PT  - JOURNAL ARTICLE
AU  - Jasper Iske
AU  - Rachid El Fatimy
AU  - Yeqi Nian
AU  - Siawosh K. Eskandari
AU  - Hector Rodriguez Cetina Biefer
AU  - Anju Vasudevan
AU  - Abdallah Elkhal
TI  - NAD<sup>+</sup> prevents septic shock by non-canonical inflammasome blockade and IL-10
AID  - 10.1101/2020.03.29.013649
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.03.29.013649
4099  - http://biorxiv.org/content/early/2020/03/30/2020.03.29.013649.short
4100  - http://biorxiv.org/content/early/2020/03/30/2020.03.29.013649.full
AB  - 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.Summary NAD+ protects against septic shock by blocking the non-canonical inflammasome specifically and via a systemic production of IL-10 cytokine