Secretion of mitochondrial DNA via exosomes promotes inflammation in Behçet's syndrome

Mitochondrial DNA (mtDNA) leakage into the cytoplasm can occur when cells are exposed to noxious stimuli. Specific sensors recognize cytoplasmic mtDNA to promote cytokine production. Cytoplasmic mtDNA can also be secreted extracellularly, leading to sterile inflammation. However, the mode of secretion of mtDNA out of cells upon noxious stimuli and its relevance to human disease remain unclear. Here, we show that pyroptotic cells secrete mtDNA encapsulated within exosomes. Activation of caspase‐1 leads to mtDNA leakage from the mitochondria into the cytoplasm via gasdermin‐D. Caspase‐1 also induces intraluminal membrane vesicle formation, allowing for cellular mtDNA to be taken up and secreted as exosomes. Encapsulation of mtDNA within exosomes promotes a strong inflammatory response that is ameliorated upon exosome biosynthesis inhibition in vivo . We further show that monocytes derived from patients with Behçet's syndrome (BS), a chronic systemic inflammatory disorder, show enhanced caspase‐1 activation, leading to exosome‐mediated mtDNA secretion and similar inflammation pathology as seen in BS patients. Collectively, our findings support that mtDNA‐containing exosomes promote inflammation, providing new insights into the propagation and exacerbation of inflammation in human inflammatory diseases. image Mitochondrial DNA (mtDNA) secreted by pyroptotic cells is encapsulated within exosomes and induces excessive inflammation resembling symptoms seen in patients with Behçet's syndrome. In pyroptotic cells, the activation of caspase‐1 and subsequent action of gasdermin‐D promote the efflux of mtDNA from the mitochondria into the cytoplasm. Activation of caspase‐1 promotes the formation of intracellular vesicles (ILVs), mtDNA uptake into ILVs, and its release into the extracellular space via exosomes. The encapsulation of mtDNA within exosomes promotes inflammation, leukocyte mobilization, and cytokine production. Patients with Behçet's syndrome show increased mtDNA in the blood and caspase‐1‐mediated mitochondrial damage in the isolated monocytes. In patients with Behçet's syndrome monocytes secrete mtDNA‐containing exosomes that induce pathological inflammation in an NLRP3‐ and TLR9‐dependent manner.