Tissue factor binds to and inhibits interferon-α receptor 1 signaling
Manoharan J, Rana R, Kuenze G, Gupta D, Elwakiel A, Ambreen S, Wang H, Banerjee K, Zimmermann S, Singh K, Gupta A, Fatima S, Kretschmer S, Schaefer L, Zeng-Brouwers J, Schwab C, Al-Dabet M, Gadi I, Altmann H, Koch T, Poitz D, Baber R, Kohli S, Shahzad K, Geffers R, Lee-Kirsch M, Kalinke U, Meiler J, Mackman N, Isermann B
Erschienen in
Immunity: Volume 57, Issue 1, Page 68-85.e11
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 (Pod(ΔF3)) 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 Pod(ΔF3) 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.
In PubMed öffnenAutoren
Prof. Dr. Ulrich Kalinke
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