| First Author | Manoharan J | Year | 2024 |
| Journal | Immunity | Volume | 57 |
| Issue | 1 | Pages | 68-85.e11 |
| PubMed ID | 38141610 | Mgi Jnum | J:344292 |
| Mgi Id | MGI:7574082 | Doi | 10.1016/j.immuni.2023.11.017 |
| Citation | Manoharan J, et al. (2024) Tissue factor binds to and inhibits interferon-alpha receptor 1 signaling. Immunity 57(1):68-85.e11 |
| abstractText | 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-alpha 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(DeltaF3)) 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(DeltaF3) 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. |
