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SIGIRR is a negative regulator of TLR4 signaling in the developing intestine, and its insufficiency results in native intestinal TLR hyper-responsiveness conducive to the development of severe experimental necrotizing enterocolitis in mice
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Here the authors show that hyperactivation of the interleukin 1 pathway, through either ablation of the interleukin 1 receptor 8 (IL-1R8, also known as SIGIRR or Tir8) or activation of IL-1R, leads to up-regulation of the mTOR pathway and increased levels of the epigenetic regulator MeCP2, bringing to disruption of dendritic spine morphology, synaptic plasticity and plasticity-related gene expression.
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Commensal flora depletion and IL-1R1 deficiency abated platelet hyperactivity and the increased platelet/neutrophil aggregation observed in Il1r8(-/-) mice in vitro and in vivo, suggesting a key role of IL-1R8 in regulating platelet TLR and IL-1R1 function
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Tir8/SIGIRR acts anti-inflammatory on different immune responses,its function in allergic asthma is a controversial issue, since anti- as well as pro-inflammatory effects have been reported
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Expression of SIGIRR(N86/102S) in the colonic epithelium of mice increases expression of inflammatory cytokines and formation and size of colitis-associated tumors.
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IL-37 requires IL-18Ralpha and SIGIRR/IL-1R8 to diminish allergic airway inflammation in mice
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IL-37 requires the receptors IL-18Ralpha and IL-1R8 to carry out its multifaceted anti-inflammatory program upon innate signal transduction.
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impairs the antibacterial host defense during pneumonia and sepsis caused by S. pneumoniae
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IL-37 acts as an extracellular cytokine by binding to the IL-18 receptor but using the IL-1R8 for its anti-inflammatory properties.
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Lipopolysaccharide decreases SIGIRR expression by suppressing specificity protein 1 Sp1 via the TLR4-p38 pathway in monocytes and neutrophils.
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Thus, SIGIRR expression by IEC reflects a strategy that sacrifices maximal innate responsiveness by IEC in order to promote commensal microbe based colonization resistance against bacterial pathogens.
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This study identifies TIR8/SIGIRR as a novel intrinsic negative regulator of innate IL-17A expression
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Absence of TIR8 reduces house dust mite-induced allergic airway inflammation in mice.
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data suggest that TIR8 is an important negative regulator of an LPS-mediated inflammatory response in tubular epithelial cells and dampens an effective antibacterial host response during pyelonephritis
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TIR8 has a nonredundant effect in modulating the inflammation caused by Pseudomonas aeruginosa, in particular, by negatively regulating IL-1RI signaling, which plays a major role in the pathogenesis of bacterial pneumonia.
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in the absence of TIR8 the appearance of monoclonal B-cell expansions is accelerated and mouse life span is shortened in chronic lymphocytic leukemia
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Data argue against a significant role of SIGIRR in renal fibrosis.
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These findings highlight the functional role of SIGIRR in regulating inflammatory-mediated synaptic and cognitive decline
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modulating the expression level of SIGIRR may be a promising potential treatment for acute lung injury.
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SIGIRR is expressed constitutively in intestinal epithelial cells to maintain gut innate immunity and then down-regulated during inflammation by inhibition of an SP1-mediated pathway.
