmed its potent PGE2-blocking efficacy. mPGES-1 inhibition resulted in an incomplete removal of neutrophils and a concomitant increase in monocytes and Mϕ during the resolution process. The mRNA-seq analysis identified enhanced C-X3-C motif receptor 1 (CX3CR1) expression in resident and infiltrating Mϕ upon mPGES-1 inhibition. Besides elevated Cx3cr1 expression, its ligand CX3CL1 was enriched in the peritoneal lavage of the mice, produced by epithelial cells upon mPGES-1 inhibition. CX3CL1 not only increased adhesion and survival of Mϕ but its neutralization also completely reversed elevated inflammatory cell numbers, thereby normalizing the cellular, peritoneal composition during resolution. Our data suggest that mPGES-1-derived PGE2 contributes to the resolution of inflammation by preventing CX3CL1-mediated retention of activated myeloid cells at sites of injury.
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Affiliation(s)
- Peter Rappl
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Silvia Rösser
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Patrick Maul
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Rebekka Bauer
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Arnaud Huard
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Yannick Schreiber
- Fraunhofer Institute for Translational Medicine and Pharmacology, Frankfurt, Germany
| | - Dominique Thomas
- Institute of Clinical Pharmacology, pharmazentrum Frankfurt/ZAFES, University Hospital, Goethe-University Frankfurt, Frankfurt, Germany
| | - Gerd Geisslinger
- Fraunhofer Institute for Translational Medicine and Pharmacology, Frankfurt, Germany
- Institute of Clinical Pharmacology, pharmazentrum Frankfurt/ZAFES, University Hospital, Goethe-University Frankfurt, Frankfurt, Germany
| | - Per-Johan Jakobsson
- Rheumatology Unit, Dep. of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Andreas Weigert
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Bernhard Brüne
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.
- Fraunhofer Institute for Translational Medicine and Pharmacology, Frankfurt, Germany.
- German Cancer Consortium (DKTK), Partner Site Frankfurt, Frankfurt, Germany.
- Frankfurt Cancer Institute, Goethe-University Frankfurt, Frankfurt, Germany.
| | - Tobias Schmid
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.
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Suresh P, Phasuk S, Liu IY. Modulation of microglia activation and Alzheimer's disease: CX3 chemokine ligand 1/CX3CR and P2X 7R signaling. Tzu Chi Med J 2021; 33:1-6. [PMID: 33505871 PMCID: PMC7821819 DOI: 10.4103/tcmj.tcmj_144_20] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 08/05/2020] [Accepted: 08/24/2020] [Indexed: 12/20/2022] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive deficits. Two hallmarks of AD that cause chronic inflammation and lead to neuronal dysfunction and damage are tau tangles and amyloid plaques. Microglial cells, the primary immune cells of the central nervous system, maintain a homeostatic active/inactive state via a bidirectional, dynamic communication with neurons. Several studies have revealed that dysregulated microglial activation leads to AD pathology. Therefore, we reviewed the relationship between AD and two important signaling complexes, CX3 chemokine ligand 1 (CX3CL1)/CX3CR1 and ATP/P2X7R, that play critical roles in the regulation of microglial activation. CX3CL1/CX3CR1 is one important signaling which controls the microglia function. Altering this pathway can have opposite effects on amyloid and tau pathology in AD. Another important molecule is P2X7R which involves in the activation of microglia. Over activation of P2X7R is evident in AD pathogenesis. In this review, we discuss influence of the two signaling pathways at different stages of AD pathology as well as the drug candidates that can modulate CX3CL1/CX3CR1 and ATP/P2X7R.
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Affiliation(s)
- Pavithra Suresh
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
| | - Sarayut Phasuk
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
| | - Ingrid Y Liu
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
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Wu W, Ren F, Guo M, Yang J, Xiao Y, Liu W. Increased expression of CX3CL1 and CX3CR1 in papillary thyroid carcinoma. Histol Histopathol 2020; 35:1189-1196. [PMID: 32975307 DOI: 10.14670/hh-18-265] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
CX3CL1 and its receptor CX3CR1 axis are involved in the development, progression and metastasis of many types of cancers. It has been reported that CX3CL1 and CX3CR1 expression was upregulated in some solid tumors. However, their roles in thyroid cancer remain unknown. In the present study, we investigated the expression of CX3CL1 and CX3CR1 in human papillary thyroid carcinoma (PTC) and their clinical significance. In this study, using immunohistochemistry, we examined the expression of CX3CL1 and CX3CR1 in the tissues of 26 human PTC (including 17 classical or conventional (CPTC) and 9 follicular (FVPTC) variants of PTC; 15 cases without and 11 cases with lymph node metastasis) and 10 cases of nodular goiter (NG). Compared to NG, a significant increase in the expression of CX3CL1 and CX3CR1 was found in PTC overall, as well as in CPTC and FVPTC separately. Higher CX3CL1 expression was found in CPTC than in FVPTC, but there was no significant difference in CX3CR1 expression between these subtypes of PTC. When analyzing their expressions in PTC without and with lymph node metastasis, an increased expression of CX3CL1 and CX3CR1 was observed when compared to NG respectively. There was however no significant difference in CX3CL1 and CX3CR1 expressions in PTC without lymph node metastasis when compared to PTC with lymph node metastasis. Furthermore, when compared to NG, an increased expression of CX3CL1 was correlated with an increased expression of CX3CR1 in PTC. Our data indicate that CX3CL1 and CX3CR1 can be used as tumor markers for PTC and may be potential novel targets for cancer prevention and treatment.
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Affiliation(s)
- Wei Wu
- School of Humanities and Management, Jinzhou Medical University, Jinzhou, Liaoning, China.,Institute of Biological Anthropology, Jinzhou Medical University, Jinzhou, Liaoning, China.,Liaoning Province Key Laboratory of Human Phenome Research (LPKL-HPR), Jinzhou, Liaoning, China
| | - Fu Ren
- Institute of Biological Anthropology, Jinzhou Medical University, Jinzhou, Liaoning, China.,Liaoning Province Key Laboratory of Human Phenome Research (LPKL-HPR), Jinzhou, Liaoning, China.,Department of Anatomy, School of Basic Medical Sciences of Shenyang Medical College, Shenyang, Liaoning, China
| | - Miao Guo
- Department of Clinical Laboratory, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Jing Yang
- Department of Pathology, College of Basic Medical Sciences of Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Yanjie Xiao
- Department of Epidemiology, Public Health College of Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Wei Liu
- Institute of Biological Anthropology, Jinzhou Medical University, Jinzhou, Liaoning, China.,Liaoning Province Key Laboratory of Human Phenome Research (LPKL-HPR), Jinzhou, Liaoning, China.
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Yandamuri SS, Jiang R, Sharma A, Cotzomi E, Zografou C, Ma AK, Alvey JS, Cook LJ, Smith TJ, Yeaman MR, O'Connor KC. High-throughput investigation of molecular and cellular biomarkers in NMOSD. NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION 2020; 7:7/5/e852. [PMID: 32753407 PMCID: PMC7413712 DOI: 10.1212/nxi.0000000000000852] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Accepted: 06/19/2020] [Indexed: 12/21/2022]
Abstract
Objective To identify candidate biomarkers associated with neuromyelitis optica spectrum disorder (NMOSD) using high-throughput technologies that broadly assay the concentrations of serum analytes and frequencies of immune cell subsets. Methods Sera, peripheral blood mononuclear cells (PBMCs), and matched clinical data from participants with NMOSD and healthy controls (HCs) were obtained from the Collaborative International Research in Clinical and Longitudinal Experience Study NMOSD biorepository. Flow cytometry panels were used to measure the frequencies of 39 T-cell, B-cell, regulatory T-cell, monocyte, natural killer (NK) cell, and dendritic cell subsets in unstimulated PBMCs. In parallel, multiplex proteomics assays were used to measure 46 serum cytokines and chemokines in 2 independent NMOSD and HC cohorts. Multivariable regression models were used to assess molecular and cellular profiles in NMOSD compared with HC. Results NMOSD samples had a lower frequency of CD16+CD56+ NK cells. Both serum cohorts and multivariable logistic regression revealed increased levels of B-cell activating factor associated with NMOSD. Interleukin 6, CCL22, and CCL3 were also elevated in 1 NMOSD cohort of the 2 analyzed. Multivariable linear regression of serum analyte levels revealed a correlation between CX3CL1 (fractalkine) levels and the number of days since most recent disease relapse. Conclusions Integrative analyses of cytokines, chemokines, and immune cells in participants with NMOSD and HCs provide congruence with previously identified biomarkers of NMOSD and highlight CD16+CD56+ NK cells and CX3CL1 as potential novel biomarker candidates.
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Affiliation(s)
- Soumya S Yandamuri
- From the Department of Neurology (S.S.Y., A.S., E.C., C.Z., K.C.O.C.), Department of Immunobiology (R.J., K.C.O.C.), and Department of Pathology (A.K.M.), Yale School of Medicine, New Haven, CT; University of Utah School of Medicine (J.S.A., L.J.C.), Salt Lake City; Departments of Ophthalmology and Visual Sciences and Internal Medicine (T.J.S.), University of Michigan Medical School, Ann Arbor; Department of Medicine (M.R.Y.), David Geffen School of Medicine at the University of California, Los Angeles; Divisions of Molecular Medicine & Infectious Diseases (M.R.Y.), Harbor-UCLA Medical Center, Torrance; and Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center (M.R.Y.), Torrance
| | - Ruoyi Jiang
- From the Department of Neurology (S.S.Y., A.S., E.C., C.Z., K.C.O.C.), Department of Immunobiology (R.J., K.C.O.C.), and Department of Pathology (A.K.M.), Yale School of Medicine, New Haven, CT; University of Utah School of Medicine (J.S.A., L.J.C.), Salt Lake City; Departments of Ophthalmology and Visual Sciences and Internal Medicine (T.J.S.), University of Michigan Medical School, Ann Arbor; Department of Medicine (M.R.Y.), David Geffen School of Medicine at the University of California, Los Angeles; Divisions of Molecular Medicine & Infectious Diseases (M.R.Y.), Harbor-UCLA Medical Center, Torrance; and Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center (M.R.Y.), Torrance
| | - Aditi Sharma
- From the Department of Neurology (S.S.Y., A.S., E.C., C.Z., K.C.O.C.), Department of Immunobiology (R.J., K.C.O.C.), and Department of Pathology (A.K.M.), Yale School of Medicine, New Haven, CT; University of Utah School of Medicine (J.S.A., L.J.C.), Salt Lake City; Departments of Ophthalmology and Visual Sciences and Internal Medicine (T.J.S.), University of Michigan Medical School, Ann Arbor; Department of Medicine (M.R.Y.), David Geffen School of Medicine at the University of California, Los Angeles; Divisions of Molecular Medicine & Infectious Diseases (M.R.Y.), Harbor-UCLA Medical Center, Torrance; and Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center (M.R.Y.), Torrance
| | - Elizabeth Cotzomi
- From the Department of Neurology (S.S.Y., A.S., E.C., C.Z., K.C.O.C.), Department of Immunobiology (R.J., K.C.O.C.), and Department of Pathology (A.K.M.), Yale School of Medicine, New Haven, CT; University of Utah School of Medicine (J.S.A., L.J.C.), Salt Lake City; Departments of Ophthalmology and Visual Sciences and Internal Medicine (T.J.S.), University of Michigan Medical School, Ann Arbor; Department of Medicine (M.R.Y.), David Geffen School of Medicine at the University of California, Los Angeles; Divisions of Molecular Medicine & Infectious Diseases (M.R.Y.), Harbor-UCLA Medical Center, Torrance; and Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center (M.R.Y.), Torrance
| | - Chrysoula Zografou
- From the Department of Neurology (S.S.Y., A.S., E.C., C.Z., K.C.O.C.), Department of Immunobiology (R.J., K.C.O.C.), and Department of Pathology (A.K.M.), Yale School of Medicine, New Haven, CT; University of Utah School of Medicine (J.S.A., L.J.C.), Salt Lake City; Departments of Ophthalmology and Visual Sciences and Internal Medicine (T.J.S.), University of Michigan Medical School, Ann Arbor; Department of Medicine (M.R.Y.), David Geffen School of Medicine at the University of California, Los Angeles; Divisions of Molecular Medicine & Infectious Diseases (M.R.Y.), Harbor-UCLA Medical Center, Torrance; and Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center (M.R.Y.), Torrance
| | - Anthony K Ma
- From the Department of Neurology (S.S.Y., A.S., E.C., C.Z., K.C.O.C.), Department of Immunobiology (R.J., K.C.O.C.), and Department of Pathology (A.K.M.), Yale School of Medicine, New Haven, CT; University of Utah School of Medicine (J.S.A., L.J.C.), Salt Lake City; Departments of Ophthalmology and Visual Sciences and Internal Medicine (T.J.S.), University of Michigan Medical School, Ann Arbor; Department of Medicine (M.R.Y.), David Geffen School of Medicine at the University of California, Los Angeles; Divisions of Molecular Medicine & Infectious Diseases (M.R.Y.), Harbor-UCLA Medical Center, Torrance; and Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center (M.R.Y.), Torrance
| | - Jessica S Alvey
- From the Department of Neurology (S.S.Y., A.S., E.C., C.Z., K.C.O.C.), Department of Immunobiology (R.J., K.C.O.C.), and Department of Pathology (A.K.M.), Yale School of Medicine, New Haven, CT; University of Utah School of Medicine (J.S.A., L.J.C.), Salt Lake City; Departments of Ophthalmology and Visual Sciences and Internal Medicine (T.J.S.), University of Michigan Medical School, Ann Arbor; Department of Medicine (M.R.Y.), David Geffen School of Medicine at the University of California, Los Angeles; Divisions of Molecular Medicine & Infectious Diseases (M.R.Y.), Harbor-UCLA Medical Center, Torrance; and Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center (M.R.Y.), Torrance
| | - Lawrence J Cook
- From the Department of Neurology (S.S.Y., A.S., E.C., C.Z., K.C.O.C.), Department of Immunobiology (R.J., K.C.O.C.), and Department of Pathology (A.K.M.), Yale School of Medicine, New Haven, CT; University of Utah School of Medicine (J.S.A., L.J.C.), Salt Lake City; Departments of Ophthalmology and Visual Sciences and Internal Medicine (T.J.S.), University of Michigan Medical School, Ann Arbor; Department of Medicine (M.R.Y.), David Geffen School of Medicine at the University of California, Los Angeles; Divisions of Molecular Medicine & Infectious Diseases (M.R.Y.), Harbor-UCLA Medical Center, Torrance; and Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center (M.R.Y.), Torrance
| | - Terry J Smith
- From the Department of Neurology (S.S.Y., A.S., E.C., C.Z., K.C.O.C.), Department of Immunobiology (R.J., K.C.O.C.), and Department of Pathology (A.K.M.), Yale School of Medicine, New Haven, CT; University of Utah School of Medicine (J.S.A., L.J.C.), Salt Lake City; Departments of Ophthalmology and Visual Sciences and Internal Medicine (T.J.S.), University of Michigan Medical School, Ann Arbor; Department of Medicine (M.R.Y.), David Geffen School of Medicine at the University of California, Los Angeles; Divisions of Molecular Medicine & Infectious Diseases (M.R.Y.), Harbor-UCLA Medical Center, Torrance; and Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center (M.R.Y.), Torrance
| | - Michael R Yeaman
- From the Department of Neurology (S.S.Y., A.S., E.C., C.Z., K.C.O.C.), Department of Immunobiology (R.J., K.C.O.C.), and Department of Pathology (A.K.M.), Yale School of Medicine, New Haven, CT; University of Utah School of Medicine (J.S.A., L.J.C.), Salt Lake City; Departments of Ophthalmology and Visual Sciences and Internal Medicine (T.J.S.), University of Michigan Medical School, Ann Arbor; Department of Medicine (M.R.Y.), David Geffen School of Medicine at the University of California, Los Angeles; Divisions of Molecular Medicine & Infectious Diseases (M.R.Y.), Harbor-UCLA Medical Center, Torrance; and Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center (M.R.Y.), Torrance
| | - Kevin C O'Connor
- From the Department of Neurology (S.S.Y., A.S., E.C., C.Z., K.C.O.C.), Department of Immunobiology (R.J., K.C.O.C.), and Department of Pathology (A.K.M.), Yale School of Medicine, New Haven, CT; University of Utah School of Medicine (J.S.A., L.J.C.), Salt Lake City; Departments of Ophthalmology and Visual Sciences and Internal Medicine (T.J.S.), University of Michigan Medical School, Ann Arbor; Department of Medicine (M.R.Y.), David Geffen School of Medicine at the University of California, Los Angeles; Divisions of Molecular Medicine & Infectious Diseases (M.R.Y.), Harbor-UCLA Medical Center, Torrance; and Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center (M.R.Y.), Torrance.
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Meghraoui-Kheddar A, Barthelemy S, Boissonnas A, Combadière C. Revising CX3CR1 Expression on Murine Classical and Non-classical Monocytes. Front Immunol 2020; 11:1117. [PMID: 32582197 PMCID: PMC7283740 DOI: 10.3389/fimmu.2020.01117] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 05/07/2020] [Indexed: 12/25/2022] Open
Abstract
In mice, monocytes (Mo) are conventionally described as CX3CR1low classical Mo (CMo) and CX3CR1high non-classical Mo (NCMo) based on the expression of EGFP in Cx3cr1+/EGFP mice and by analogy with human CX3CR1 expression. Although this terminology is widely used, it may not reflect the expression of CX3CR1 on Mo subsets. Using an unsupervised multiparametric analysis of blood Mo in steady state and after sterile peritonitis, we observed that CX3CR1 expression did not discriminate the CMo from the NCMo subsets. Our results highlight that despite being a reliable reporter to discriminate Mo subpopulations, EGFP level in Cx3cr1+/EGFP mice does not reflect CX3CR1 expression measured by a fluorescently-labeled CX3CL1 chemokine and a CX3CR1 specific antibody. In conclusion, authors should be cautious not to identify murine classical and non-classical Mo as CX3CR1low and CX3CR1high but rather use alternative markers such as the combination of Ly6C and CD43.
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Affiliation(s)
- Aïda Meghraoui-Kheddar
- Sorbonne Université, Inserm, CNRS, Centre d'Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France.,Université Côte d'Azur, CNRS UMR7275, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Valbonne, France
| | - Sandrine Barthelemy
- Sorbonne Université, Inserm, CNRS, Centre d'Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France
| | - Alexandre Boissonnas
- Sorbonne Université, Inserm, CNRS, Centre d'Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France
| | - Christophe Combadière
- Sorbonne Université, Inserm, CNRS, Centre d'Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France
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Fractalkine/CX3CL1 in Neoplastic Processes. Int J Mol Sci 2020; 21:ijms21103723. [PMID: 32466280 PMCID: PMC7279446 DOI: 10.3390/ijms21103723] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 05/20/2020] [Accepted: 05/21/2020] [Indexed: 02/06/2023] Open
Abstract
Fractalkine/CX3C chemokine ligand 1 (CX3CL1) is a chemokine involved in the anticancer function of lymphocytes-mainly NK cells, T cells and dendritic cells. Its increased levels in tumors improve the prognosis for cancer patients, although it is also associated with a poorer prognosis in some types of cancers, such as pancreatic ductal adenocarcinoma. This work focuses on the 'hallmarks of cancer' involving CX3CL1 and its receptor CX3CR1. First, we describe signal transduction from CX3CR1 and the role of epidermal growth factor receptor (EGFR) in this process. Next, we present the role of CX3CL1 in the context of cancer, with the focus on angiogenesis, apoptosis resistance and migration and invasion of cancer cells. In particular, we discuss perineural invasion, spinal metastasis and bone metastasis of cancers such as breast cancer, pancreatic cancer and prostate cancer. We extensively discuss the importance of CX3CL1 in the interaction with different cells in the tumor niche: tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC) and microglia. We present the role of CX3CL1 in the development of active human cytomegalovirus (HCMV) infection in glioblastoma multiforme (GBM) brain tumors. Finally, we discuss the possible use of CX3CL1 in immunotherapy.
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