DPP3 restrains the non-canonical inflammasome through PEBP1 cleavage

The non-canonical inflammasome is a protein complex involved in bacterial infections, and its activation leads to excessive inflammatory responses during sepsis. The precise regulation of the non-canonical inflammasome in the body remains unclear. Here, we found that some chemicals that chelate zinc ions positively regulated the activation of the non-canonical inflammasome. These chemicals acted by inhibiting the activity of dipeptidyl peptidase 3 (DPP3). DPP3 cleaved phosphatidylethanolamine binding protein 1 (PEBP1) to generate an N-terminal fragment, which could bind to caspase-4/11 and inhibit the response intensity of the non-canonical inflammasome. PEBP1 N terminus appeared in the serum of mice and patients with sepsis. DPP3-deficient mice exhibited stronger inflammatory cytokine responses and had poor survival in the LPS-induced sepsis model. Promoting the activity of DPP3 effectively constrained the response intensity of sepsis in mice and increased their survival. Our findings provide a perspective for understanding the molecular regulatory process of the non-canonical inflammasome in sepsis.