BATF2 is a regulator of interferon-γ signaling in astrocytes during neuroinflammation.

Abstract

Astrocytic interferon (IFN)γ signaling is associated with reduced neuroinflammation; however, downstream effectors responsible for regulating this protection are unknown. Here, we identify an IFN-specific transcription factor, basic leucine zipper ATF-like transcription factor (BATF)2, that plays a key role in modulating the consequences of IFNγ signaling in astrocytes. Chromatin immunoprecipitation sequencing revealed that BATF2 binds and prevents the overexpression of IFN regulatory factor (IRF)1 and IRF1 targets such as caspase-1. We also show that Batf2^-/- mice exhibit exacerbated clinical disease severity in a murine model of central nervous system autoimmunity and express increased astrocyte-specific IRF1 and caspase-1, suggesting an amplified IFN response in vivo. Additionally, we demonstrate that BATF2 is expressed primarily in astrocytes within multiple sclerosis lesions and that this expression is colocalized with IRF1. Collectively, our results further support evidence of protective functions for IFNγ and implicate BATF2 as a key suppressor of overactive immune signaling in astrocytes during neuroinflammation.