Modulation of a novel death, pyroptosis by alarmins in septic shock

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Pyroptosis is a caspase-1 dependent cell death, associated with proinflammatory cytokine production, and plays a crucial role in sepsis. Pyroptosis is induced by microbial PAMPs and endogenous DAMPs. Notably, human antimicrobial peptide LL-37 protects the septic animal models. Thus, to elucidate the action of LL-37 on sepsis, we utilized LPS (lipopolysaccharide) and ATP as a PAMP and a DAMP, respectively. The data indicated that the LPS/ATP-treatment of macrophage-like J774 cell induces the features of pyroptosis (IL-1 mRNA expression, caspase-1 activation, inflammasome formation and cell death). Moreover, LL-37 inhibits the LPS/ATP-induced IL-1 expression, caspase-1 activation, inflammasome formation and cell death. Notably, LL-37 suppressed the LPS binding to target cells and ATP-induced/P2X7-mediated caspase-1 activation. These observations suggest that LL-37 potently inhibits the LPS/ATP-induced pyroptosis by blocking the action of LPS and inhibiting the response of P2X7 to ATP.