Advanced glycation end products reduce macrophage-mediated killing ofStaphylococcus aureusby ARL8 upregulation and inhibition of autolysosome formation
Advanced glycation end products reduce macrophage-mediated killing ofStaphylococcus aureusby ARL8 upregulation and inhibition of autolysosome formation
复制标题
高级糖基化终末产物通过 ARL8 上调和自溶酶体形成抑制减少巨噬细胞介导的金黄色葡萄球菌杀伤
DOI：
10.1002/eji.201948477
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发表时间：
2020
影响因子：
5.4
通讯作者：
Yan Li
中科院分区：
文献类型：
--
作者：
Xie Xiaoying;Yang Chuan;Duan Chaohui;Chen Hongxing;Zeng Tingting;Huang Songyin;Li Hongyu;Ren Meng;Lin Wei-Jye;Yan Li
金黄色葡萄球菌是糖尿病足溃疡感染中最常见的病原体，最近被认为是一种细胞内病原体。在专业吞噬细胞如巨噬细胞中的自噬允许选择性破坏细胞内病原体，并且其功能障碍可以增加内化病原体的存活，导致感染恶化和扩散。以前的工作表明，S。糖尿病组金黄色葡萄球菌感染表现为更严重和侵袭性，与糖尿病大鼠真皮组织自噬抑制相一致，但确切机制尚不清楚。在这里，我们证明了晚期糖基化终产物（AGEs）的积累有助于减少自噬介导的S清除。金黄色葡萄球菌素诱导从PMA处理的人单核细胞系THP-1分化的巨噬细胞。重要的是，感染的巨噬细胞显示S增加。aureus的自噬体，但随后融合的S.在AGEs预处理的细胞中，含有自噬体和溶酶体的金黄色葡萄球菌被抑制，表明AGEs阻断了自噬通量并使S。aureus生存和逃生。在分子水平上，AGEs处理的巨噬细胞中溶酶体ARL 8表达升高是AGEs介导的自噬体-溶酶体融合抑制所必需的。沉默AGEs处理的巨噬细胞中的ARL 8可以恢复自噬通量并增加S。金清除。因此，我们的研究结果证明了一种新的机制，AGEs加速。通过ARL 8依赖性抑制自噬体-溶酶体融合和杀菌能力在巨噬细胞中进行金免疫逃避。
Staphylococcus aureus, a pathogen most frequently found in diabetic foot ulcer infection, was recently suggested as an intracellular pathogen. Autophagy in professional phagocytes like macrophages allows selective destruction of intracellular pathogens, and its dysfunction can increase the survival of internalized pathogens, causing infections to worsen and spread. Previous works have shown thatS. aureusinfections in diabetes appeared more severe and invasive, and coincided with the suppressed autophagy in dermal tissues of diabetic rat, but the exact mechanisms are unclear. Here, we demonstrated that accumulation of advanced glycation end products (AGEs) contributed to the diminished autophagy‐mediated clearance ofS. aureusin the macrophages differentiated from PMA‐treated human monocytic cell line THP‐1. Importantly, infected macrophages showed increasedS. aureuscontaining autophagosome, but the subsequent fusion ofS. aureuscontaining autophagosome and lysosome was suppressed in AGEs‐pretreated cells, suggesting AGEs blocked the autophagic flux and enabledS. aureussurvival and escape. At the molecular level, elevated lysosomal ARL8 expression in AGEs‐treated macrophages was required for AGEs‐mediated inhibition of autophagosome‐lysosome fusion. Silencing ARL8 in AGEs‐treated macrophages restored autophagic flux and increasedS. aureusclearance. Our results therefore demonstrate a new mechanism, in which AGEs accelerateS. aureusimmune evasion in macrophages by ARL8‐dependent suppression of autophagosome‐lysosome fusion and bactericidal capability.