The Essential Role of Single Ig IL-1 Receptor-Related Molecule/Toll IL-1R8 in Regulation of Th2 Immune Response

Abstract

A novel cytokine IL-33, an IL-1 family member, signals via ST2 receptor and promotes Th2 responses, through the activation of NF-κB and MAP kinases. Previous studies reported that single Ig IL-1R-related molecule (SIGIRR)/Toll IL-1R8 acts as negative regulator for TLR-IL-1R-mediated signaling. We now found that SIGIRR formed a complex with ST2 upon IL-33 stimulation and specifically inhibited IL-33/ST2-mediated signaling in cell culture model. Furthermore, IL-33-induced Th2 response was enhanced in SIGIRR-deficient mice compared with that in wild-type control mice, suggesting a negative regulatory role of SIGIRR in IL-33/ST2 signaling in vivo. Similar to ST2, SIGIRR was highly expressed in in vitro polarized Th2 cells, but not Th1 cells. SIGIRR-deficient Th2 cells produce higher levels of Th2 cytokines, including IL-5, IL-4, and IL-13, than that in wild-type cells. Moreover, SIGIRR-deficient mice developed stronger Th2 immune response in OVA-challenged asthma model. Taken together, our results suggest that SIGIRR plays an important role in the regulation of Th2 response in vivo, possibly through its impact on IL-33-ST2-mediated signaling.

Lipopolysaccharide Decreases Single Immunoglobulin Interleukin-1 Receptor-related Molecule (SIGIRR) Expression by Suppressing Specificity Protein 1 (Sp1) via the Toll-like Receptor 4 (TLR4)-p38 Pathway in Monocytes and Neutrophils

“…Despite many reports that basal SIGIRR expression is high in epithelial cell lines and tissues (6,10), recent studies have demonstrated that SIGIRR expression in non-epithelial lineages is also higher than originally thought (11)(12)(13)(14). Our findings on the prevalence of functional expression of SIGIRR and its downregulation by LPS in monocytic and neutrophilic cells alongside these studies showing a contributory role of non-epithelial systems under physiological and pathophysiological conditions further highlighted the need for a better understanding of how SIGIRR expression is regulated in this lesser-studied non-epithelial innate immune systems.…”

“…Thomassen et al (10) demonstrated that expression levels of SIGIRR is generally kept high in organs such as the liver, lung, and gut, which may contribute to maintain an activation threshold of TIR signaling, whereas SIGIRR expression is down-regulated upon treatment with pathogenassociated molecular patterns to reach maximum induction of immune responses in various organs (6). Based on the previous reports, SIGIRR seems to be dominantly expressed in epithelial tissues, but recent reports focusing on the expression and function of SIGIRR in non-epithelial immune cells such as Th2-lymphocytes (11), macrophages (12), Langerhans cells (13), and Payer's patch dendritic cells (14) suggest a fundamental role of SIGIRR in these cells. Despite the finding showing that SIGIRR proximal promoter has a binding site for Sp1, which enhances its transcription in basal conditions in epithelial tissues (15), little is known regarding the regulatory mechanism of SIGIRR expression in non-epithelial immune cells such as monocytes/ macrophages and neutrophils during inflammatory responses.…”

Characterization of SIGIRR/IL-1R8 Homolog from Zebrafish Provides New Insights into Its Inhibitory Role in Hepatic Inflammation

“…In contrast with other TIR family members, SIGIRR comprises a single extracellular Ig domain, a transmembrane region, and a conserved intracellular TIR domain with substitutions of the two amino acid sites (Ser 447 and Arg-Tyr 536 ) required for the signaling of IL-1RI, as well as a unique 95-aa-long cytoplasmic tail, which differentiates SIGIRR from other TIR-containing family members (4,5). SIGIRR has become increasingly attractive for its critical negative regulatory function on IL-1RI, IL-18R, T1/ST2, and various TLR (TLR-1-5, -7, and -9) signaling pathways (5)(6)(7)(8)(9)(10). Dysfunction of SIGIRR results in various inflammatory diseases, as well as autoimmune-relevant disorders and tumors, such as ulcerative colitis, psoriatic inflammation, rheumatoid arthritis, lupus nephritis, and chronic lymphocytic leukemia.…”

Transgenic modelling of cytokine polarization in the lung

“…58 The TIR8 is expressed in Th2 cells and inhibits IL-133/ T1/ST2-mediated signalling and Th2 cytokine production. 59 Mice that are TIR8 null had exaggerated Th2 responses in allergic pulmonary inflammation induced by ovalbumin. 59 They also exhibited hyper-responsiveness to IL-133 with elevated serum levels of IL-5 and IL-13, splenomegaly and lung inflammation.…”

“…59 Mice that are TIR8 null had exaggerated Th2 responses in allergic pulmonary inflammation induced by ovalbumin. 59 They also exhibited hyper-responsiveness to IL-133 with elevated serum levels of IL-5 and IL-13, splenomegaly and lung inflammation. These findings from the genetically modified mice suggest that TIR8 potentially serves as a negative feedback control in Th2 polarization in the control of allergic inflammatory responses.…”