Interleukin-1 receptor 8 (IL-1R8)

Interleukin-1 receptor 8 (IL-1R8), also known as SIGIRR or TIR8, is a member of the interleukin-1 receptor family that functions as a critical negative regulator of innate and adaptive immune responses. Unlike other family members, IL-1R8 possesses a single extracellular immunoglobulin domain and a unique intracellular Toll/IL-1 receptor (TIR) domain that lacks conventional signaling motifs. It acts as a molecular brake by interfering with the assembly of signaling complexes for various Toll-like receptors (TLRs) and interleukin receptors (such as IL-1R1, IL-18R, and ST2), thereby dampening pro-inflammatory pathways like NF-κB and JNK. Additionally, IL-1R8 serves as a necessary co-receptor for the anti-inflammatory cytokine IL-37, mediating its suppressive effects on inflammation. In the context of oncology, IL-1R8 is recognized as an immune checkpoint on natural killer (NK) cells; its genetic or pharmacological blockade can unleash NK cell-mediated anti-tumor activity, making it a promising target for cancer immunotherapy. Conversely, its downregulation or deficiency is associated with chronic inflammatory conditions, autoimmune diseases like rheumatoid arthritis and lupus, and increased susceptibility to certain infections.

Other names

SIGIRRTIR8Single Ig IL-1-related receptorSingle immunoglobulin and toll-interleukin 1 receptor (TIR) domainSingle Ig and TIR domain containing

IL-1R8 acts as a negative regulator by interfering with the association of TIR-containing adaptor molecules (e.g., MyD88) with receptor complexes, thereby dampening NF-κB and JNK signaling. It also functions as a co-receptor for IL-37 to mediate anti-inflammatory signaling and serves as an immune checkpoint on NK cells, where its blockade enhances anti-tumor immunity.