Microglial CARD19 ameliorates post-stroke neuroinflammation by stabilizing mitochondrial cristae

Microglia are the first immune cells that are activated in the brain following ischemic stroke. Mitochondrial dysfunction exacerbates microglia-mediated neuroinflammation post-stroke. Caspase activation and recruitment domain 19 (CARD19) is involved in innate immune response and inflammatory response, which are also important functions of microglia. However, the role of CARD19 in microglial biology and ischemic stroke remains unknown. Here, we observed that CARD19 expression was significantly elevated in microglia in the penumbra after ischemic stroke via analyzing the spatial transcriptomic sequencing data of ischemic brain tissue, as well as in an in vitro model of microglial activation. Remarkably, conditional knockdown of Card19 in microglia promoted poststroke neuroinflammation and worsened neurological outcomes in a mouse model of ischemic stroke. Mechanistically, we found that CARD19 localized to mitochondria and promoted the assembly of mitochondrial intermembrane bridge components, while CARD19 deficiency in microglia caused ultrastructural and functional damage to the mitochondrial cristae, leading to an exaggerated pro-inflammatory response. Thus, our findings suggest that preserving mitochondrial cristae, by targeting CARD19 could be a novel therapeutic strategy for ameliorating neuroinflammation post-stroke and decreasing the volume of the ischemic penumbra.