Astrocytic TRIM21 downregulation exacerbates NMOSD via potentiating IRF3/IRF7-mediated type I interferon response

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system (CNS) driven by aquaporin-4 (AQP4) antibody-mediated astrocyte damage, and subsequent microglial activation and demyelination. Accumulating evidence suggests a deleterious role for type I IFNs (IFN-I) and dysregulated IFN-I-IFNAR signaling in the pathogenesis of NMOSD. However, the cellular sources for IFN-I production in the CNS remain unclear. Interferon regulatory factor 3 (IRF3) and IRF7 are key transcription factors governing IFN-I synthesis. Here, we demonstrated a downregulation of astrocytic TRIM21, an E3 ubiquitin ligase, in both in vivo and in vitro NMOSD models. This downregulation gave rise to elevated levels of IRF3 and IRF7, as well as an increase in IFN-I production, particularly IFN-α, due to the impaired ubiquitination-mediated degradation by TRIM21. In addition, enhanced IFN-I signaling in astrocytes intensified microglial inflammatory activation. Administration of lentiviral-mediated overexpression of TRIM21 in astrocytes significantly attenuated NMOSD-related pathology, including astrocyte loss, microglial activation and demyelination. Further, astrocyte-specific silencing of IRF3 or IRF7 rescued demyelinating pathology in NMOSD mice. Collectively, these findings not only put forth a mechanism for the contribution of astrocytes to IFN-I production in the CNS, but also unravel the TRIM21-IRF3/7 axis as a new therapeutic approach for NMOSD.