The Role of Interferon-g in the Determination of Central Nervous System Damage in Experimental Autoimmune Encephalomyelitis.

[摘要] In multiple Sclerosis (MS), a multifocal inflammatory demyelinating disease of the central nervous system (CNS), lesion distribution is variable between patients resulting in distinct patterns of disease progression and clinical deficits. The mechanisms regulating immune cell migration to and subsequent lesion development in different areas of the CNS are not well understood. Experimental Autoimmune Encephalomyelits (EAE), a critical model in developing effectiveMS therapies, can also be used to examine mechanisms driving lesion localization. In the adoptive transfer EAE model,myelin-specific CD4+ T cell transfer into wild type (WT) mice results in an ascending paralysis due to inflammation in the spinal cord (SC) (conventional EAE), while transfer of these same T cells into mice lacking the interferon-g receptor (IFNgR) results in balance deficits due to inflammation in the brainstem (BS) (atypical EAE). The reciprocal transfer of IFNg KO myelin-specific T cells into WT mice results predominantly in atypical EAE. In addition to deficiencies in IFN signaling, increased IL-17 signaling has also been shown to promote brain inflammation and atypical EAE pathogenesis. However, the mechanisms by which these cytokines promote distinct lesion localization are incompletely characterized.IFNg and IL-17 play reciprocal roles in the recruitment of neutrophils to sites of inflammation. The absence of IFNg or increased IL-17 signaling promote neutrophil infiltration in multiple infection and autoimmune models of disease. Some early studies examined neutrophil infiltration in EAE but none have examined their absolute requirement in atypical EAE. Using adoptive transfer models of EAE, we show that atypical EAE is driven by CXCR2-mediated recruitment of neutrophils to the brainstem, whereas conventional EAE is driven by CCR2-mediated recruitment of monocytes to the spinal cord. We also find that IFNg signaling suppresses atypical EAE by directly inhibiting CXCL2-dependent neutrophil recruitment axis.IFNg directly inhibits CXCL2 production by monocyte and microglia in the BS during EAE. Additionally, IFNg suppresses neutrophil production of CXCL2 in response to CXCR2 binding by directly inhibiting expression of the CXCR2 receptor on neutrophils in the CNS.Overall, these studies identify a distinct CXCR2-dependent recruitment pathway in CNS autoimmunity that is not currently targeted by current disease modifying therapies.

[发布机构] University of Michigan

[效力级别] Microbiology and Immunology

[关键词] Lesion Localization in Animal Model of Multiple Sclerosis;Microbiology and Immunology;Science;Immunology