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bioRxiv · 10.1101/2020.03.29.013649

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

Iske, J.·EL Fatimy, R.·Nian, Y.·Eskandari, S.·Rodriguez Cetina Biefer, H.·Vasudevan, A.·Elkhal, A.
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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 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-1{beta} and IL-18 production and GSDMD-mediated pyroptosis of macrophages via the IFN-{beta}/STAT-1 signaling machinery. More importantly, NAD+ administration not only improved casp-11 KO (knockout) 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.

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Iske, J., EL Fatimy, R., Nian, Y., Eskandari, S., Rodriguez Cetina Biefer, H., Vasudevan, A., Elkhal, A.. 2020-03-30. NAD+ prevents septic shock by non-canonical inflammasome blockade and IL-10. https://doi.org/10.1101/2020.03.29.013649

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