德国莱比锡大学Berend Isermann研究组发现，组织因子与干扰素-α受体1结合并抑制其信号传导。相关论文于2023年12月22日在线发表在《免疫》杂志上。

研究人员发现组织因子（TF）与干扰素-α受体1（IFNAR1）结合并拮抗其信号传导，从而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显示，TF C端纤维蛋白III结构域与IFNAR1结合，从而限制了干扰素刺激基因（ISG）的表达。小鼠足细胞特异性缺失TF（Pod^ΔF3）会导致无菌性肾炎，表现为JAK/STAT信号传导、促炎细胞因子表达、免疫稳态紊乱和肾小球病变。

抑制IFNAR1信号传导或足细胞中Ifnar1的表达可减轻Pod^ΔF3小鼠的这些影响。作为异聚体，TF和IFNAR1都没有活性，而TF-IFNAR1异聚体的分离则促进了TF的活性和IFNAR1信号的传递。这些数据表明，TF-IFNAR1异聚体是控制血栓-炎症的分子开关。

据介绍，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。

附：英文原文

Title: Tissue factor binds to and inhibits interferon-α receptor 1 signaling

Author: Jayakumar Manoharan, Rajiv Rana, Georg Kuenze, Dheerendra Gupta, Ahmed Elwakiel, Saira Ambreen, Hongjie Wang, Kuheli Banerjee, Silke Zimmermann, Kunal Singh, Anubhuti Gupta, Sameen Fatima, Stefanie Kretschmer, Liliana Schaefer, Jinyang Zeng-Brouwers, Constantin Schwab, Moh’d Mohanad Al-Dabet, Ihsan Gadi, Heidi Altmann, Thea Koch, David M. Poitz, Ronny Baber, Shrey Kohli, Khurrum Shahzad, Robert Geffers, Min Ae Lee-Kirsch, Ulrich Kalinke, Jens Meiler, Nigel Mackman, Berend Isermann

Issue&Volume: 2023-12-22

Abstract: Tissue factor (TF), which is a member of the cytokine receptor family, promotes coagulationand coagulation-dependent inflammation. TF also exerts protective effects throughunknown mechanisms. Here, we showed that TF bound to interferon-α receptor 1 (IFNAR1)and antagonized its signaling, preventing spontaneous sterile inflammation and maintainingimmune homeostasis. Structural modeling and direct binding studies revealed bindingof the TF C-terminal fibronectin III domain to IFNAR1, which restricted the expressionof interferon-stimulated genes (ISGs). Podocyte-specific loss of TF in mice (PodΔF3) resulted in sterile renal inflammation, characterized by JAK/STAT signaling, proinflammatorycytokine expression, disrupted immune homeostasis, and glomerulopathy. InhibitingIFNAR1 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 theTF-IFNAR1 heteromer promoted TF activity and IFNAR1 signaling. These data suggestthat the TF-IFNAR1 heteromer is a molecular switch that controls thrombo-inflammation.

DOI: 10.1016/j.immuni.2023.11.017

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00499-5