Single immunoglobulin interleukin-1 receptor-related protein (IL-1R8) (IL-1R8)

Single immunoglobulin interleukin-1 receptor-related protein (IL-1R8), also known as SIGIRR or TIR8, is a member of the interleukin-1 receptor (IL-1R) family that acts as a critical negative regulator of the innate immune system [1, 4]. Unlike other members of the family, IL-1R8 lacks conventional signaling capacity and instead functions as a "molecular brake" by interfering with the recruitment of adaptor molecules like MyD88 to IL-1R and Toll-like receptor (TLR) complexes [8, 13]. This inhibition dampens downstream NF-κB and JNK signaling, thereby controlling inflammatory responses and preventing excessive tissue damage [1, 15]. In the context of oncology, IL-1R8 has emerged as a novel immune checkpoint, particularly in natural killer (NK) cells, where its expression limits their maturation and anti-tumor effector functions [4, 24]. Therapeutic strategies targeting IL-1R8 are currently focused on checkpoint inhibition to unleash NK cell-mediated immunity against various cancers, including colorectal and liver malignancies [18, 21]. Conversely, its role as a co-receptor for the anti-inflammatory cytokine IL-37 makes it a potential target for treating autoimmune and inflammatory disorders where its activity is deficient [11, 22]. While no drugs are currently approved, monoclonal antibodies and silencing RNAs are being explored in translational research to modulate its activity [18, 29]. Safety concerns primarily involve the risk of uncontrolled inflammation or autoimmunity resulting from the removal of this natural regulatory mechanism [1, 14].

Other names

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

Checkpoint inhibition