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

焦亡是一种caspase-1依赖性细胞死亡，与促炎细胞因子的产生有关，在脓毒症中起着至关重要的作用。焦亡是由微生物PAMPs和内源性DAMPs诱导的。值得注意的是，人抗菌肽LL-37对脓毒症动物模型具有保护作用。因此，为了阐明LL-37对脓毒症的作用，我们将LPS（脂多糖）和ATP分别作为PAMP和DAMP。结果表明，LPS/ atp处理可诱导巨噬细胞样J774细胞发生焦亡（IL-1 mRNA表达、caspase-1激活、炎性体形成和细胞死亡）。此外，LL-37抑制LPS/ atp诱导的IL-1表达、caspase-1激活、炎性体形成和细胞死亡。值得注意的是，LL-37抑制了LPS与靶细胞的结合和atp诱导的/ p2x7介导的caspase-1激活。这些结果表明，LL-37通过阻断LPS的作用和抑制P2X7对ATP的反应，有效地抑制了LPS/ATP诱导的焦亡。

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.