Tir8/Sigirr prevents murine lupus by suppressing the immunostimulatory effects of lupus autoantigens

Abstract

The Sigirr gene (also known as Tir8) encodes for an orphan receptor of the Toll-like receptor (TLR)/interleukin 1 receptor family that inhibits TLR-mediated pathogen recognition in dendritic cells. Here, we show that Sigirr also inhibits the activation of dendritic cells and B cells upon exposure to RNA and DNA lupus autoantigens. To evaluate the functional role of Sigirr in the pathogenesis of systemic lupus erythematosus (SLE), we generated Sigirrdefi cient C57BL/6-lpr/lpr mice. These mice developed a progressive lymphoproliferative syndrome followed by severe autoimmune lung disease and lupus nephritis within 6 mo of age as compared with the minor abnormalities observed in C57BL/6-lpr/lpr mice. Lack of Sigirr was associated with enhanced activation of dendritic cells and increased expression of multiple proinfl ammatory and antiapoptotic mediators. In the absence of Sigirr , CD4 T cell numbers were increased and CD4 + CD25 + T cell numbers were reduced. Furthermore, lack of Sigirr enhanced the activation and proliferation of B cells, including the production of autoantibodies against multiple nuclear lupus autoantigens. These data identify Sigirr as a novel SLE susceptibility gene in mice.

The decreased frequency of SIGIRR-positive CD4+ T cells in peripheral blood of patients with SLE and its correlation with disease activity

“…In recent years, SIGIRR, a negative regulator of the ILR/ TLR superfamily, has been shown to play an important role in the pathogenesis of immune inflammatory diseases [5,10,12,[20][21][22][23][24]. SIGRR-deficient mice showed increased susceptibility to fungal infection and produced more inflammatory cytokines [22,25,26].…”

“…Drexler et al [11] reported SIGIRR overexpression inhibited cytokines release in human RA synovial cells. Moreover, SIGIRR-deficient C57BL/6 lpr/lpr mice increased the production of autoantibodies, for example, anti-dsDNA IgG, anti-nucleosome, anti-Sm antigen, anti-snRNP and rheumatoid factor (RF) compared to C57BL/6 lpr/lpr mice [12]. However, tubular atrophy and interstitial fibrosis after unilateral ureteral obstruction develop independent of the SIGIRR mainly because TLR2, TLR9, and their essential adaptor molecule and SIGIRR's interaction target MyD88 do not significantly contribute to the postobstructive renal inflammation and tissue remodeling [30].…”

“…Individual disease activity was quantified by using the SLE disease activity index (SLEDAI) score. SLE activity was defined on basis of SLEDAI scores: no or mild activity (SLE-DAI = 0-5), moderate activity (SLEDAI = 6-10), high activity (SLEDAI = [11][12][13][14][15][16][17][18][19], and very high activity (SLEDAI C 20) [19]. The study protocol was approved by the Ethics Committee of Anhui Medical University.…”

“…In contrast, overexpression of wild-type SIGIRR inhibited the release of IL-6, tumor necrosis factor a (TNFa) and IL-10 in synovial membranes of human rheumatoid arthritis (RA) [11]. In SIGIRR-deficient C57BL/6 lpr/lpr mice, spleen and lymph nodes were enlarged, and anti-dsDNA IgG, anti-Sm antigen, antisnRNP as well as rheumatoid factor were increased compared to C57BL/6 lpr/lpr mice [12]. Another study showed that SIGIRR protects from hydrocarbon oil-induced lupus [13].…”

Molecular pathways in cancer-related inflammation

“…It in hi bi ts TLR and IL-1R sig nal ling and is hig hly expres sed in in tes ti nal mu co sa. TI-R8 ge ne de fi cien cy is as so cia ted wi th in crea sed sus cep ti bi li ty to in tes ti nal in fl am ma tion and car cino ge ne sis (47,48) as we ll as to B ce ll lymphop ro life ra tion and au toim mu ni ty (49,50). Anot her ne gati ve re gu la tor of in fl am ma tion, na me ly A20 (al so known as TNFAI P3), has been pro po sed to function as tu mour sup pres sor in se ve ral hu man B-cell lympho ma (51).…”