Activation and infiltration of neutrophils in the cerebellum and brainstem is associated with the atypical experimental autoimmune encephalomyelitis phenotype

Abstract

Abstract The JAK/STAT signaling is critical for the initiation, regulation and termination of immune responses, and dysregulation of JAK/STAT signaling is associated with many pathological conditions such as multiple sclerosis. We previously demonstrated that myeloid lineage–specific deletion of SOCS3, a negative regulator of STAT3, resulted in a severe, non-resolving atypical form of experimental autoimmune encephalomyelitis (EAE). Mice with atypical EAE exhibit ataxia and tremors and are characterized by lesions, inflammatory infiltrates, elevated STAT3 activation, and increased cytokine and chemokine expression in the cerebellum. In the current study, our data indicate that the atypical EAE observed in LysMCre-SOCS3fl/fl mice is associated with elevated pro-inflammatory cytokines and chemokines in the cerebellum and brainstem. Greater numbers of infiltrating neutrophils were found in the cerebellum and brainstem of LysMCre-SOCS3fl/fl mice compared to SOCS3fl/fl mice, however, neutrophil numbers in the periphery were comparable. Infiltrating neutrophils in LysMCre-SOCS3fl/fl mice have hyper-activated STAT3 and express higher levels of IL-6 and CCL2. Recruitment of Ly6Chi monocytes in LysMCre-SOCS3fl/flmice is comparable to SOCS3fl/fl mice. During the peak stage of disease, LysMCre-SOCS3fl/fl mice had increased numbers of both Th1 and Th17 cells, and significantly increased numbers of IFN-γ+IL-17+ T cells in the cerebellum and brainstem, compared to SOCS3fl/fl mice. Depletion of neutrophils in LysMCre-SOCS3fl/fl mice prevented the atypical EAE phenotype, rather, classical EAE was observed. This study illustrates the critical function of neutrophils in the pathogenesis of atypical EAE.