Complement C5a exacerbates acute lung injury induced through autophagy-mediated alveolar macrophage apoptosis.
Complement C5a exacerbates acute lung injury induced through autophagy-mediated alveolar macrophage apoptosis.
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补体 C5a 加剧自噬介导的肺泡巨噬细胞凋亡诱导的急性肺损伤
DOI：
10.1038/cddis.2014.274
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发表时间：
2014-07-17
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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作者：
肠缺血具有高死亡率，并且经常引起急性肺损伤（ALI），这是一种严重的并发症，并且伴随高达40%的高死亡率。肠缺血/再灌注（IR）诱导的肺损伤是由免疫反应激活引起的局部和全身炎症反应。已有研究表明，补体C5 a在IR肺损伤的发生、发展过程中起重要作用，但其具体的分子机制尚不清楚。在这项研究中，我们发现，肠IR诱导ALI样症状，C5 a受体（C5 aR）的表达上调肺泡巨噬细胞，这是在肺组织中的常驻巨噬细胞，是重要的肺稳态。在肺损伤期间产生的C5 a与肺泡巨噬细胞中的C5 aR结合，启动促进自噬的下游信号传导，导致肺泡巨噬细胞的凋亡。使用Mφ-ATG 5 −/−小鼠，其中atg 5特异性地在巨噬细胞中缺乏并且自噬被抑制，我们证实了体内C5 a与C5 aR相互作用诱导肺泡巨噬细胞中的自噬，这促进了肺泡巨噬细胞凋亡。进一步的研究表明，自噬是通过C5 aR介导的bcl-2的降解而诱导的。综上所述，我们的研究结果表明，C5 aR介导的自噬诱导肺泡巨噬细胞凋亡，破坏肺内稳态，并有助于ALI的发展。这一新的机制提示了自噬调控在ALI中的新的治疗潜力。
Intestinal ischemia has a high mortality and often causes acute lung injury (ALI), which is a serious complication, and is accompanied by high mortality up to 40%. An intense local and systemic inflammation occurs during intestinal ischemia/reperfusion (IR)-induced lung injury resulting from activation of immune responses. It has been reported that one component of complement, C5a, is indispensable for the full development of IR-induced lung injury, whereas the detailed molecular mechanism remains to be elucidated. In this study, we found that intestinal IR induced ALI-like symptoms, and C5a receptor (C5aR) expression was upregulated in alveolar macrophages, which are resident macrophages in lung tissue and are important in pulmonary homeostasis. C5a produced during lung injury binds to C5aR in alveolar macrophages, initiates downstream signaling that promotes autophagy, leading to apoptosis of alveolar macrophages. Using Mφ-ATG5−/− mice, in which the atg5 is deficient specifically in macrophages and autophagy is inhibited, we confirmed that in vivo C5a interacting with C5aR induced autophagy in alveolar macrophages, which promoted alveolar macrophage apoptosis. Further study indicated that autophagy was induced through C5aR-mediated degradation of bcl-2. Taken together, our results demonstrated that C5aR-mediated autophagy induced apoptosis in alveolar macrophages, disrupting pulmonary homeostasis and contributing to the development of ALI. This novel mechanism suggests new therapeutic potential of autophagy regulation in ALI.
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影响因子：
4.4
作者：
Kambas, Konstantinos;Markiewski, Maciej M.;Ritis, Konstantinos D.
通讯作者：
Ritis, Konstantinos D.
影响因子：
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作者：
Bosmann, Markus;Ward, Peter A.
通讯作者：
Ward, Peter A.
DOI：
10.1038/nri3532
发表时间：
2013-10
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Deretic V;Saitoh T;Akira S
通讯作者：
Akira S
影响因子：
7.3
作者：
Farrar CA;Asgari E;Schwaeble WJ;Sacks SH
通讯作者：
Sacks SH
缺血和再灌注 - 从翻译机构。
影响因子：
82.9
作者：
通讯作者：
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