Our bodies turn over billions of cells daily via apoptosis and are in turn cleared by phagocytes via the process of “efferocytosis.” Defects in efferocytosis are now linked to various inflammatory diseases. Here, we designed a strategy to boost efferocytosis, denoted “chimeric receptor for efferocytosis” (CHEF). We fused a specific signaling domain within the cytoplasmic adapter protein ELMO1 to the extracellular phosphatidylserine recognition domains of the efferocytic receptors BAI1 or TIM4, generating BELMO and TELMO, 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 and chaperones to overcome protein-folding-associated toxicity, which was further validated in a model of ER-stress-induced renal ischemia-reperfusion injury. Finally, TELMO introduction after onset of kidney injury significantly reduced fibrosis. Collectively, these data advance a concept of chimeric efferocytic receptors to boost efferocytosis and dampen inflammation.

我们的身体每天通过细胞凋亡更新数十亿个细胞，然后通过“胞吞作用”过程被吞噬细胞清除。胞吞作用的缺陷现在与各种炎症性疾病有关。在这里，我们设计了一种促进胞吞作用的策略，称为“胞吞作用嵌合受体”（CHEF）。我们将细胞质接头蛋白 ELMO1 内的特定信号传导结构域与细胞受体 BAI1 或 TIM4 的细胞外磷脂酰丝氨酸识别结构域融合，分别生成 BELMO 和 TELMO。表达 CHEF 的吞噬细胞的胞吞作用显着增加。在炎症小鼠模型中，BELMO 表达可减轻结肠炎、肝毒性和肾毒性。在机制研究中，BELMO 增加了 ER 驻留酶和伴侣，以克服蛋白质折叠相关的毒性，这在 ER 应激诱导的肾缺血再灌注损伤模型中得到了进一步验证。最后，TELMO介绍肾损伤发作后纤维化显着减少。总的来说，这些数据提出了嵌合胞吞受体的概念，以促进胞吞作用并抑制炎症。