Group 2 Innate Lymphoid Cells In Central Nervous System Inflammation And Autoimmunity

Objective:Central nervous system（CNS）immune and inflammatory responses participate in the pathogenesis of multiple neurological diseases including CNS autoimmune diseases including CNS autoimmune diseases（i.e.neuromyelitis optica spectrum disorders,NMOSD,and multiple sclerosis,MS）,and acute brain injury（i.e.intracerebral hemorrhage,ICH,and traumatic brain injury）.Previous studies have demonstrated that CNS inflammation contribute to the initiation and progression of neurological disorders.Yet little is known about endogenous counter-regulatory immune mechanisms that may repress CNS inflammation and autoimmunity.Group 2innate lymphoid cells（ILC2）are a distinct lineage of innate lymphocytes that are different from Th2 cells.ILC2 can mount potent type 2 immune responses.In the peripheral,ILC2 are known to control the imitation and resolution of tissue inflammation.However,still unknown are whether and how ILC2 influence CNS inflammation and autoimmunity.Using animal models of NMOSD and ICH,we aim to determine the role and mechanisms of ILC2 in CNS inflammation and autoimmunity.Method:Peripheral blood mononuclear cells（PBMCs）were extracted from peripheral blood of patients with neuromyelitis optica spectrum disorders.The number,frequency and proliferation of peripheral ILC2 were analyzed by flow cytometry.EDSS cores were obtained to compare the correlation between the number of ILC2 and the degree of disability.NMOSD animal model was induced by intra-parenchymal injections of NMO-Ig G and human complement（HC）.The CNS infiltration of ILC2 in NMOSD mice was confirmed by immunofluorescence staining.Flow cytometry was used to detect the number and function of peripheral and central ILC2 in NMOSD mice.To investigate whether ILC2 affects NMOSD pathology,we used antibody to deplete ILC2 in vivo.Anti-CD90.2 m Ab depletes both ILC2 and CD4⁺T cells.In contrast,anti-CD4 m Ab only depletes CD4⁺T cells.The size of the lesions was observed by 7T-MRI,and ¹⁸F-FDG PET/CT was scanned to visualize and evaluate cerebral glucose metabolism in the ipsilateral hemisphere after NMOSD.In addition,AQP4,GFAP,MBP,Iba1 and C5b-9 immunofluorescence staining were used to investigate pathological changes of NMOSD.Finally,recombinant IL-33 protein was used to amplify ILC2 in vivo.Immunofluorescence staining and 7T-MRI were used to observe NMOSD pathology.In the second part,ICH was induced by injection of bacterial collagenase.Flow cytometry was used to detect the number and function of peripheral and central ILC2in ICH mice.Result:In NMOSD patients,we identified a significant reduction of circulating ILC2in peripheral blood.In a mouse model of NMOSD induced by intracerebral injection of NMO-Ig G and human complement,we found infiltration of ILC2 into the CNS lesions.Notably,a large portion of CNS-infiltrating ILC2 express IL-5.Depletion of ILC2 led to increased lesion size,astrocyte injury and the loss of aquaporin-4 in the CNS.The exacerbated NMOSD pathology was accompanied by increased accumulation of microglia/macrophages in the CNS lesions.In addition,expansion of ILC2 using IL-33 attenuates NMOSD pathology.In the second part,we found infiltration of ILC2 into the CNS lesions after ICH induction.Besides,a large portion of CNS-infiltrating ILC2 express IL-5.Conclusion:These findings suggest that ILC2 can suppress CNS inflammation and autoimmunity.Immune interventions targeting ILC2 deserve further investigation as a potential therapy to benefit patients with NMOSD or ICH.