Interleukin-1 mediated hyperinflammation in XIAP-deficiency is associated with defective autophagy.

• Activation of the NLRP3 inflammasome during nutrient starvation results in excessive interleukin-1b production by XIAP-deficient cells.

• XIAP-deficient monocytes exhibit defective autophagic flux during nutrient starvation.

Deficiency of X-linked Inhibitor of Apoptosis Protein (XIAP) is a rare genetic condition that can present with recurrent episodes of hemophagocytic lymphohistiocytosis (HLH), though the exact mechanisms leading to this hyperinflammatory disorder are unclear. Understanding its biology is critical to developing targeted therapies for this potentially fatal disease. Here we report on a novel multi-exonic intragenic duplication leading to XIAP deficiency with recurrent HLH that demonstrated complete response to interleukin (IL)-1b blockade. We further demonstrate using both primary patient cells and genetically modified THP-1 monocyte cell lines that, contrary to what has previously been shown in mouse cells, XIAP-deficient human macrophages do not produce excess IL-1b when stimulated under standard conditions. Instead, NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated hyperproduction of IL-1b is observed only when the XIAP-deficient cells are stimulated under autophagy-promoting conditions and this correlates with defective autophagic flux as measured by decreased accumulation of the early autophagy marker LC3-II. This work therefore highlights IL-1b blockade as a therapeutic option for patients with XIAP deficiency experiencing recurrent HLH and identifies a critical role for XIAP in promoting autophagy as a means of limiting IL-1b-mediated hyperinflammation during periods of cellular stress.