Administration of neuritin as a novel therapeutic strategy for autoimmune and inflammatory diseases

Autoimmune and inflammatory diseases are characterized by dysregulated T cell-mediated immune responses leading to tissue damage. Despite therapeutic advancements, patients remain resistant to treatment, highlighting the urgent need for alternative therapeutic strategies. Here, we identified neuritin (NRN), an immunosuppressive molecule, capable of restraining effector CD4+ T cell responses and mitigating autoimmune and inflammatory diseases. NRN is downregulated in CD4+ T cells of rheumatoid arthritis (RA) patients, driving T cell-mediated autoimmune pathology. Nrn^fl/flCD4^Cre mice exacerbate both experimental autoimmune encephalomyelitis (EAE) and dextran sulfate sodium (DSS)-induced colitis, characterized by regulatory T cell (Treg) depletion and expansion of interferon (IFN)-γ+ and interleukin (IL)-17+ pro-inflammatory cells. Mechanistically, NRN selectively binds to cannabinoid receptor 2 (CB2), but not to CB1, specifically through its threonine residues at positions T78 and T81. Meanwhile, mice lacking CB2 (CB2^-/- or CB2^fl/flCD4^Cre) exhibit worsened colitis, with an increased IFN-γ+ and IL-17+ cells, mirroring the Nrn^fl/flCD4^Cre phenotype. T cell-specific Nrn knockin (Nrn^KI/KICD4^Cre) or exogenous NRN administration ameliorated disease severity in multiple autoimmune models, including DSS-induced colitis, IMQ-induced psoriasis, and collagen-induced arthritis, by promoting Treg expansion and suppressing IFN-γ+ and IL-17+ pro-inflammatory cells. However, these protective effects of NRN were abolished in CB2-deficient mice. Overall, NRN is an immunosuppressive molecule with therapeutic potential in autoimmune and inflammatory diseases.