{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The type I interferon receptor IFNAR1 is a pivotal component of the receptor complex that binds IFN‐α/β and initiates a cascade of intracellular events leading to the expression of interferon‐stimulated genes. These events establish an antiviral state and modulate the balance between antimicrobial defense and inflammation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Structural studies have demonstrated that ligand-specific interactions with IFNAR1 and its partner IFNAR2 effectively “proofread” the incoming signals by modulating STAT phosphorylation profiles, receptor internalization, and downstream gene expression. In this way, IFNAR1 is not only a trigger for robust antiviral defenses but also a regulator that tailors the magnitude and quality of the immune response."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its role in antiviral immunity, IFNAR1 signaling contributes to the negative feedback regulation of inflammation. By engaging IFNAR1, various cell types can modulate the production of pro‐inflammatory cytokines and upregulate inhibitors such as SOCS, which ultimately serve to restrain excessive Toll-like receptor and cytokine-mediated responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}, {"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, the absence or disruption of IFNAR1 signaling has been shown to influence cell death pathways and disease outcomes. For instance, in models of Gram-negative bacterial infection, IFNAR1 deficiency renders macrophages resistant to necroptosis and improves host survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In parallel, studies in the central nervous system demonstrate that IFNAR1 expressed by myeloid cells is critical for limiting autoimmune inflammation, with its absence correlating with exacerbated disease in models of CNS autoimmunity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}, {"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies underscore the multifaceted functions of IFNAR1. It integrates extracellular interferon signals to not only induce potent antiviral programs but also fine-tune inflammatory responses and cell death processes that are critical for maintaining immune homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "8"}, {"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "4"}, {"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Carla V Rothlin, Sourav Ghosh, Elina I Zuniga, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TAM receptors are pleiotropic inhibitors of the innate immune response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2007.10.034"}], "href": "https://doi.org/10.1016/j.cell.2007.10.034"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18083102"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18083102"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Christoph Thomas, Ignacio Moraga, Doron Levin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural linkage between ligand discrimination and receptor activation by type I interferons."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2011.06.048"}], "href": "https://doi.org/10.1016/j.cell.2011.06.048"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21854986"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21854986"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Markus Mordstein, Georg Kochs, Laure Dumoutier, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Interferon-lambda contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Pathog (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.ppat.1000151"}], "href": "https://doi.org/10.1371/journal.ppat.1000151"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18787692"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18787692"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Beichu Guo, Elmer Y Chang, Genhong Cheng "}, {"type": "b", "children": [{"type": "t", "text": "The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI33342"}], "href": "https://doi.org/10.1172/JCI33342"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18382764"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18382764"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Christopher P Dillon, Ricardo Weinlich, Diego A Rodriguez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2014.04.018"}], "href": "https://doi.org/10.1016/j.cell.2014.04.018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24813850"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24813850"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Nirmal Robinson, Scott McComb, Rebecca Mulligan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni.2397"}], "href": "https://doi.org/10.1038/ni.2397"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22922364"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22922364"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Marco Prinz, Hauke Schmidt, Alexander Mildner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunity (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.immuni.2008.03.011"}], "href": "https://doi.org/10.1016/j.immuni.2008.03.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18424188"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18424188"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Nina Ank, Marie B Iversen, Christina Bartholdy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An important role for type III interferon (IFN-lambda/IL-28) in TLR-induced antiviral activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.180.4.2474"}], "href": "https://doi.org/10.4049/jimmunol.180.4.2474"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18250457"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18250457"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Kevin R King, Aaron D Aguirre, Yu-Xiang Ye, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IRF3 and type I interferons fuel a fatal response to myocardial infarction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm.4428"}], "href": "https://doi.org/10.1038/nm.4428"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29106401"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29106401"}]}]}]}