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 major inhibitor of Toll-like receptor signaling and negatively modulates immune responses [1,2]. Sigirr is involved in pathways like the STAT3-dependent microRNA expression pathway, IL-1R/TLR downstream signaling pathways, and the MyD88/NF-κB inflammatory signaling pathway [2,3,5]. It plays a crucial role in maintaining system homeostasis by reducing inflammation in tissues [3]. Genetic models, such as transgenic mice, are valuable for studying Sigirr.

In Sigirr-deficient mice, increased intestinal inflammation and NF-κB activation were observed, along with decreased expression of miR-146a and miR-155 in the intestine, uncovering a novel SIGIRR-STAT3-miRNA-IRAK1 repression pathway disrupted by SIGIRR mutation in human necrotizing enterocolitis (NEC) [2]. Sigirr -/- mice also showed elevated IL-36 responsiveness in dendritic cells and keratinocytes, leading to increased neutrophil infiltration and exacerbated psoriasiform inflammation, indicating SIGIRR as a negative regulator of IL-36-driven psoriatic inflammation [4]. SIGIRR-deficient mice were more susceptible to antigen-induced arthritis (AIA) due to enhanced TNF-α production in memory CD4 T cells, revealing SIGIRR's role in regulating the IL-1/C/EBPβ/TNF-α signaling axis in rheumatoid arthritis [5].

In conclusion, Sigirr is a key negative regulator in multiple signaling pathways related to inflammation and immune responses. Gene-knockout mouse models have significantly contributed to understanding its role in diseases like NEC, psoriasis, and rheumatoid arthritis. These insights provide potential targets for treating these diseases by modulating Sigirr-related pathways.

References:

1. Wang, Chao, Feng, Chen-Chen, Pan, Hai-Feng, Wang, De-Guang, Ye, Dong-Qing. 2013. Therapeutic potential of SIGIRR in systemic lupus erythematosus. In Rheumatology international, 33, 1917-21. doi:10.1007/s00296-013-2733-0. https://pubmed.ncbi.nlm.nih.gov/23546688/

2. Yu, Wei, Haque, Inamul, Venkatraman, Aparna, Geurts, Aron M, Sampath, Venkatesh. 2021. SIGIRR Mutation in Human Necrotizing Enterocolitis (NEC) Disrupts STAT3-Dependent microRNA Expression in Neonatal Gut. In Cellular and molecular gastroenterology and hepatology, 13, 425-440. doi:10.1016/j.jcmgh.2021.09.009. https://pubmed.ncbi.nlm.nih.gov/34563711/

3. Ye, Yanshuo, Shi, Yunpeng, Wei, Zhenhong, Liu, Hongyu, Li, Wei. 2024. SIGIRR suppresses hepatitis B virus X protein-induced chronic inflammation in hepatocytes. In Gene, 928, 148768. doi:10.1016/j.gene.2024.148768. https://pubmed.ncbi.nlm.nih.gov/39013482/

4. Giannoudaki, Eirini, Stefanska, Anna M, Lawler, Hazel, Fallon, Padraic G, Walsh, Patrick T. 2021. SIGIRR Negatively Regulates IL-36-Driven Psoriasiform Inflammation and Neutrophil Infiltration in the Skin. In Journal of immunology (Baltimore, Md. : 1950), 207, 651-660. doi:10.4049/jimmunol.2100237. https://pubmed.ncbi.nlm.nih.gov/34253575/

5. Teng, Xiu, Mou, Da-Chao, Li, Hui-Fang, Tang, Meng, Liu, Yi. 2022. SIGIRR deficiency contributes to CD4 T cell abnormalities by facilitating the IL1/C/EBPβ/TNF-α signaling axis in rheumatoid arthritis. In Molecular medicine (Cambridge, Mass.), 28, 135. doi:10.1186/s10020-022-00563-9. https://pubmed.ncbi.nlm.nih.gov/36401167/