An IFNγ/CXCL2 regulatory pathway determines lesion localization during EAE.

Autor: 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.
Jazyk: angličtina
Zdroj: Journal of neuroinflammation [J Neuroinflammation] 2018 Jul 16; Vol. 15 (1), pp. 208. Date of Electronic Publication: 2018 Jul 16.
DOI: 10.1186/s12974-018-1237-y
Abstrakt: 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.
Databáze: MEDLINE
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