New Study Finds NAD⁺ Protects Against Septic Shock via Dual Immune Pathways

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PASADENA, Calif. — February 2024 — A new paper co-authored by Dr. Anju Vasudevan and Dr. Abdallah Elkhalof Huntington Medical Research Institutes (HMRI) demonstrates that the metabolite Nicotinamide Adenine Dinucleotide (NAD⁺) dramatically increases survival in models of septic shock by acting on two immune-regulatory fronts.

Published in eLife under the title “NAD⁺ prevents septic shock-induced death by non-canonical inflammasome blockade and IL-10 cytokine production in macrophages”, the study shows that NAD⁺ both inhibits the non-canonical inflammasome pathway (via caspase-11/GSDMD) and promotes anti-inflammatory IL-10 signaling.

The research team — Jasper Iske, Rachid El Fatimy, Yeqi Nian, Amina Ghouzlani, Siawosh K. Eskandari, Hector Rodriguez Cetina Biefer, Anju Vasudevan and Abdallah Elkhal — found that:

  • NAD⁺ treatment in mice protected against lethal bacterial or LPS-induced shock without reducing bacterial load.

  • NAD⁺ blocked non-canonical inflammasome activation (reduced IL-1β/IL-18, reduced pyroptosis in macrophages) via IFN-β/STAT-1 signaling.

  • Crucially, NAD⁺ also induced IL-10-mediated immune homeostasis, which rendered wild-type mice completely resistant to septic shock — showing that protection extended beyond inflammasome inhibition.

“This two-armed mechanism of NAD⁺ — both dampening harmful inflammation and promoting protective immune signaling — offers a fresh therapeutic angle for septic shock,” said Dr. Vasudevan.

The findings strengthen HMRI’s portfolio of research into immunometabolism and cardiovascular-immune interfaces, and suggest that NAD⁺ may merit investigation as a novel adjunct in severe systemic inflammation and shock.

Full article: eLife, February 2024