Immunity-related GTPase Irgm1 guards against interferonopathy through mitochondrial maintenance Prashant Rai1, Hideki Nakano1, Wan-Chi Lin1, Gregory A. Taylor2, Michael B. Fessler1 1Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC USA; 2Geriatric Research, Education, and Clinical Center, VA Medical Center, Durham, NC USA; Departments of Medicine; Molecular Genetics and Microbiology; and Immunology; Duke University Medical Center, Durham, NC USA
Irgm1 is an interferon-γ (IFNγ)-inducible immunity-related GTPase that is thought to support macrophage host defense against intracellular pathogens through promoting autophagic clearance of both invasive microbes (xenophagy) and defective mitochondria (mitophagy). Recently, we reported that naïve Irgm1-deficient mice have bronchus-associated lymphoid tissue-like lung lesions and an autoimmune exocrinopathy accompanied by increased autoantibodies and spontaneous induction of IFN-stimulated genes (ISGs) in several organs. We hypothesized that the spontaneous IFN response observed in Irgm1-deficient cells is driven by cGAMP synthase (cGAS)-dependent sensing of uncleared mitochondrial DNA (mtDNA) that has soiled the cytoplasm. Here, we show that Irgm1-/- macrophages and murine embryonic fibroblasts exhibit defective autophagic flux, associated with decreased mitochondrial membrane potential, relative opening of the mitochondrial permeability transition pore, increased cytoplasmic mtDNA, and abnormal induction of type I IFNs and ISGs. This abnormal cell-autonomous IFN response is normalized upon depletion of cellular mtDNA with ethidium bromide, as well as by silencing or inhibition of cGAS, stimulator of IFN genes (STING), TANK-binding kinase 1 (TBK1), or IFN regulatory factor 3 (IRF3), together suggesting that a mtDNA-cGAS-STING-TBK1-IRF3 axis drives the abnormal IFN signature of Irgm1-deficient cells. Genetic deletion of the type I IFN receptor rescues the in vivo autoimmune tissue pathology and excess serum autoantibody levels of Irgm1-/- animals. Taken together, our findings support a model wherein Irgm1-mediated mitochondrial maintenance represses inappropriate mtDNA-dependent activation of autoinflammatory IFN responses. We propose that this fundamental mechanism may play a key role in suppression of type I interferonopathy syndromes.
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