An unexpected role of neutrophils in clearing apoptotic hepatocytes in vivo.
An unexpected role of neutrophils in clearing apoptotic hepatocytes in vivo.
复制标题
中性粒细胞在清除体内肝细胞凋亡中的意外作用。
作者：
Cao L;Ma L;Zhao J;Wang X;Fang X;Li W;Qi Y;Tang Y;Liu J;Peng S;Yang L;Zhou L;Li L;Hu X;Ji Y;Hou Y;Zhao Y;Zhang X;Zhao YY;Zhao Y;Wei Y;Malik AB;Saiyin H;Xu J
在成年人中，每天有数十亿凋亡细胞被专职吞噬细胞（例如巨噬细胞）和邻近的非专职吞噬细胞（例如基质细胞）清除。尽管是一种专职吞噬细胞，但中性粒细胞被认为被排除在凋亡位点之外，以避免组织炎症。在这里，我们报告了一个基本的和意想不到的作用，中性粒细胞作为主要的吞噬细胞负责清除凋亡的肝细胞在稳态。与巨噬细胞吞噬死细胞相反，中性粒细胞直接钻入凋亡的肝细胞，我们称之为穿孔细胞作用，并从内部摄取衰竭的细胞。中性粒细胞的耗竭导致凋亡小体的去除缺陷，诱导小鼠肝脏组织损伤，并导致自身抗体的产生。人类自身免疫性肝病在嗜铬细胞瘤介导的凋亡肝细胞清除中表现出类似的缺陷。因此，中性粒细胞具有通过穿孔细胞作用清除凋亡肝细胞的专门免疫沉默机制，并且中性粒细胞的这种关键管家功能的缺陷有助于自身免疫性肝病的发生。每一天，免疫细胞都会清除数十亿个已经经历了受控形式死亡的旧细胞和受损细胞的残骸。快速去除它们有助于防止炎症或自身免疫性疾病的发展。虽然称为中性粒细胞的免疫细胞通常负责清除入侵的细菌，但巨噬细胞被认为负责清除死亡细胞。然而，在健康组织中，这一过程发生得如此有效，以至于很难确定哪些细胞负责。为了更仔细地研究，Cao等人通过对人体样本进行染色来识别免疫细胞和死亡细胞，从而将重点放在肝脏上。出乎意料的是，在死亡的肝细胞内可见大量的中性粒细胞。在小鼠身上的进一步实验表明，在进入死细胞后，中性粒细胞吞噬了内容物，并从内到外消化了死细胞。这是一个令人惊讶的发现，因为不仅中性粒细胞通常与死亡细胞无关，而且免疫细胞通常从外部吞噬细胞和细菌，而不是在它们内部挖洞。当Cao等人研究来自免疫细胞攻击肝脏的自身免疫性疾病患者的样本时，显示了这种中性粒细胞行为的重要性。在这种情况下，很少有死亡的肝细胞含有中性粒细胞，而中性粒细胞本身似乎没有能力清除死亡细胞，从而导致炎症。这表明中性粒细胞功能缺陷可能是这种自身免疫性疾病的关键因素。这些发现确定了中性粒细胞在维持肝脏健康功能方面的新作用，并揭示了治疗自身免疫性疾病的新靶点。在未来，Cao等人计划探索增强中性粒细胞清除死细胞的化合物是否可用于治疗小鼠模型中的自身免疫性肝病。
Billions of apoptotic cells are removed daily in a human adult by professional phagocytes (e.g. macrophages) and neighboring nonprofessional phagocytes (e.g. stromal cells). Despite being a type of professional phagocyte, neutrophils are thought to be excluded from apoptotic sites to avoid tissue inflammation. Here, we report a fundamental and unexpected role of neutrophils as the predominant phagocyte responsible for the clearance of apoptotic hepatic cells in the steady state. In contrast to the engulfment of dead cells by macrophages, neutrophils burrowed directly into apoptotic hepatocytes, a process we term perforocytosis, and ingested the effete cells from the inside. The depletion of neutrophils caused defective removal of apoptotic bodies, induced tissue injury in the mouse liver, and led to the generation of autoantibodies. Human autoimmune liver disease showed similar defects in the neutrophil-mediated clearance of apoptotic hepatic cells. Hence, neutrophils possess a specialized immunologically silent mechanism for the clearance of apoptotic hepatocytes through perforocytosis, and defects in this key housekeeping function of neutrophils contribute to the genesis of autoimmune liver disease. Every day, the immune cells clears the remains of billions of old and damaged cells that have undergone a controlled form of death. Removing them quickly helps to prevent inflammation or the development of autoimmune diseases. While immune cells called neutrophils are generally tasked with removing invading bacteria, macrophages are thought to be responsible for clearing dead cells. However, in healthy tissue, the process occurs so efficiently that it can be difficult to confirm which cells are responsible. To take a closer look, Cao et al. focused on the liver by staining human samples to identify both immune and dead cells. Unexpectedly, there were large numbers of neutrophils visible inside dead liver cells. Further experiments in mice revealed that after entering the dead cells, neutrophils engulfed the contents and digested the dead cell from the inside out. This was a surprising finding because not only are neutrophils not usually associated with dead cells, but immune cells usually engulf cells and bacteria from the outside rather than burrowing inside them. The importance of this neutrophil behaviour was shown when Cao et al. studied samples from patients with an autoimmune disease where immune cells attack the liver. In this case, very few dead liver cells contained neutrophils, and the neutrophils themselves did not seem capable of removing the dead cells, leading to inflammation. This suggests that defective neutrophil function could be a key contributor to this autoimmune disease. The findings identify a new role for neutrophils in maintaining healthy functioning of the liver and reveal a new target in the treatment of autoimmune diseases. In the future, Cao et al. plan to explore whether compounds that enhance clearance of dead cells by neutrophils can be used to treat autoimmune liver disease in mouse models of the disease.
凋亡过程中拆卸细胞 - 细胞接触与β-catenin的caspase依赖性蛋白水解裂解耦合。
影响因子：
7.8
作者：
Brancolini, C;Lazarevic, D;Rodriguez, J;Schneider, C
通讯作者：
Schneider, C
DOI：
10.1084/jem.20140508
发表时间：
2015-02-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Liu X;Yang T;Suzuki K;Tsukita S;Ishii M;Zhou S;Wang G;Cao L;Qian F;Taylor S;Oh MJ;Levitan I;Ye RD;Carnegie GK;Zhao Y;Malik AB;Xu J
通讯作者：
Xu J