Regulatory Role of IL-1R8 in Immunity and Disease

Abstract

Interleukin-1 receptor family members (ILRs) and toll-like receptors (TLRs) are characterized by the presence of a conserved intracellular domain and the toll-IL-1resistance (TIR) domain and are key players in immunity and inflammation. ILR and TLR signaling is tightly regulated at different levels. All cell types of the innate immune system express ILRs and TLRs. In addition, IL-1 family members are emerging as key players in the differentiation and function of innate and adaptive lymphoid cells. IL-1R8, also known as TIR8 or SIGIRR, is a fringe member of the ILR family and acts as a negative regulator of ILR and TLR signaling, which dampens ILR- and TLR-mediated cell activation. IL-1R8 is a component of the receptor recognizing human IL-37. Here, we summarize our current understanding of the structure and function of IL-1R8, focusing on its role in different pathological conditions, ranging from infectious and sterile inflammation to autoimmunity and cancer-related inflammation.

Keywords: cytokine; infection; inflammation; inflammation-associated cancer; interleukin-1; toll-like receptors.

Figure 1

The IL-1 receptor (ILRs) and toll-like receptor (TLRs) superfamily. Ligands, receptors, accessory proteins, and regulators are shown. Ligands of the ILR family include IL-1α, IL-1β, IL-38, IL-33, IL-36α, IL-36β, IL-36γ, and IL-18. Microbial compounds (LPS, CpG, poly IC, flagellin, and others), β-amyloid, and danger signals are ligands for TLRs. IL-1R, IL-33R, IL-36R, and IL-18R complexes transduce positive signals. IL-R2, sIL-1R1, IL-1Ra, IL-36Ra IL-18BP, and IL-1R8 are negative regulators acting at different levels. IL-37 is an anti-inflammatory cytokine, which signal is dependent on the formation of a tripartite complex (IL-37/IL-1R5/IL-1R8). IL-1R3 is an accessory protein, which activity is necessary for IL-R1, IL-1R2, IL-1R4, and IL-1R6 function. IL-1R8, IL-1R9, and IL-1R10 are still orphan receptors.

Figure 2

IL-37–IL-1R5–IL-1R8 tripartite complex. IL-37 anti-inflammatory activity is exerted through the formation of a membrane bound tripartite complex composed of IL-37, IL-1R5, and IL-1R8.

Figure 3

Negative regulation exerted by IL-1R8. IL-1R8 is composed of a single extracellular domain, a transmembrane domain, a cytoplasmic TIR domain, and an unusually long tail (95 residues). The IL-1R8 TIR domain lacks two conserved residues (Ser447 and Tyr536), which are replaced by Cys222 and Leu305 suggesting unconventional signaling. IL-1R8 acts as a negative regulator of ILR and TLR signaling, inhibiting TIR-containing receptors and adaptor proteins, and thus blocking Akt, JNK, MAPKs, TAK1, and consequently mTOR and NFκB activation.

Figure 4

Roles of IL-1R8 in pathology. IL-1R8-deficient mice have demonstrated that IL-1R8 acts a key modulator of acute and chronic inflammation in several pathological contexts. For instance, IL-1R8 plays a non-redundant role in models of bacterial infections, fungal infections, autoimmune diseases, allergy, asthma, renal inflammation, brain inflammation, intestinal inflammation, and cancer (colorectal cancer and CLL).