Quercetin ameliorates XIAP deficiency-associated hyperinflammation.

Area of Science:

• Immunology
• Molecular Biology
• Pharmacology

Background:

• X-linked inhibitor of apoptosis (XIAP) deficiency is a rare genetic disorder.
• It leads to hyperinflammation driven by dysregulated TNF-receptor signaling and NLRP3 inflammasome activation.
• Effective long-term treatments are crucial to prevent severe complications and reduce the need for hematopoietic cell transplantation.

Purpose of the Study:

• To evaluate inflammasome inhibitors, specifically the natural flavonoid quercetin, as potential therapeutics for XIAP deficiency.
• To investigate the efficacy of quercetin in preventing hyperinflammation associated with XIAP deficiency in preclinical models.

Main Methods:

• Bone marrow-derived macrophages from XIAP-deficient or wild-type mice and human monocytes from control or XIAP-deficient patients were used.
• Cells were stimulated with Toll-like receptor (TLR) agonists or TNF-α, with or without quercetin.
• In vivo studies involved challenging mice with lipopolysaccharide (LPS) after quercetin supplementation.
• Interleukin-1β (IL-1β) and IL-18 levels were measured using ELISA.

Main Results:

• Quercetin prevented IL-1β secretion in XIAP-deficient cells stimulated with TLR agonists or TNF-α.
• It significantly reduced IL-18 production in both wild-type and XIAP-deficient cells.
• In vivo, quercetin administration decreased blood levels of IL-1β and IL-18 in LPS-challenged mice.
• Quercetin also reduced IL-1β secretion in human monocytes from XIAP-deficient patients.

Conclusions:

• Quercetin demonstrates potential as a natural therapeutic agent for managing XIAP deficiency-associated hyperinflammation.
• Further clinical trials are warranted to confirm efficacy and establish optimal dosing and pharmacokinetics.