TIR8/SIGIRR is an Interleukin-1 Receptor/Toll Like Receptor Family Member with Regulatory Functions in Inflammation and Immunity

Abstract

Interleukin-1R like receptors (ILRs) and Toll Like Receptors (TLRs) are key receptors of innate immunity, inflammation, and orientation of the adaptive response. They belong to a superfamily characterized by the presence of a conserved intracellular domain, the Toll/IL-1R (TIR) domain, which is involved in the activation of a signaling cascade leading to activation of transcription factors associated to inflammation. The activation of inflammatory responses and immunity by ILRs or TLRs signaling is potentially detrimental for the host in acute and chronic conditions and is tightly regulated at different levels by receptor antagonists, decoy receptors or signaling molecules, and miRNAs. Recent evidence suggests that the ILRs family member TIR8 (also known as SIGIRR) is a regulatory protein acting intracellularly to inhibit ILRs and TLRs signaling. In particular, current evidence suggests that TIR8/SIGIRR dampens TLRs-mediated activation and inhibits signaling receptor complexes of IL-1 family members associated with Th1 (IL-18), Th2 (IL-33), and Th17 (IL-1) differentiation. Studies with Tir8/Sigirr-deficient mice showed that the ability to dampen signaling from ILRs and TLRs family members makes TIR8/SIGIRR a key regulator of inflammation. Here, we summarize our current understanding of the structure and function of TIR8/SIGIRR, 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, adaptors, and extracellular and intracellular negative regulators are shown. The ILRs family includes the receptors (IL-1RI, IL-18R, T1/ST2, IL-1Rrp2) and the accessory proteins (IL-1RAcP) for IL-1, IL-18, IL-33, and other IL-1 family members (IL-36α, IL-36β, and IL-36γ). IL-1Ra, soluble IL-1RI, IL-36Ra, IL-37, IL-18 binding protein (IL-18BP), IL-1RII, and TIR8/SIGIRR are negative regulators acting at different levels, as receptor antagonists, decoy receptors, scavengers, or dominant negative. TIR8/SIGIRR, TIGIRR-1, and TIGIRR-2 are still orphan receptors. Microbial moieties (LPS, Poly I:C, CpG, Flagellin, and others) and necrotic cell-derived danger signals are the ligands for TLRs.

Figure 2

Regulatory function of TIR8/SIGIRR in signaling. TIR8/SIGIRR is a receptor composed by a single extracellular Ig domain (amino acids 17–112), a transmembrane domain (amino acids 117–139); an intracellular conserved TIR domain (amino acids 166–305), and a 95 amino acid-long intracellular tail. Two conserved amino acid (Ser, Tyr in TIR domain) necessary for IL-1R-signaling are replaced in TIR8/SIGIRR (Cys 222, Leu 305) potentially leading to a non-conventional activation. TIR8/SIGIRR is an orphan receptor, but IL-36Ra has been proposed as a TIR8/SIGIRR ligand in glial cells. TIR8/SIGIRR inhibits ILR (IL-1RI, IL-18R, T1/ST2) and TLR (TLR2, TLR3, TLR4, TLR5, TLR7/8, TLR9, and possibly others) signaling and NF-κB activation. In T cells and epithelial cells, TIR8/SIGIRR inhibits IL-1-dependent activation of the Akt-mTOR pathway and of JNK.

Figure 3

Regulatory function of TIR8/SIGIRR in pathology. TIR8/SIGIRR inhibits ILR (IL-1RI, IL-18R, T1/ST2) and TLR (TLR4, TLR7, TLR9, and possibly others) signaling and NF-κB activation. Gene-targeted mice demonstrate that Tir8/Sigirr acts as a non-redundant negative regulator in vivo in different inflammatory conditions dependent on ILR and TLR activation. For some of these, the pathway prominently regulated by TIR8/SIGIRR and playing a relevant role in the pathogenesis of the disease has been defined. For instance, in autoimmunity (EAE) TIR8/SIGIRR regulates IL-1-dependent Th17 cell differentiation, survival, and proliferation; in asthma TIR8/SIGIRR regulates the IL-33/ST2 pathway and Th2 responses; in models of infections (Candida albicans, Aspergillus fumigatus, Mycobacterium tuberculosis, and Pseudomonas aeruginosa) TIR8/SIGIRR regulates IL-1RI signaling controlling Th17 and Treg responses (fungal infections) and pro-inflammatory cytokine production (bacterial infections). In colitis-associated colon cancer, TIR8/SIGIRR plays a major role in controlling microbial flora-dependent activation of TLRs, but the control on ILRs-dependent inflammation can not be excluded. In other contexts (chronic lymphocytic leukemia, arthritis, kidney transplantation, and brain inflammation), the molecular pathway regulated by TIR8/SIGIRR remains to be addressed.