title: Preferential Recruitment of Neutrophils into the Cerebellum and Brainstem Contributes to the Atypical Experimental Autoimmune Encephalomyelitis Phenotype.
abstract: The JAK/STAT pathway is critical for development, regulation, and termination of immune responses, and dysregulation of the JAK/STAT pathway, that is, hyperactivation, has pathological implications in autoimmune and neuroinflammatory diseases. Suppressor of cytokine signaling 3 (SOCS3) regulates STAT3 activation in response to cytokines that play important roles in the pathogenesis of neuroinflammatory diseases, including IL-6 and IL-23. We previously demonstrated that myeloid lineage-specific deletion of SOCS3 resulted in a severe, nonresolving atypical form of experimental autoimmune encephalomyelitis (EAE), characterized by lesions, inflammatory infiltrates, elevated STAT activation, and elevated cytokine and chemokine expression in the cerebellum. Clinically, these mice exhibit ataxia and tremors. In this study, we provide a detailed analysis of this model, demonstrating that the atypical EAE observed in LysMCre-SOCS3(fl/fl) mice is characterized by extensive neutrophil infiltration into the cerebellum and brainstem, increased inducible NO synthase levels in the cerebellum and brainstem, and prominent axonal damage. Importantly, infiltrating SOCS3-deficient neutrophils produce high levels of CXCL2, CCL2, CXCL10, NO, TNF-α, and IL-1β. Kinetic studies demonstrate that neutrophil infiltration into the cerebellum and brainstem of LysMCre-SOCS3(fl/fl) mice closely correlates with atypical EAE clinical symptoms. Ab-mediated depletion of neutrophils converts the atypical phenotype to the classical EAE phenotype and, in some cases, a mixed atypical/classical phenotype. Blocking CXCR2 signaling ameliorates atypical EAE development by reducing neutrophil infiltration into the cerebellum/brainstem. Thus, neutrophils lacking SOCS3 display elevated STAT3 activation and expression of proinflammatory mediators and play a critical role in the development of atypical EAE.
authors.affiliation: Department of Cell, Developmental and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Yudong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cell, Developmental and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Holdbrooks
authors.affiliation: Department of Cell, Developmental and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Gordon P
authors.initials: GP
authors.lastname: Meares
authors.affiliation: Department of Cell, Developmental and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Buckley
authors.affiliation: Department of Cell, Developmental and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL 35294 hqin@uab.edu tika@uab.edu.
authors.forename: Etty N
authors.initials: EN
authors.lastname: Benveniste
authors.affiliation: Department of Cell, Developmental and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL 35294 hqin@uab.edu tika@uab.edu.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qin
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000166:cytology / Q000276:immunology*; D002531:Cerebellum / Q000166:cytology / Q000276:immunology*; D018925:Chemokines / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis; D053759:Interleukin-23 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D018925:Chemokines; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D053759:Interleukin-23; D015850:Interleukin-6; D023063:Receptors, Interleukin-8B; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse