Preferential Recruitment of Neutrophils into the Cerebellum and Brainstem Contributes to the Atypical Experimental Autoimmune Encephalomyelitis Phenotype

摘要: The JAK/STAT pathway is critical for development, regulation, and termination of immune responses, dysregulation the pathway, that is, hyperactivation, has pathological implications in autoimmune neuroinflammatory diseases. Suppressor cytokine signaling 3 (SOCS3) regulates STAT3 activation response to cytokines play important roles pathogenesis diseases, including IL-6 IL-23. We previously demonstrated myeloid lineage–specific deletion SOCS3 resulted a severe, nonresolving atypical form experimental encephalomyelitis (EAE), characterized by lesions, inflammatory infiltrates, elevated STAT activation, chemokine expression cerebellum. Clinically, these mice exhibit ataxia tremors. In this study, we provide detailed analysis model, demonstrating EAE observed LysMCre-SOCS3fl/fl extensive neutrophil infiltration into cerebellum brainstem, increased inducible NO synthase levels prominent axonal damage. Importantly, infiltrating SOCS3-deficient neutrophils produce high CXCL2, CCL2, CXCL10, NO, TNF-α, IL-1β. Kinetic studies demonstrate brainstem closely correlates with clinical symptoms. Ab-mediated depletion converts phenotype classical and, some cases, mixed atypical/classical phenotype. Blocking CXCR2 ameliorates development reducing cerebellum/brainstem. Thus, lacking display proinflammatory mediators role EAE.