Tuning inflammation and immunity by the negative regulators IL-1R2 and IL-1R8

Abstract

Interleukin-1 receptor family members (ILRs) and Toll-Like Receptors (TLRs) are key players in immunity and inflammation and are tightly regulated at different levels. Most cell types, including cells of the innate and adaptive 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-1R2 and IL-1R8 (also known as TIR8 or SIGIRR) are members of the ILR family acting as negative regulators of the IL-1 system. IL-1R2 binds IL-1 and the accessory protein IL-1RAcP without activating signaling and can be released as a soluble form (sIL-1R2), thus modulating IL-1 availability for the signaling receptor. IL-1R8 dampens ILR- and TLR-mediated cell activation and it is a component of the receptor recognizing human IL-37. Here, we summarize our current understanding of the structure and function of IL-1R2 and IL-1R8, focusing on their role in different pathological conditions, ranging from infectious and sterile inflammation, to autoimmunity and cancer-related inflammation. We also address the emerging evidence regarding the role of IL-1R8 as a crucial checkpoint molecule in NK cells in anti-cancer and antiviral activity and the potential therapeutic implications of IL-1R8 blockade in specific pathological contexts.

Keywords: infection; inflammation; inflammation-associated cancer; interleukin-1.

Figure 1. The IL-1 system and Toll Like Receptors

Ligands of the IL-1 receptor (ILR) family are shown (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 Toll Like Receptors (TLRs). IL-1R, IL-33R, IL-36R and IL-18R complexes activate signal transduction. IL-R2, sIL-1R1, IL-1Ra, IL-36Ra IL-18BP and IL-1R8 are negative regulators acting with different mechanisms. IL-37 is an anti-inflammatory cytokine, signaling upon the formation of a tripartite complex (IL-37/IL-1R5/IL-1R8). IL-1R3 is an accessory protein for IL-R1, IL-1R2, IL-1R4 and IL-1R6. Ligands for IL-1R8, IL-1R9 and IL-1R10 are still partially defined.

Figure 2. Negative regulation exerted by IL-1R8

IL-1R8 comprises 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 3. Roles of IL-1R8 in pathology

IL-1R8 emerged as a key modulator of inflammation, and innate and adaptive immune responses in several pathological contexts. IL-1R8 plays a non-redundant role in models of bacterial and fungal infections, autoimmune diseases, allergy, renal inflammation, platelet activation, brain inflammation and neuronal plasticity, intestinal inflammation and cancer (colorectal cancer, CLL and breast cancer). IL-1R8 acts as a checkpoint molecule regulating NK cell antitumor and antiviral activity.