Tissue factor binds to and inhibits interferon-α receptor 1 signaling.

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. Copyright © 2023 Elsevier Inc. All rights reserved.

Citation

Jayakumar Manoharan, Rajiv Rana, Georg Kuenze, Dheerendra Gupta, Ahmed Elwakiel, Saira Ambreen, Hongjie Wang, Kuheli Banerjee, Silke Zimmermann, Kunal Singh, Anubhuti Gupta, Sameen Fatima, Stefanie Kretschmer, Liliana Schaefer, Jinyang Zeng-Brouwers, Constantin Schwab, Moh'd Mohanad Al-Dabet, Ihsan Gadi, Heidi Altmann, Thea Koch, David M Poitz, Ronny Baber, Shrey Kohli, Khurrum Shahzad, Robert Geffers, Min Ae Lee-Kirsch, Ulrich Kalinke, Jens Meiler, Nigel Mackman, Berend Isermann. Tissue factor binds to and inhibits interferon-α receptor 1 signaling. Immunity. 2024 Jan 09;57(1):68-85.e11

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PMID: 38141610

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