Anti–IL-6R antibody treatment changes microglial phenotype in AQP4 peptide–immunized mice, leading to suppression of myelitis severity

Abstract

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease characterized by periods of remission and relapse; severe relapses often lead to permanent neurological disability. Satralizumab, an anti–interleukin-6 receptor (anti–IL-6R) antibody, has been proven in previous studies to reduce the frequency and severity of relapses in patients with NMOSD. There are several reports on the mechanisms through which anti–IL-6R antibodies are thought to suppress relapse. However, the mechanisms underlying how anti–IL-6R antibodies reduce the severity of myelitis have not been elucidated. We investigated the effect of an anti–IL-6R antibody (MR16–1) on the severity of myelitis in an AQP4 peptide–immunized mice model. This mouse model exhibits NMOSD-like pathological characteristics and the production of anti-AQP4 autoantibodies. Unlike the previously reported experimental protocol where antibody and peptide are administered simultaneously, we tested delayed administration of MR16–1 (9 days after peptide immunization). We found that delayed MR16–1 administration suppressed the clinical score of AQP4 peptide–immunized mice experiencing myelitis. Mice treated with MR16–1 showed a greater percentage of CD11c⁺ microglia in the spinal cord, along with upregulated expression of phagocytosis-related genes. Blockade of IL-6R by anti–IL-6R antibodies may suppress the severity of myelitis by increasing CD11c⁺ microglia and enhancing phagocytic function in AQP4 peptide–immunized mice.