Type I interferon‐activated microglia are critical for neuromyelitis optica pathology

Abstract

Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system (CNS) most frequently mediated by serum autoantibodies against the water channel aquaporin 4, expressed on CNS astrocytes, resulting in primary astrocytopathy. There is no cure for NMO, and treatment with Type I interferon (IFNI)‐IFNβ is ineffective or even detrimental. We have previously shown that both NMO lesions and associated microglial activation were reduced in mice lacking the receptor for IFNβ. However, the role of microglia in NMO is not well understood. In this study, we clarify the pathomechanism for IFNI dependence of and the role of microglia in experimental NMO. Transcriptome analysis showed a strong IFNI footprint in affected CNS tissue as well as in microglial subpopulations. Treatment with IFNβ led to exacerbated pathology and further microglial activation as evidenced by expansion of a CD11c+ subset of microglia. Importantly, depletion of microglia led to suppression of pathology and decrease of IFNI signature genes. Our data show a pro‐pathologic role for IFNI‐activated microglia in NMO and open new perspectives for microglia‐targeted therapies.

The protective effect of Angiotensin AT2-receptor stimulation in Neuromyelitis optica spectrum disorder is independent of astrocyte-derived BDNF

“…This indicates that the protective effect of AT2R stimulation with C21 in NMOSD-like pathology is not dependent on astrocyte-derived BDNF. All measured, established markers of NMSDO-like pathology in our study, which were AQP4 loss, GFAP loss and macrophage/microglia infiltration (Wlodarczyk et al, 2021), were equally improved by AT2R stimulation in WT and GfapF mice.…”

“…2A, B). Infiltration (H&E staining) and microglia/macrophage activation (IBA-1 staining) in the areas of AQP4/GFAP loss (Khorooshi et al, 2019;Wlodarczyk et al, 2021) were reduced in C21-treated mice, and BDNF deficiency in astrocytes had no effect on this (Fig. 3A-C).…”

An Experimental Model of Neuromyelitis Optica Spectrum Disorder–Optic Neuritis: Insights Into Disease Mechanisms

“…In line with others, our group has previously evaluated the pathogenic impact of AQP4-IgG in the cerebrospinal fluid (CSF) and reported that intrathecal injection of AQP4-IgG together with human C into the CSF or brain striatum was sufficient to induce NMOSD-like pathology in the brain of naive mice (14)(15)(16). The pathology was dependent on type I interferon (IFN) response (16,17). We have reported NMOSD-like lesions in various areas of the brain, cerebellum, brain stem, and periventricular areas following intrathecal administration (14).…”

“…A number of studies have reported induction of NMOSDlike histopathology in experimental animals (11)(12)(13). In line with others, our group has previously evaluated the pathogenic impact of AQP4-IgG in the cerebrospinal fluid (CSF) and reported that intrathecal injection of AQP4-IgG together with human C into the CSF or brain striatum was sufficient to induce NMOSD-like pathology in the brain of naive mice (14)(15)(16). The pathology was dependent on type I interferon (IFN) response (16,17).…”

“…We have previously published that transfer of pathology in the brain with AQP4-IgG depends on type I IFN signaling (16,17). We assessed induction of cytokines, chemokines, and transcription factors in the optic nerve by NMOSD-like pathology by performing RT-qPCR 2 days after the first of the two consecutive intrathecal injections of AQP4-IgG+C to WT mice to measure gene expression.…”