{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSIGIRR, also known as IL‐1R8 or TIR8, is a unique member of the IL‐1 receptor family that acts as a broad negative regulator of inflammatory signaling. It exerts its anti‐inflammatory actions by interfering with interleukin‐1 (IL‐1) and Toll‐like receptor (TLR) pathways. In several studies, SIGIRR was shown to participate in the formation of receptor complexes—for example, binding to IL‐37 and IL‐18Rα to form a tripartite complex that inhibits kinases such as TAK1, Fyn and the transcription factor NF‐κB, ultimately reining in pro‐inflammatory signals triggered by lipopolysaccharide and other agonists."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn diverse pathophysiological contexts, SIGIRR’s function as an inhibitory receptor has critical implications. In neonatal necrotizing enterocolitis, loss‐of-function mutations in SIGIRR lead to exaggerated Toll‐like receptor responses and promote inflammation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In infectious and inflammatory diseases, including bacterial vaginosis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", colitis and rheumatoid arthritis"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": ", its regulatory role in epithelial cells and immune populations helps maintain mucosal and systemic homeostasis. In the airways and circulation, SIGIRR has been implicated in dampening TLR-mediated cytokine release in epithelial cells"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "and in platelets"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", while aberrant function or expression of SIGIRR has been noted in allergic bronchial asthma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ", breast cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", and Kawasaki disease where it mediates protective endothelial responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " Moreover, studies focusing on autoimmunity have revealed a complex picture in systemic lupus erythematosus (SLE), in which SIGIRR expression, genetic polymorphisms and functional deficits in B or T cells are linked to disease severity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the regulatory level, SIGIRR expression and function are themselves finely tuned by multiple intracellular mechanisms. In myeloid and epithelial cells, inflammatory stimuli such as LPS can downregulate SIGIRR via TLR4-p38 pathways and through modulation of transcription factors including Sp1, while interactions with adaptor proteins like PALM3 further contribute to its inhibitory effects."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": " Genetic polymorphisms in the SIGIRR gene have been associated with differential susceptibility to diseases including SLE and rheumatoid arthritis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": " In addition, SIGIRR modulates key signaling events such as TRAF6 ubiquitination and subsequent NF‐κB activation, processes that are central to the innate immune response in conditions like acute lung injury."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": " Emerging reports also highlight alterations in SIGIRR expression in the context of viral infections such as HIV"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": ", and its polymorphic variations have been explored in rheumatoid arthritis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": "as well as in severe acute pancreatitis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": "and acute liver injury."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": " Finally, comprehensive reviews have underscored the broader role of SIGIRR as a checkpoint molecule regulating natural killer cell function in cancer and infection."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Claudia A Nold-Petry, Camden Y Lo, Ina Rudloff, et al. 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