Fine-tuning of
cytokine-inducing pathways is essential for immune homeostasis. Consistently, a dysregulated increase or decrease in
pattern-recognition receptor (PRR)-induced signaling and
cytokine secretion can lead to
inflammatory bowel disease. Multiple gene loci are associated with
inflammatory bowel disease, but their functional effects are largely unknown. One such region in chromosome 2q12 (rs917997), also associated with other immune-mediated diseases, encompasses IL18RAP. We found that human monocyte-derived macrophages (MDMs) from rs917997 AA risk carriers secrete significantly less
cytokines than G carriers upon stimulation of multiple
PRRs, including
nucleotide-binding oligomerization domain 2 (NOD2). We identified that
IL-18 signaling through IL-18RAP was critical in amplifying PRR-induced
cytokine secretion in MDMs. IL-18RAP responded to NOD2-initiated early, caspase-1-dependent autocrine
IL-18, which dramatically enhanced MAPK, NF-κB, PI3K, and calcium signaling. Reconstituting MAPK activation was sufficient to rescue decreased
cytokines in NOD2-stimulated IL-18RAP-deficient MDMs. Relative to GG carriers, MDM from rs917997 AA carriers had decreased expression of cell-surface IL-18RAP
protein, as well as of IL-18R1 and IL-1R1, genes also located in the IL18RAP region. Accordingly, these risk-carrier MDMs show diminished PRR-, IL-18-, and IL-1-induced MAPK and NF-κB signaling. Taken together, our results demonstrate clear functional consequences of the rs917997 risk polymorphism; this polymorphism leads to a loss-of-function through decreased IL-18RAP, IL-18R1, and IL-1R1
protein expression, which impairs autocrine
IL-18 and
IL-1 signaling, thereby leading to decreased
cytokine secretion in MDMs upon stimulation of a broad range of
PRRs.