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SIGIRR (single immunoglobulin IL-1R-related receptor), a member of the IL-1 receptor (ILR) family, acts as a negative regulator of ILR and Toll-like receptor (TLR) downstream signaling pathways and inflammation. The aim of this study was to investigate the potential roles of SIGIRR on memory CD4 T cells in RA and the underlying cellular and molecular mechanisms.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Single-cell transcriptomics and bulk RNA sequencing data were integrated to predict <jats:italic>SIGIRR<\/jats:italic> gene distribution on different immune cell types of human PBMCs. Flow cytometry was employed to determine the differential expression of SIGIRR on memory CD4 T cells between the healthy and RA cohorts. A Spearman correlation study was used to determine the relationship between the percentage of SIGIRR<jats:sup>+<\/jats:sup> memory CD4 T cells and RA disease activity. An AIA mouse model (antigen-induced arthritis) and CD4 T cells transfer experiments were performed to investigate the effect of SIGIRR deficiency on the development of arthritis in vivo. Overexpression of <jats:italic>SIGIRR<\/jats:italic> in memory CD4 T cells derived from human PBMCs or mouse spleens was utilized to confirm the roles of SIGIRR in the intracellular cytokine production of memory CD4 T cells. Immunoblots and RNA interference were employed to understand the molecular mechanism by which SIGIRR regulates TNF-\u03b1 production in CD4 T cells.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p><jats:italic>SIGIRR<\/jats:italic> was preferentially distributed by human memory CD4 T cells, as revealed by single-cell RNA sequencing. SIGIRR expression was substantially reduced in RA patient-derived memory CD4 T cells, which was inversely associated with RA disease activity and related to enhanced TNF-\u03b1 production. <jats:italic>SIGIRR<\/jats:italic>-deficient mice were more susceptible to antigen-induced arthritis (AIA), which was attributed to unleashed TNF-\u03b1 production in memory CD4 T cells, confirmed by decreased TNF-\u03b1 production resulting from ectopic expression of <jats:italic>SIGIRR<\/jats:italic>. Mechanistically, SIGIRR regulates the IL-1\/C\/EBP\u03b2\/TNF-\u03b1 signaling axis, as established by experimental evidence and cis-acting factor bioinformatics analysis.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Taken together, SIGIRR deficiency in memory CD4 T cells in RA raises the possibility that receptor induction can target key abnormalities in T cells and represents a potentially novel strategy for immunomodulatory therapy.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s10020-022-00563-9","type":"journal-article","created":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T12:03:38Z","timestamp":1668773018000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["SIGIRR deficiency contributes to CD4 T cell abnormalities by facilitating the IL1\/C\/EBP\u03b2\/TNF-\u03b1 signaling axis in rheumatoid arthritis"],"prefix":"10.1186","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2576-9495","authenticated-orcid":false,"given":"Xiu","family":"Teng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Da-Chao","family":"Mou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui-Fang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Jiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sha-Sha","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin-Kui","family":"Pi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng-Li","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,11,18]]},"reference":[{"issue":"3","key":"563_CR1","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1681\/ASN.2019080778","volume":"31","author":"S Aiello","year":"2020","unstructured":"Aiello S, et al. 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