NAD(+) prevents septic shock by non-canonical inflammasome blockade and IL-10

Non-canonical inflammasome activation is crucial in the development of septic shock promoting pyroptosis and pro-inflammatory cytokine production via caspase-11 and Gasdermin-D (GSDMD). Here, we show that NAD treatment protected mice towards bacterial and 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 survival but rendered 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.