An IFN gamma/CXCL2 regulatory pathway determines lesion localization during EAE

作者：Stoolman Joshua S; Duncker Patrick C; Huber Amanda K; Giles David A; Washnock Schmid Jesse M; Soulika Athena M; Segal Benjamin M^*

来源：Journal of Neuroinflammation, 2018, 15(1): 208.

DOI：10.1186/s12974-018-1237-y

• Experimental autoimmune encephalomyelitis
• Multiple sclerosis
• Chemokines
• Cytokines
• Neutrophils
• Monocytes
• Interferon-gamma

Background: Myelin oligodendrocyte glycoprotein (MOG)-reactive T-helper (Th) 1 cells induce conventional experimental autoimmune encephalomyelitis (cEAE), characterized by ascending paralysis and monocytepredominant 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 IFN gamma receptor (IFN gamma R)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 IFN gamma-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 IFN.RKO adoptive transfer recipients during aEAE. In WT transfer recipients, IFN. 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 IFN gamma.
Conclusions: We provide evidence for an IFN gamma-regulated CXCR2/CXCL2 autocrine/paracrine feedback loop in innate immune cells that determines the location of CNS infiltrates during Th1-mediated EAE. When IFN. signaling is impaired, myeloid cell production of CXCL2 increases, which promotes brainstem inflammation and results in clinical ataxia. IFN., 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 IFN. and CXCL2 interact to direct regional recruitment of leukocytes in the CNS, resulting in distinct clinical presentations.

• 出版日期2018-7-16