mtDNA Activates AIM2-Mediated PANoptosis in Interstitial Macrophages to Promote Immune Checkpoint Inhibitor Pneumonitis

Abstract

Immune checkpoint inhibitor pneumonitis (CIP) is a serious immune-related adverse event, yet its mechanisms remain unclear. Using a mouse model of anti-PD-1-induced CIP, we show that PD-1 blockade induces pulmonary inflammation and dysfunction, accompanied by accumulation of lung interstitial macrophages (IMs) and PANoptosis, preferentially in IMs rather than alveolar macrophages. Anti-PD-1 also causes mitochondrial stress and cytosolic mtDNA accumulation. AIM2 deficiency attenuates pulmonary inflammation, IM accumulation, and PANoptosis-associated signaling; NLRP3 or GSDMD deficiency similarly reduces inflammation and PANoptotic responses. In macrophages, TNF- plus IFN-{gamma} induces mitochondrial dysfunction and cytosolic mtDNA accumulation, and mtDNA amplifies cytokine-induced cell death and caspase-1/GSDMD activation, which is abolished by AIM2 deficiency. Thus, AIM2-mediated PANoptosis in lung IMs drives CIP, and mtDNA-associated innate immune signaling amplifies inflammatory macrophage death during CIP.