PDF(Pubmed)
Abstract：
Septic shock is characterized by an excessive inflammatory response depicted in a cytokine storm that results from invasive bacterial, fungi, protozoa, and viral infections. Non-canonical inflammasome activation is crucial in the development of septic shock promoting pyroptosis and proinflammatory cytokine production via caspase-11 and gasdermin D (GSDMD). Here, we show that NAD+ treatment protected mice toward bacterial and lipopolysaccharide (LPS)-induced endotoxic shock by blocking the non-canonical inflammasome specifically. NAD+ administration impeded systemic IL-1β and IL-18 production and GSDMD-mediated pyroptosis of macrophages via the IFN-β/STAT-1 signaling machinery. More importantly, NAD+ administration not only improved casp-11 KO (knockout) survival but rendered wild type (WT) mice completely resistant to septic shock via the IL-10 signaling pathway that was independent from the non-canonical inflammasome. Here, we delineated a two-sided effect of NAD+ blocking septic shock through a specific inhibition of the non-canonical inflammasome and promoting immune homeostasis via IL-10, underscoring its unique therapeutic potential.
摘要：
脓毒性休克的特征是由侵袭性细菌引起的细胞因子风暴中描述的过度炎症反应。真菌,原生动物,和病毒感染。非规范的炎性体激活在脓毒性休克的发展中至关重要，通过caspase-11和gasderminD（GSDMD）促进焦亡和促炎细胞因子的产生。这里,我们显示NAD+治疗通过特异性阻断非规范炎性体保护小鼠对抗细菌和脂多糖(LPS)诱导的内毒素性休克。NAD+给药通过IFN-β/STAT-1信号传导机制阻碍了全身IL-1β和IL-18的产生和GSDMD介导的巨噬细胞的焦亡。更重要的是,NAD+施用不仅改善了casp-11KO(敲除)存活,而且使野生型(WT)小鼠通过IL-10信号传导途径完全抵抗感染性休克,所述IL-10信号传导途径独立于非规范炎性体。这里,我们描述了NAD+通过特异性抑制非典型炎性体和通过IL-10促进免疫稳态,阻断感染性休克的双侧效应,强调了其独特的治疗潜力.
