Therapeutic potential of SIGIRR in systemic lupus erythematosus

Wang, Chao; Feng, Chen-Chen; Pan, Hai‐Feng; Wang, Deguang; Ye, Dong-Qing

doi:10.1007/s00296-013-2733-0

“…These results were consistent with previous studies which suggested that Th17 cells may be involved in the pathogenesis of SLE and LN (22,25). SIGIRR, a negative regulator of the TLR/ILR pathway, has been studied in patients with SLE (27). Studies had revealed that SIGIRR-knockdown mice manifested with diffuse membrane proliferative glomerulone- phritis, macrophage invasion, immune complex deposition and the formation of autoantibodies including rheumatoid factor, anti-double stranded DNA and anti-Sm (15,28,29).…”

Section: Discussionsupporting

confidence: 92%

Increased ratio of Th17 cells to SIGIRR+CD4+ T�cells in peripheral blood of patients with SLE is associated with disease activity

Xiao

¹

,

Wang

²

,

Wang

³

et al. 2018

Self Cite

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To investigate the clinical significance of the ratio of T helper cell 17 (Th17) cells to single immunoglobulin IL-1-related receptor (SIGIRR) cluster of differentiation (CD4) T cells in patients with systemic lupus erythematosus (SLE), novel data and data from previous studies were analyzed. The frequency of Th17 cells in peripheral blood mononuclear cells (PBMCs) and their correlation with clinical data were evaluated in 48 patients with SLE and 38 healthy controls through flow cytometry. Compared with healthy controls, the percentage of Th17 cells was significantly increased in the PBMCs of patients with SLE (Z=-5.82, P<0.001). Compared with inactive SLE (ISLE), the percentage of Th17 cells in active SLE (ASLE) were significantly increased (Z=-4.26, P<0.0001). Compared with patients without lupus nephritis, the frequency of Th17 cells was significant increased (Z=-2.20, P=0.028). The frequency of Th17 cells was inversely correlated with the frequency of SIGIRRCD4 T cells (r=-0.61, P<0.001). The ratio of Th17 cells to SIGIRRCD4 T cells in ASLE was significantly increased compared with healthy controls or patients with ISLE (P<0.001) and was inversely correlated with complement component 3 and complement component 4, and positively correlated with SLE disease activity index and 24-h proteinuria (P<0.05). In summary, increased numbers of Th17 cells and decreased numbers of SIGIRRCD4 T cells in patients with SLE suggested that SIGIRRCD4 T and Th17 cells may be involved in the pathogenesis of SLE.

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“…SIGIRR deficiency was associated with exacerbated inflammatory and immune reactions under a variety of conditions (Molgora et al 2017). Previous studies have demonstrated that SIGIRR influences chronic inflammatory or autoimmune diseases, such as intestinal inflammation, systemic lupus erythematosus, and psoriatic inflammation, by regulating the activities of NK cells, CD8 T cells or γδ T cells (Wang et al 2022;Wang et al 2013;Molgora et al 2017;Xiao et al 2007;Russell et al 2013). Memory CD4 T cells are of great interest in the context of autoimmune diseases because of their long-lived nature, efficient responses to antigens, and unique potential to mediate recurring autoimmune responses (Raphael et al 2020).…”

Section: Discussionmentioning

confidence: 99%

SIGIRR deficiency contributes to CD4 T cell abnormalities by facilitating the IL1/C/EBPβ/TNF-α signaling axis in rheumatoid arthritis

Teng

¹

,

Mou

²

,

Li

³

et al. 2022

Mol Med

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Background Rheumatoid arthritis (RA) is a complex autoimmune disease with multiple etiological factors, among which aberrant memory CD4 T cells activation plays a key role in the initiation and perpetuation of the disease. 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. Methods Single-cell transcriptomics and bulk RNA sequencing data were integrated to predict SIGIRR 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+ 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 SIGIRR 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-α production in CD4 T cells. Results SIGIRR 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-α production. SIGIRR-deficient mice were more susceptible to antigen-induced arthritis (AIA), which was attributed to unleashed TNF-α production in memory CD4 T cells, confirmed by decreased TNF-α production resulting from ectopic expression of SIGIRR. Mechanistically, SIGIRR regulates the IL-1/C/EBPβ/TNF-α signaling axis, as established by experimental evidence and cis-acting factor bioinformatics analysis. Conclusion 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.

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“…Increasing evidence proved that SIGIRR could be an essential regulator of inflammation and innate and adaptive immune responses [5][6][7][8][9][10][11][12][13][14][15]. Recent studies have demonstrated that SIGIRR levels are upregulated in PBMCs and synovial cells of RA patients and involved in the pathogenesis of this disease [10,16,17].…”

Section: Discussionmentioning

confidence: 99%

“…The interleukin-1 receptor (IL-1R) superfamily includes two subfamilies of IL-1R-like receptors (ILRs) and Toll-like receptors (TLRs); both of which are involved in inflammatory response and innate immunity [ 5 ]. Single Ig IL-1-related receptor (SIGIRR), also named Toll/IL-1 receptor 8 (TIR8) or IL-1R8, is a new member of the IL-1R superfamily [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Single Immunoglobulin IL-1-Related Receptor (SIGIRR) Gene rs7396562 Polymorphism and Expression Level in Rheumatoid Arthritis

Yang

¹

,

Zhang

²

,

Xu

³

et al. 2021

BioMed Research International

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Objectives. The aim of our study was to investigate the association of single-nucleotide polymorphism (SNP) and mRNA expression profile of single immunoglobulin IL-1-related receptor (SIGIRR) in rheumatoid arthritis (RA) in a Chinese population. Methods. SIGIRR rs7396562 polymorphism was genotyped using TaqMan allelic discrimination assay in 517 RA patients and 601 healthy controls. Simultaneously, the SIGIRR mRNA expression levels of 79 RA patients and 76 healthy controls were examined by real-time quantitative polymerase chain reaction (RT-qPCR). Results. The frequency of SIGIRR rs7396562 T allele was significantly higher in RA patients compared with healthy controls (T versus G: OR = 1.277 , 95 % CI = 1.079 − 1.511 , P = 0.004 ). The TT genotype of SIGIRR rs7396562 was more frequent in RA patients than in healthy controls ( OR = 1.547 , 95 % CI = 1.107 − 2.163 , P = 0.011 ). Moreover, we also found a significant difference in the recessive model (TT versus TG+GG: OR = 1.439 , 95 % CI = 1.122 − 1.847 , P = 0.004 ). However, no significant evidence was observed for the association of the SIGIRR rs7396562 with RA in dominant model (TT+TG versus GG: OR = 1.275 , 95 % CI = 0.947 − 1.717 , P = 0.109 ). Further analysis showed no association between SIGIRR rs7396562 polymorphism and laboratory parameters of RA patients (all P > 0.05 ). The mRNA expression of SIGIRR was decreased in PBMCs of patients with RA when compared to healthy controls ( Z = − 2.459 , P = 0.014 ). No significant differences in SIGIRR mRNA expression levels were observed in patients with RA with different genotypes ( P = 0.280 ). Conclusions. Our findings demonstrated that the dysregulation of SIGIRR might be associated with the pathogenesis of RA, and SIGIRR rs7396562 polymorphism might contribute to RA susceptibility in the Chinese population.

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Therapeutic potential of SIGIRR in systemic lupus erythematosus

Cited by 8 publications

References 25 publications

Increased ratio of Th17 cells to SIGIRR+CD4+ T�cells in peripheral blood of patients with SLE is associated with disease activity

Increased ratio of Th17 cells to SIGIRR+CD4+ T�cells in peripheral blood of patients with SLE is associated with disease activity

SIGIRR deficiency contributes to CD4 T cell abnormalities by facilitating the IL1/C/EBPβ/TNF-α signaling axis in rheumatoid arthritis

Single Immunoglobulin IL-1-Related Receptor (SIGIRR) Gene rs7396562 Polymorphism and Expression Level in Rheumatoid Arthritis

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