NAD Prevents Septic Shock-induced Death by Non-canonical Inflammasome Blockade and IL-10 Cytokine Production in Macrophages

Overview

Journal Elife

Specialty Biology

Date 2024 Feb 19

PMID 38372712

Authors

Jasper Iske

Rachid El Fatimy

Yeqi Nian

Amina Ghouzlani

Siawosh K Eskandari

Hector Rodriguez Cetina Biefer

Anju Vasudevan

Abdallah Elkhal

Affiliations

Soon will be listed here.

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.

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