美国弗吉尼亚大学
研究人员设计了一个促进胞葬的策略，即“胞葬作用的嵌合受体”（CHEF）。研究人员将细胞质适配蛋白ELMO1中的一个特定信号域与胞葬受体BAI1或TIM4的细胞外磷脂酰丝氨酸识别域相融合，分别产生了BELMO和TELMO。表达CHEF的吞噬细胞显示出惊人的胞葬作用增加。在炎症的小鼠模型中，BELMO的表达能减弱结肠炎、肝脏毒性和肾脏毒性。在机理研究中，BELMO增加ER驻留的酶和伴侣，从而克服蛋白质折叠相关的毒性，这在ER压力诱导的肾脏缺血再灌注损伤模型中得到进一步验证。最后，在肾脏损伤发生后引入TELMO可明显减少纤维化。总的来说，这些数据推进了一个嵌合型胞葬受体的概念，可用于促进胞葬作用的产生和抑制炎症。
据介绍，人类的身体每天通过细胞凋亡来周转数十亿个细胞，反过来被吞噬细胞通过“胞葬作用”过程清除。胞葬细胞的缺陷现在与各种炎症性疾病有关。
附：英文原文
Title: Chimeric efferocytic receptors improve apoptotic cell clearance and alleviate inflammation
Author: Sho Morioka, Daiki Kajioka, Yusuke Yamaoka, Rochelle M. Ellison, Turan Tufan, Inge L. Werkman, Shinji Tanaka, Brady Barron, Satoshi T. Ito, Sarah Kucenas, Mark D. Okusa, Kodi S. Ravichandran
Issue&Volume: 2022/12/22
Abstract: Our bodies turn over billions of cells daily via apoptosis and are in turn clearedby phagocytes via the process of “efferocytosis.” Defects in efferocytosis are nowlinked to various inflammatory diseases. Here, we designed a strategy to boost efferocytosis, denoted “chimeric receptor for efferocytosis” (CHEF). We fused a specific signalingdomain within the cytoplasmic adapter protein ELMO1 to the extracellular phosphatidylserinerecognition domains of the efferocytic receptors BAI1 or TIM4, generating BELMO andTELMO, respectively. CHEF-expressing phagocytes display a striking increase in efferocytosis.In mouse models of inflammation, BELMO expression attenuates colitis, hepatotoxicity,and nephrotoxicity. In mechanistic studies, BELMO increases ER-resident enzymes andchaperones to overcome protein-folding-associated toxicity, which was further validatedin a model of ER-stress-induced renal ischemia-reperfusion injury. Finally, TELMOintroduction after onset of kidney injury significantly reduced fibrosis. Collectively,these data advance a concept of chimeric efferocytic receptors to boost efferocytosisand dampen inflammation.
DOI: 10.1016/j.cell.2022.11.029
Source: https://www.cell.com/cell/fulltext/S0092-8674(22)01504-5