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 binds to interferon-α receptor 1 (IFNAR1) and antagonizes 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 (TFΔPOD) resulted in sterile renal inflammation, which was characterized by JAK/STAT signaling, proinflammatory cytokine expression, disrupted immune homeostasis, and glomerulopathy. Inhibiting IFNAR1 signaling or the loss of IFNAR1 expression in podocytes attenuated or prevented these effects in TFΔPOD mice, respectively. Intriguingly, in the heteromer, TF and IFNAR1 are both inactive, while dissociation of the TF-IFNAR1 heteromer promotes TF activity and IFNAR1 signaling. These data suggest that the TF-IFNAR1 heteromer is a new molecular switch that controls thrombo-inflammation. The aim of this study was to examine the impact of podocyte TF loss on kidney immune homeostasis. Initially, primary mouse podocytes carrying TFLoxP and TFΔPOD genotypes were cultured and differentiated for 14 days in vitro, followed by comprehensive analysis of their whole cell transcriptome. Subsequently, to delve into the repercussions of podocyte TF loss on kidney immune homeostasis, we conducted a screening of whole kidney RNA extracted from TFLoxP and TFΔPOD mice. Lastly, the regulatory role of human podocyte TF in IFNAR1 signaling was confirmed by simultaneously disrupting TF and IFNAR1 in immortalized human podocytes. This multifaceted approach sheds light on the intricate interplay between podocyte TF, immune responses, and kidney homeostasis.

组织因子（Tissue factor, TF）作为细胞因子受体家族成员，可促进凝血及凝血依赖性炎症反应，同时亦通过尚未阐明的机制发挥保护作用。本研究证实，TF可与Ⅰ型干扰素受体1（interferon-α receptor 1, IFNAR1）结合并拮抗其信号转导，从而抑制自发性无菌性炎症、维持机体免疫稳态。结构建模与直接结合实验表明，TF的C端纤连蛋白Ⅲ结构域可与IFNAR1结合，进而限制干扰素刺激基因（interferon-stimulated genes, ISGs）的表达。小鼠足细胞特异性敲除TF（TFΔPOD）可引发无菌性肾脏炎症，其特征为JAK/STAT信号通路激活、促炎细胞因子表达上调、免疫稳态紊乱及肾小球病变。在TFΔPOD小鼠体内，抑制IFNAR1信号转导或敲除足细胞中的IFNAR1，可分别减轻或完全阻断上述病理改变。值得注意的是，在TF-IFNAR1异源多聚体中，二者均处于失活状态；而该异源多聚体的解离则可同时激活TF的功能与IFNAR1信号转导。上述研究结果表明，TF-IFNAR1异源多聚体是调控血栓炎症的新型分子开关。本研究旨在探究足细胞TF缺失对肾脏免疫稳态的影响。首先，我们体外培养携带TFLoxP与TFΔPOD基因型的原代小鼠足细胞，诱导分化14天后对其全细胞转录组进行全面分析。随后，为深入解析足细胞TF缺失对肾脏免疫稳态的影响，我们对提取自TFLoxP与TFΔPOD小鼠的全肾RNA进行了转录组筛选。最后，通过在永生化人足细胞中同时敲除TF与IFNAR1，我们证实了人足细胞TF对IFNAR1信号通路的调控作用。本多维度研究策略揭示了足细胞TF、免疫应答与肾脏稳态之间的复杂相互作用。