دورية أكاديمية
An IFNγ/CXCL2 regulatory pathway determines lesion localization during EAE.
| العنوان: | An IFNγ/CXCL2 regulatory pathway determines lesion localization during EAE. |
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| المؤلفون: | Stoolman JS; Holtom-Garrett Program in Neuroimmunology and Multiple Sclerosis Center, Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA.; Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA.; Division of Allergy-Immunology, Division of Pulmonary and Critical Care, Northwestern University, Feinberg School of Medicine, 240 E. Huron Street, McGaw M410, Chicago, IL, 60611, USA., Duncker PC; Holtom-Garrett Program in Neuroimmunology and Multiple Sclerosis Center, Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA.; Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA., Huber AK; Holtom-Garrett Program in Neuroimmunology and Multiple Sclerosis Center, Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA., Giles DA; Holtom-Garrett Program in Neuroimmunology and Multiple Sclerosis Center, Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA.; Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA., Washnock-Schmid JM; Holtom-Garrett Program in Neuroimmunology and Multiple Sclerosis Center, Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA., Soulika AM; Institute for Pediatric Regenerative Medicine, UC Davis School of Medicine and Shriners Hospital, 2425 Stockton Blvd, Sacramento, CA, 95817, USA., Segal BM; Holtom-Garrett Program in Neuroimmunology and Multiple Sclerosis Center, Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA. bmsegal@umich.edu.; Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA. bmsegal@umich.edu.; Graduate Program in Neuroscience, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA. bmsegal@umich.edu.; Neurology Service, VA Ann Arbor Health Care System, Ann Arbor, MI, USA. bmsegal@umich.edu. |
| المصدر: | Journal of neuroinflammation [J Neuroinflammation] 2018 Jul 16; Vol. 15 (1), pp. 208. Date of Electronic Publication: 2018 Jul 16. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: BioMed Central Country of Publication: England NLM ID: 101222974 Publication Model: Electronic Cited Medium: Internet ISSN: 1742-2094 (Electronic) Linking ISSN: 17422094 NLM ISO Abbreviation: J Neuroinflammation Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [London] : BioMed Central, c2004- |
| مواضيع طبية MeSH: | Brain/*metabolism , Chemokine CXCL2/*metabolism , Encephalomyelitis, Autoimmune, Experimental/*pathology , Interferon-gamma/*metabolism , Signal Transduction/*physiology, Animals ; Brain/pathology ; Disease Models, Animal ; Encephalomyelitis, Autoimmune, Experimental/chemically induced ; Glial Fibrillary Acidic Protein/metabolism ; Interferon-gamma/genetics ; Interferon-gamma/pharmacology ; Leukocyte Common Antigens/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Monocytes/drug effects ; Monocytes/pathology ; Myelin-Oligodendrocyte Glycoprotein/toxicity ; Myeloid Cells/drug effects ; Neutrophil Infiltration/drug effects ; Neutrophils/pathology ; Parenchymal Tissue/pathology ; Peptide Fragments/toxicity ; RNA, Messenger/metabolism ; Signal Transduction/drug effects |
| مستخلص: | Background: Myelin oligodendrocyte glycoprotein (MOG)-reactive T-helper (Th)1 cells induce conventional experimental autoimmune encephalomyelitis (cEAE), characterized by ascending paralysis and monocyte-predominant spinal cord infiltrates, in C57BL/6 wildtype (WT) hosts. The same T cells induce an atypical form of EAE (aEAE), characterized by ataxia and neutrophil-predominant brainstem infiltrates, in syngeneic IFNγ receptor (IFNγR)-deficient hosts. Production of ELR+ CXC chemokines within the CNS is required for the development of aEAE, but not cEAE. The cellular source(s) and localization of ELR+ CXC chemokines in the CNS and the IFNγ-dependent pathways that regulate their production remain to be elucidated. Methods: The spatial distribution of inflammatory lesions and CNS expression of the ELR+ CXC chemokines, CXCL1 and CXCL2, were determined via immunohistochemistry and/or in situ hybridization. Levels of CXCL1 and CXCL2, and their cognate receptor CXCR2, were measured in/on leukocyte subsets by flow cytometric and quantitative PCR (qPCR) analysis. Bone marrow neutrophils and macrophages were cultured with inflammatory stimuli in vitro prior to measurement of CXCL2 and CXCR2 by qPCR or flow cytometry. Results: CNS-infiltrating neutrophils and monocytes, and resident microglia, are a prominent source of CXCL2 in the brainstem of IFNγRKO adoptive transfer recipients during aEAE. In WT transfer recipients, IFNγ directly suppresses CXCL2 transcription in microglia and myeloid cells, and CXCR2 transcription in CNS-infiltrating neutrophils. Consequently, infiltration of the brainstem parenchyma from the adjacent meninges is blocked during cEAE. CXCL2 directly stimulates its own expression in cultured neutrophils, which is enhanced by IL-1 and suppressed by IFNγ. Conclusions: We provide evidence for an IFNγ-regulated CXCR2/CXCL2 autocrine/paracrine feedback loop in innate immune cells that determines the location of CNS infiltrates during Th1-mediated EAE. When IFNγ signaling is impaired, myeloid cell production of CXCL2 increases, which promotes brainstem inflammation and results in clinical ataxia. IFNγ, produced within the CNS of WT recipients, suppresses myeloid cell CXCR2 and CXCL2 production, thereby skewing the location of neuroinflammatory infiltrates to the spinal cord and the clinical phenotype to an ascending paralysis. These data reveal a novel mechanism by which IFNγ and CXCL2 interact to direct regional recruitment of leukocytes in the CNS, resulting in distinct clinical presentations. |
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| معلومات مُعتمدة: | R01 NS057670 National Institute of Neurological Disorders and Stroke; R01 NS057670 United States NS NINDS NIH HHS; R01 NS105385 United States NS NINDS NIH HHS; I01RX000416 U.S. Department of Veterans Affairs; I01 BX001387 United States BX BLRD VA; I01 RX000416 United States RX RRD VA; R01 NS105385 National Institute of Neurological Disorders and Stroke |
| فهرسة مساهمة: | Keywords: Chemokines; Cytokines; Experimental autoimmune encephalomyelitis; Interferon-gamma; Monocytes; Multiple sclerosis; Neutrophils |
| المشرفين على المادة: | 0 (Chemokine CXCL2) 0 (Glial Fibrillary Acidic Protein) 0 (IFNG protein, mouse) 0 (Myelin-Oligodendrocyte Glycoprotein) 0 (Peptide Fragments) 0 (RNA, Messenger) 0 (myelin oligodendrocyte glycoprotein (35-55)) 82115-62-6 (Interferon-gamma) EC 3.1.3.48 (Leukocyte Common Antigens) |
| تواريخ الأحداث: | Date Created: 20180718 Date Completed: 20190520 Latest Revision: 20190520 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC6048869 |
| DOI: | 10.1186/s12974-018-1237-y |
| PMID: | 30012158 |
| قاعدة البيانات: | MEDLINE |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 1742-2094 |
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| DOI: | 10.1186/s12974-018-1237-y |