<br>IFP35 通过促进 Nrf2 调节的铁死亡而加重金黄色葡萄球菌感染,Journal of Advanced Research

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IFP35 通过促进 Nrf2 调节的铁死亡而加重金黄色葡萄球菌感染
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2023-09-29 , DOI: 10.1016/j.jare.2023.09.042
Min Dai ₁ , Wei Ouyang ₁ , Yangle Yu ₂ , Tao Wang ₂ , Yanling Wang ₂ , Mengyuan Cen ₃ , Liping Yang ₄ , Yu Han ₁ , Yushi Yao ₂ , Feng Xu ₅

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严重（SA）感染是最危及生命的疾病之一。干扰素诱导蛋白35（IFP35）是一种多效因子，参与多种生物学功能，然而，其在SA感染中的生物学作用尚不完全清楚。铁死亡是一种新型的受调节细胞死亡，由游离铁和有毒脂质过氧化物的积累驱动，在组织损伤中发挥着关键作用。铁死亡是否参与 SA 诱导的免疫病理学及其调节机制仍不清楚。我们的目的是确定 IFP35 在 SA 诱导的肺部感染中的作用和潜在机制。使用野生型（WT）和IFP35敲除（）小鼠或巨噬细胞建立SA感染模型。进行组织学分析以评估肺损伤。进行定量实时 PCR、蛋白质印迹、流式细胞术和共聚焦显微镜来检测铁焦亡。 Co-IP 和免疫荧光用于阐明分子调控机制。我们发现 SA 感染小鼠的巨噬细胞和肺组织中 IFP35 水平增加。 IFP35 缺陷可防止 SA 引起的小鼠肺损伤。此外，SA感染后发生铁死亡并导致肺损伤，IFP35缺乏可改善这种情况。从机械角度来看，IFP35促进核因子E2相关因子2（Nrf2）的泛素化和降解，加重SA诱导的铁死亡和肺损伤。我们的数据表明，IFP35 通过促进 Nrf2 泛素化和降解来加剧 SA 感染，从而促进铁死亡。靶向 IFP35 可能是治疗 SA 引起的传染病的一种有前途的方法。

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IFP35 aggravates Staphylococcus aureus infection by promoting Nrf2-regulated ferroptosis

Serious (SA) infection is one of the most life-threatening diseases. Interferon-induced protein 35 (IFP35) is a pleiotropic factor that participates in multiple biological functions, however, its biological role in SA infection is not fully understood. Ferroptosis is a new type of regulated cell death driven by the accretion of free iron and toxic lipid peroxides and plays critical roles in tissue damage. Whether ferroptosis is involved in SA-induced immunopathology and its regulatory mechanisms remain unknown. We aimed to determine the role and underlying mechanisms of IFP35 in SA-induced lung infections. SA infection models were established using wild-type (WT) and IFP35 knockout () mice or macrophages. Histological analysis was performed to assess lung injury. Quantitative real-time PCR, western blotting, flow cytometry, and confocal microscopy were performed to detect ferroptosis. Co-IP and immunofluorescence were used to elucidate the molecular regulatory mechanisms. We found that IFP35 levels increased in the macrophages and lung tissue of SA-infected mice. IFP35 deficiency protected against SA-induced lung damage in mice. Moreover, ferroptosis occurred and contributed to lung injury after SA infection, which was ameliorated by IFP35 deficiency. Mechanically, IFP35 facilitated the ubiquitination and degradation of nuclear factor E2-related factor 2 (Nrf2), aggravating SA-induced ferroptosis and lung injury. Our data demonstrate that IFP35 promotes ferroptosis by facilitating the ubiquitination and degradation of Nrf2 to exacerbate SA infection. Targeting IFP35 may be a promising approach for treating infectious diseases caused by SA.

更新日期：2023-09-29

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