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.
Authors
- Ritu Rana
- Liliana Schaefer (ORCID: https://orcid.org/0000-0002-3318-3005)
- Heidi Altmann (ORCID: https://orcid.org/0000-0003-1967-0330)
- Anand Kumar Gupta (ORCID: https://orcid.org/0000-0001-7917-9194)
- Ulrich Kalinke (ORCID: https://orcid.org/0000-0003-0503-9564)
- Jerena Manoharan (ORCID: https://orcid.org/0000-0003-1611-2712)
- Jinyang Zeng-Brouwers
- Ihsan Gadi
- Jens Meiler (ORCID: https://orcid.org/0000-0001-8945-193X)
- Silke Zimmermann (ORCID: https://orcid.org/0000-0001-9644-8907)
- Constantin Schwab (ORCID: https://orcid.org/0000-0002-0979-2943)
- Kunal Kumar Singh (ORCID: https://orcid.org/0000-0003-1026-1282)
- Khurrum Shahzad
- Georg Kuenze (ORCID: https://orcid.org/0000-0003-1799-346X)
- Ahmed Elwakiel (ORCID: https://orcid.org/0000-0001-6784-8370)
- Stefanie Kretschmer (ORCID: https://orcid.org/0000-0001-6571-570X)
- Robert Geffers (ORCID: https://orcid.org/0000-0003-4409-016X)
- Nigel Mackman (ORCID: https://orcid.org/0000-0002-9170-7700)
- Shrey Kohli (ORCID: https://orcid.org/0000-0003-2118-7380)
- Dhanu Gupta (ORCID: https://orcid.org/0000-0003-0163-2678)
- Sameen Fatima (ORCID: https://orcid.org/0000-0001-6905-6916)
- Thomas Koch (ORCID: https://orcid.org/0000-0002-0417-5700)
- Berend Isermann (ORCID: https://orcid.org/0000-0003-0714-6160)
- Hong Wang (ORCID: https://orcid.org/0000-0002-6192-3082)
- Kakoli Banerjee (ORCID: https://orcid.org/0000-0002-4306-2194)
- Saira Ambreen (ORCID: https://orcid.org/0000-0001-7960-5181)
- Ronny Baber
- Aishwarya Bharathi H.M.
- Poitz D.M.
- Lee-Kirsch M.A.
Institutions
- University of North Carolina at Chapel Hill (US)
Publication Details
- Journal
- UNC Libraries
- Published
- 2024-12-23
- DOI
- https://doi.org/10.17615/e1kj-m719
- Primary Topic
- Cytokine Signaling Pathways and Interactions
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutscher Akademischer Austauschdienst
- Deutsche Forschungsgemeinschaft
- Cardio-Pulmonary Institute