Division of Transplant Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States; Department of Cardiothoracic and Vascular Surgery, Germany Heart Center Berlin, Berlin, Germany
Rachid El Fatimy
Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, United States; Institute of Biological Sciences (ISSB-P), Mohammed VI Polytechnic University, Benguerir, Morocco
Yeqi Nian
Institute of Transplant Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China
Amina Ghouzlani
NAD<sup>6</sup> Immunology Laboratory, Huntington Medical Research Institutes, Pasadena, United States
Siawosh K Eskandari
Department of Internal Medicine, University of Groningen, Groningen, Netherlands
Hector Rodriguez Cetina Biefer
Division of Transplant Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States; Department of Cardiac Surgery, Stadtspital Zurich Triemli, Zurich, Switzerland
Division of Transplant Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States; NAD<sup>6</sup> Immunology Laboratory, Huntington Medical Research Institutes, Pasadena, United States
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.
