Wang Yu-Chen, Ma Hong-Di, Yin Xue-Ying, Wang Yin-Hu, Liu Qing-Zhi, Yang Jing-Bo, Shi Qing-Hua, Sun Baolin, Gershwin M Eric, Lian Zhe-Xiong
Liver Immunology Laboratory, Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230027, China.
The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China.
Clin Rev Allergy Immunol. 2016 Dec;51(3):353-369. doi: 10.1007/s12016-016-8531-1.
The functions of macrophages that lead to effective host responses are critical for protection against Staphylococcus aureus. Deep tissue-invading S. aureus initially countered by macrophages trigger macrophage accumulation and induce inflammatory responses through surface receptors, especially toll-like receptor 2 (TLR2). Here, we found that macrophages formed sporadic aggregates in the liver during infection. Within those aggregates, macrophages co-localized with T cells and were indispensable for their infiltration. In addition, we have focused on the mechanisms underlying the polarization of macrophages in Forkhead box transcription factor O1 (FoxO1) conditional knockout Lys FoxO1 mice following S. aureus infection and report herein that macrophage M1-M2 polarization via TLR2 is intrinsically regulated by FoxO1. Indeed, for effective FoxO1 activity, stimulation of TLR2 is essential. However, following S. aureus challenge, there was a decrease in macrophage FoxO1, with increased phosphorylation of FoxO1 because of TLR2-mediated activation of PI3K/Akt and c-Raf/MEK/ERK pathway. Following infection in Lys FoxO1 mice, mice became more susceptible to S. aureus with reduced macrophage aggregation in the liver and attenuated Th1 and Th17 responses. FoxO1 abrogation reduced M1 pro-inflammatory responses triggered by S. aureus and enhanced M2 polarization in macrophages. In contrast, overexpression of FoxO1 in macrophages increased pro-inflammatory mediators and functional surface molecule expression. In conclusion, macrophage FoxO1 is critical to promote M1 polarization and maintain a competent T cell immune response against S. aureus infection in the liver. FoxO1 regulates macrophage M1-M2 polarization downstream of TLR2 dynamically through phosphorylation.
巨噬细胞引发有效宿主反应的功能对于抵御金黄色葡萄球菌至关重要。深部组织侵袭性金黄色葡萄球菌最初会被巨噬细胞对抗，从而触发巨噬细胞聚集，并通过表面受体，尤其是Toll样受体2（TLR2）诱导炎症反应。在此，我们发现感染期间巨噬细胞在肝脏中形成散在的聚集体。在这些聚集体中，巨噬细胞与T细胞共定位，并且对于T细胞的浸润不可或缺。此外，我们聚焦于金黄色葡萄球菌感染后Forkhead盒转录因子O1（FoxO1）条件性敲除小鼠（Lys - FoxO1小鼠）中巨噬细胞极化的潜在机制，并在此报告通过TLR2介导的巨噬细胞M1 - M2极化由FoxO1内在调节。事实上，为实现有效的FoxO1活性，TLR2的刺激至关重要。然而，在金黄色葡萄球菌攻击后，巨噬细胞中的FoxO1减少，由于TLR2介导的PI3K/Akt和c - Raf/MEK/ERK途径的激活，FoxO1的磷酸化增加。在Lys - FoxO1小鼠感染后，小鼠对金黄色葡萄球菌更易感，肝脏中的巨噬细胞聚集减少，Th1和Th17反应减弱。FoxO1缺失减少了金黄色葡萄球菌引发的M1促炎反应，并增强了巨噬细胞中的M2极化。相反，巨噬细胞中FoxO1的过表达增加了促炎介质和功能性表面分子的表达。总之，巨噬细胞FoxO1对于促进M1极化和维持针对肝脏中金黄色葡萄球菌感染的有效T细胞免疫反应至关重要。FoxO1通过磷酸化动态调节TLR2下游的巨噬细胞M1 - M2极化。
