Year: 2024
Type: article
Abstract: Tissue factor (TF), which is a member of the cytokine receptor family, promotes coagulation and coagulation-dependent inflammation. TF also exerts protective effects through unknown mechanisms. Here, we showed that TF bound to interferon-α receptor 1 (IFNAR1) and antagonized its signaling, preventing spontaneous sterile inflammation and maintaining immune homeostasis. Structural modeling and direct binding studies revealed binding of the TF C-terminal fibronectin III domain to IFNAR1, which restricted the expression of interferon-stimulated genes (ISGs). Podocyte-specific loss of TF in mice (PodΔF3) resulted in sterile renal inflammation, characterized by JAK/STAT signaling, proinflammatory cytokine expression, disrupted immune homeostasis, and glomerulopathy. Inhibiting IFNAR1 signaling or loss of Ifnar1 expression in podocytes attenuated these effects in PodΔF3 mice. As a heteromer, TF and IFNAR1 were both inactive, while dissociation of the TF-IFNAR1 heteromer promoted TF activity and IFNAR1 signaling. These data suggest that the TF-IFNAR1 heteromer is a molecular switch that controls thrombo-inflammation.
DOI: 10.17615/e1kj-m719
Authors: Zeng-Brouwers J., Gupta A., Poitz D.M., Wang H., Schaefer L., Geffers R., Rana R., Ambreen S., Isermann B., Koch T., Fatima S., Gupta D., Kuenze G., Zimmermann S., Mackman N., Altmann H., Elwakiel A., Singh K., Shahzad K., Banerjee K., Baber R., Kohli S., Kalinke U., Manoharan J., Lee-Kirsch M.A., Al-Dabet M.M., Meiler J., Schwab C., Gadi I., Kretschmer S.
Institution: University of North Carolina at Chapel Hill
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: G1462112011, G1638204096, G1698094077, G1755634470, G2013436488, G216534383, TRR 237: NukleinsäureImmunität, G3491701353, EXC 2026: CardioPulmonary Institute (CPI), G3943897152, G3964734156, SFB 1118: Reaktive Metabolite als Ursache diabetischer Folgeschäden, G5290293035, G5454435177, G551519423, G590706412, G717620769, G727481207, SFB 1177: Molekulare und funktionale Charakterisierung der selektiven Autophagie, G995400915
OpenAlex ID: W4405829293