Immunology, Infectious Diseases and Ophthalmology (I2O) Discovery and Translational Area, Roche Innovation Center, Basel, Switzerland.
Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center, Basel, Switzerland.
Cell Death Dis. 2021 May 25;12(6):538. doi: 10.1038/s41419-021-03770-0.
Removal of apoptotic cells by phagocytes (also called efferocytosis) is a crucial process for tissue homeostasis. Professional phagocytes express a plethora of surface receptors enabling them to sense and engulf apoptotic cells, thus avoiding persistence of dead cells and cellular debris and their consequent effects. Dysregulation of efferocytosis is thought to lead to secondary necrosis and associated inflammation and immune activation. Efferocytosis in primarily murine macrophages and dendritic cells has been shown to require TAM RTKs, with MERTK and AXL being critical for clearance of apoptotic cells. The functional role of human orthologs, especially the exact contribution of each individual receptor is less well studied. Here we show that human macrophages differentiated in vitro from iPSC-derived precursor cells express both AXL and MERTK and engulf apoptotic cells. TAM RTK agonism by the natural ligand growth-arrest specific 6 (GAS6) significantly enhanced such efferocytosis. Using a newly-developed mouse model of kinase-dead MERTK, we demonstrate that MERTK kinase activity is essential for efferocytosis in peritoneal macrophages in vivo. Moreover, human iPSC-derived macrophages treated in vitro with blocking antibodies or small molecule inhibitors recapitulated this observation. Hence, our results highlight a conserved MERTK function between mice and humans, and the critical role of its kinase activity in homeostatic efferocytosis.
吞噬细胞（也称为噬细胞）清除凋亡细胞是组织稳态的关键过程。专业的吞噬细胞表达大量表面受体，使它们能够感知和吞噬凋亡细胞，从而避免死细胞和细胞碎片的持续存在及其带来的影响。噬细胞作用的失调被认为会导致继发性坏死以及相关的炎症和免疫激活。已经表明，主要在鼠巨噬细胞和树突状细胞中的噬细胞作用需要 TAM RTKs，其中 MERTK 和 AXL 对于清除凋亡细胞至关重要。人类同源物的功能作用，特别是每个受体的具体贡献，研究得较少。在这里，我们表明，体外从 iPSC 衍生的前体细胞分化的人巨噬细胞表达 AXL 和 MERTK 并吞噬凋亡细胞。天然配体生长停滞特异性 6（GAS6）对 TAM RTK 的激动作用显著增强了这种噬细胞作用。使用新开发的激酶失活 MERTK 的小鼠模型，我们证明了 MERTK 激酶活性对于体内腹腔巨噬细胞的噬细胞作用是必不可少的。此外，体外用阻断抗体或小分子抑制剂处理的人 iPSC 衍生巨噬细胞重现了这一观察结果。因此，我们的结果强调了 MERTK 在小鼠和人类之间的保守功能及其激酶活性在稳态噬细胞作用中的关键作用。
