LAUSR

XIAP deficiency is a rare inborn error of immunity. XIAP deficiency causes hyperinflammatory disease manifestations due to dysregulated TNF-receptor signaling and NLRP3 inflammasome function. Safe and effective long-term treatments are needed, and are especially important to help prevent the need for high-risk allogeneic hematopoietic cell transplantation. Here we evaluated inflammasome inhibitors as potential therapeutics with a focus on the natural flavonoid antioxidant quercetin. Bone marrow derived macrophages were derived from XIAP deficient or wild type (WT) mice. Human monocytes were obtained from control or XIAP deficient patients. Cells were stimulated with TLR-agonists or TNF-α +/- inhibitors or quercetin. For in vivo LPS challenge experiments, XIAP deficient or WT mice were fed mouse chow +/- supplemental quercetin (50mg/kg/day exposure) for 7 days followed by challenge with 10ng/kg LPS. IL-1β and IL-18 were measured by ELISA. In murine studies, quercetin prevented IL-1β secretion from XIAP KO cells following TLR-agonists or TNF-α stimulation (p<0.05) and strongly reduced constitutive production of IL-18 by both WT and XIAP deficient cells (p<0.05). At 4 hours following in vivo LPS challenge, blood levels of IL-1β and IL-18 were significantly decreased in mice that had received quercetin-supplemented chow (p<0.05). In experiments using human cells, quercetin greatly reduced IL-1β secretion by monocytes following TNF-α stimulation (p<0.05). Our data suggest that quercetin may be an effective natural therapeutic for the prevention of XIAP deficiency-associated hyperinflammation. Clinical trials, including careful pharmacokinetic and pharmacodynamic studies to ensure that effective levels of quercetin can be obtained, are warranted.