Sigirr, also known as Toll/interleukin-1 receptor 8 or TIR8, is a member of the interleukin-1 receptor (IL-1R) family. It acts as a negative regulator of IL-1R and Toll-like receptor (TLR) downstream signaling pathways, playing a crucial role in modulating immune responses and inflammation [1,2,4,5]. It helps maintain the balance between amplification of innate immunity and uncontrolled inflammation [6]. Genetic models, such as gene knockout mouse models, have been valuable in studying its functions.

In a SIGIRR knockout mouse model (SigirrTg mice), increased intestinal inflammation and nuclear factor-κB activation were observed, along with decreased intestinal epithelial cell (IEC) expression of miR-146a and miR-155. This indicates that SIGIRR regulates postnatal intestine adaptation through the SIGIRR-STAT3-miRNA-IRAK1 repression pathway, which is disrupted by a SIGIRR mutation identified in human necrotizing enterocolitis (NEC) [2]. In Sigirr-/-mice, there was exacerbated psoriasiform inflammation and increased neutrophil infiltration in the skin due to elevated IL-36 responsiveness, suggesting SIGIRR negatively regulates IL-36-driven psoriatic inflammation [3]. SIGIRR-deficient mice were also more susceptible to antigen-induced arthritis (AIA), as SIGIRR deficiency in memory CD4 T cells facilitated the IL1/C/EBPβ/TNF-α signaling axis, leading to enhanced TNF-α production [4].

In conclusion, Sigirr is a key negative regulator of inflammatory signaling pathways. Gene knockout mouse models have revealed its significance in diseases like NEC, psoriasis, and rheumatoid arthritis. Understanding Sigirr's functions provides potential therapeutic targets for these and other inflammation-related diseases.