The IL18RAP Region Disease Polymorphism Decreases IL-18RAP/IL-18R1/IL-1R1 Expression and Signaling through Innate Receptor–Initiated Pathways

Abstract

Fine-tuning of cytokine-inducing pathways is essential for immune homeostasis. Consistently, a dysregulated increase or decrease in pattern recognition receptors (PRR)-induced signaling and cytokine secretion can lead to inflammatory bowel disease (IBD). Multiple gene loci are associated with IBD, 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 (MDM) from rs917997 AA risk carriers secrete significantly less cytokines than G carriers upon stimulation of multiple PRRs including NOD2. We identified that IL-18 signaling through IL-18RAP was critical in amplifying PRR-induced cytokine secretion in MDM. 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 MDM. 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 MDM 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 MDM upon stimulation of a broad range of PRR.

IL-18 Drives ILC3 Proliferation and Promotes IL-22 Production via NF-κB

“…To determine a potential mechanism by which IL-18 may be regulating IL-22 production in ILC3s, we considered the downstream intermediates through which IL-18 signals (31, 32), i.e. NF-κB (33) and MAP kinases (34, 35).…”

Inflammasomes of the intestinal epithelium

“…In humans, IL-18 expression is increased in inflamed lesions in patients with inflammatory bowel disease (IBD) and may be produced by both IECs and myeloid cells [70]. Conversely, IBD-associated polymorphisms in the IL-18R1/RAP locus were recently shown to decrease IL-18R expression and signaling, hence rather favoring a protective role for IL-18 against IBD development [75]. Consistent with this hypothesis, in a mouse T cell transfer IBD model, IECs continue to produce IL-18 in the inflamed gut and Foxp3 + regulatory T (Treg) cells require IL-18R signals to upregulate expression of several key effector molecules and to suppress intestinal inflammation [19].…”

An inflammatory bowel disease–risk variant in INAVA decreases pattern recognition receptor–induced outcomes

“…In intestinal tissues, multiple other PRRs are activated, the outcomes of which might in turn be modulated by additional IBD risk loci. Polymorphisms resulting in both decreased (e.g., NOD2, IL18RAP, ICOSL, ATG16L1, CARD9) and increased (e.g., MAP3K8, TNFSF15, IRF5) PRR-mediated signaling and downstream outcomes can be associated with intestinal inflammation (2)(3)(4)(5)(6)(7)(8)(9)(10)(11), thereby highlighting the critical role of balance in regulation of PRR-initiated outcomes in intestinal tissues. Despite the success in identification of IBD-associated loci (12), altered functions for most of the IBD loci are unknown.…”