IFP35 aggravates Staphylococcus aureus infection by promoting Nrf2-regulated ferroptosis
IFP35 aggravates Staphylococcus aureus infection by promoting Nrf2-regulated ferroptosis
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DOI：
10.1016/j.jare.2023.09.042
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发表时间：
2024-07-17
影响因子：
10.7
通讯作者：
Xu，Feng
中科院分区：
文献类型：
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作者：
Dai，Min;Ouyang，Wei;Xu，Feng
前言严重的金黄色葡萄球菌(SA)感染是危害人类生命的疾病之一。干扰素诱导蛋白35(IFP35)是一种参与多种生物学功能的多效性因子，但其在金黄色葡萄球菌感染中的生物学作用尚不完全清楚。铁下垂是一种新型的调节性细胞死亡，由游离铁和毒性过氧化脂质的堆积驱动，在组织损伤中起着关键作用。目的探讨IFP35在SA诱导的肺部感染中的作用及其机制。方法采用野生型(WT)和IFP35基因敲除(IFP35−/−)小鼠或巨噬细胞建立金黄色葡萄球菌感染模型。采用组织学方法评价肺损伤程度。采用实时荧光定量聚合酶链式反应、免疫印迹、流式细胞仪和共聚焦显微镜等方法检测上睑下垂。结果发现感染金黄色葡萄球菌的小鼠巨噬细胞和肺组织中IFP35水平升高。IFP35缺乏对SA诱导的小鼠肺损伤具有保护作用。此外，金黄色葡萄球菌感染后出现铁性下垂并导致肺损伤，IFP35缺乏可改善这种情况。IFP35在机制上促进了核因子E2相关因子2(Nrf2)的泛素化和降解，加重了SA引起的铁下垂和肺损伤。结论IFP35通过促进Nrf2的泛素化和降解而促进铁下垂，从而加重SA感染。靶向IFP35可能是治疗金黄色葡萄球菌引起的感染性疾病的一种有前途的方法。
IntroductionSeriousStaphylococcus aureus(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.ObjectivesWe aimed to determine the role and underlying mechanisms of IFP35 in SA-induced lung infections.MethodsSA infection models were established using wild-type (WT) and IFP35 knockout (Ifp35−/−) 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.ResultsWe 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.ConclusionsOur 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.