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.

组织因子(TF) 是细胞因子受体家族的成员，可促进凝血和凝血依赖性炎症。TF 还通过未知机制发挥保护作用。在这里，我们发现 TF 与干扰素 α 受体 1 (IFNAR1) 结合并拮抗其信号传导，防止自发性无菌炎症并维持免疫稳态。结构建模和直接结合研究揭示了 TF C 末端纤连蛋白 III 结构域与 IFNAR1 的结合，从而限制了干扰素刺激基因 (ISG) 的表达。小鼠足细胞特异性 TF 缺失 (Pod^{Δ F3} ) 导致无菌性肾脏炎症，其特征是 JAK/STAT 信号传导、促炎细胞因子表达、免疫稳态破坏和肾小球病。抑制 IFNAR1 信号传导或足细胞中Ifnar1^{Δ F3}小鼠的这些影响。作为异聚体，TF 和 IFNAR1 均无活性，而 TF-IFNAR1 异聚体的解离促进了 TF 活性和 IFNAR1 信号传导。这些数据表明 TF-IFNAR1 异聚体是控制血栓炎症的分子开关。