Tissue factor binds to and inhibits interferon-a 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-a 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 (TF?POD) 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 TF?POD 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. Overall design: 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 TF?POD 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 TF?POD 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.