Continued clearance of apoptotic cells critically depends on the phagocyte Ucp2 protein.
Continued clearance of apoptotic cells critically depends on the phagocyte Ucp2 protein.
复制标题
DOI：
10.1038/nature10340
复制
发表时间：
2011-08-21
期刊：
影响因子：
64.8
通讯作者：
Ravichandran, Kodi S.
中科院分区：
文献类型：
--
作者：
Park, Daeho;Han, Claudia Z.;Elliott, Michael R.;Kinchen, Jason M.;Trampont, Paul C.;Das, Soumita;Collins, Sheila;Lysiak, Jeffrey J.;Hoehn, Kyle L.;Ravichandran, Kodi S.
吞噬细胞快速有效地清除凋亡细胞在发育、组织动态平衡和控制免疫反应中起着关键作用。高效清除的一个重要特征是单个吞噬细胞能够连续吞噬多个凋亡细胞，并处理增加的身体来源细胞物质的负荷。然而，影响持续吞噬能力的因素或它们如何反过来影响吞噬细胞的持续清除尚不清楚。在这里，我们确认吞噬细胞控制其线粒体膜电位的能力是吞噬细胞吞噬凋亡细胞能力的关键因素。改变吞噬细胞线粒体膜电位(遗传或药理学)显著影响吞噬作用，低电位促进吞噬，高电位抑制摄取。然后，我们确定了Ucp2，一种作用于降低线粒体膜电位的线粒体膜蛋白，在吞噬凋亡细胞(但不是合成靶标、细菌或酵母)的吞噬细胞中上调。Ucp2的缺失限制了吞噬细胞持续吞噬凋亡细胞的能力，而Ucp2的过表达则增加了吞噬能力和吞噬多种凋亡细胞的能力。突变和药物抑制Ucp2解偶联活性逆转了Ucp2对吞噬能力的积极作用，表明Ucp2介导的线粒体功能在吞噬中起直接作用。Ucp2基因缺陷小鼠的巨噬细胞在体外吞噬凋亡细胞的能力受到损害，而Ucp2基因缺陷小鼠在体内清除胸腺和睾丸中的死亡细胞方面存在严重缺陷。综上所述，这些数据表明吞噬细胞在吞噬过程中改变线粒体膜电位来调节顺序凋亡细胞的摄取，而Ucp2是体内这一步骤的关键分子决定因素。由于Ucp2的功能也与代谢性疾病和动脉粥样硬化有关，这些数据表明Ucp2在调节细胞凋亡的清除中扮演着新的角色，这可能为理解这些疾病的复杂病因和发病机制提供更多的见解。
Rapid and efficient removal of apoptotic cells by phagocytes plays a key role during development, tissue homeostasis, and in controlling immune responses. An important feature of efficient clearance is the capacity of a single phagocyte to ingest multiple apoptotic cells successively, and to process the increased load of corpse-derived cellular material. However, factors that influence sustained phagocytic capacity or how they in turn influence continued clearance by phagocytes are not known. Here we identify that the ability of a phagocyte to control its mitochondrial membrane potential is a critical factor in the capacity of a phagocyte to engulf apoptotic cells. Changing the phagocyte mitochondrial membrane potential (genetically or pharmacologically) significantly affected phagocytosis, with lower potential enhancing engulfment and higher membrane potential inhibiting uptake. We then identified that Ucp2, a mitochondrial membrane protein that acts to lower the mitochondrial membrane potential, is upregulated in phagocytes engulfing apoptotic cells (but not synthetic targets, bacteria, or yeast). Loss of Ucp2 limited the capacity of phagocytes to continually ingest apoptotic cells, while overexpression of Ucp2 increased the capacity for engulfment and the ability to engulf multiple apoptotic cells. Mutational and pharmacological inhibition of Ucp2 uncoupling activity reversed the positive effect of Ucp2 on engulfment capacity, suggesting a direct role for Ucp2-mediated mitochondrial function in phagocytosis. Macrophages from Ucp2-deficient mice were impaired in their capacity to engulf apoptotic cells in vitro, and Ucp2-deficient mice displayed profound in vivo defects in clearing dying cells in the thymus and the testes. Collectively, these data suggest that phagocytes alter the mitochondrial membrane potential during engulfment to regulate uptake of sequential apoptotic cells, and that Ucp2 is a key molecular determinant of this step in vivo. Since Ucp2 function has also been linked to metabolic diseases and atherosclerosis, these data identifying a new role for Ucp2 in regulating apoptotic cell clearance may provide additional insights toward understanding the complex etiology and pathogenesis of these diseases.
登录
查看更多内容
影响因子：
5.5
作者：
Buckler, KJ;Vaughan-Jones, RD
通讯作者：
Vaughan-Jones, RD
影响因子：
13.8
作者：
Azzu, Vian;Brand, Martin D.
通讯作者：
Brand, Martin D.
影响因子：
30.8
作者：
Fleury, C;Neverova, M;Warden, CH
通讯作者：
Warden, CH
影响因子：
2.9
作者：
Echtay, KS;Winkler, E;Klingenberg, M
通讯作者：
Klingenberg, M
影响因子：
3.7
作者：
Lugli, E;Troiano, L;Cossarizza, A
通讯作者：
Cossarizza, A