Kojima Yoko, Ye Zhongde, Wang Fudi, Lotfi Mozhgan, Bell Caitlin Fox, Adkar Shaunak Sanjay, Luo Lingfeng, Fu Changhao, Leeper Nicholas J
Department of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, Stanford, CA, USA.
Sci Signal. 2025 Apr 8;18(881):eads6584. doi: 10.1126/scisignal.ads6584.
Stimulating efferocytosis, the phagocytic removal of apoptotic cells by macrophages, has been proposed as a method to eliminate dying or dead cells that accumulate and contribute to diseases such as cancer, atherosclerosis, and infection. Toxicity related to the off-target clearance of healthy tissue has led to the premature termination of multiple clinical programs for proefferocytic therapies. To identify potential proefferocytic therapies with established risk profiles, we screened ~3000 US Food and Drug Administration (FDA)-approved drugs and other well-characterized compounds for their capacity to stimulate efferocytosis. We found that the antipsychotic drug thiothixene stimulated efferocytosis of apoptotic and lipid-laden cells by mouse and human macrophages and enhanced the continual efferocytosis of apoptotic cells. Consistent with thiothixene's suppressive effects on dopaminergic signaling, dopamine potently inhibited efferocytosis in a manner that was only partially reversed by thiothixene. The prophagocytic effects of thiothixene in mouse macrophages depended on increased expression of the gene encoding the retinol-binding protein receptor Stra6L, which, in turn, promoted the production of the continual efferocytosis stimulator arginase 1. Our findings demonstrate that dopamine inhibits efferocytosis in macrophages and identify thiothixene, a generic, FDA-approved antipsychotic drug that has been in use for more than 50 years, as a promising candidate for promoting continual efferocytosis and the removal of diseased tissue.
促进胞葬作用，即巨噬细胞对凋亡细胞的吞噬清除，已被提议作为一种消除积累并导致癌症、动脉粥样硬化和感染等疾病的濒死或死亡细胞的方法。与健康组织的脱靶清除相关的毒性已导致多个促胞葬疗法的临床项目提前终止。为了识别具有既定风险特征的潜在促胞葬疗法，我们筛选了约3000种美国食品药品监督管理局（FDA）批准的药物和其他特征明确的化合物刺激胞葬作用的能力。我们发现抗精神病药物硫利达嗪可刺激小鼠和人类巨噬细胞对凋亡细胞和脂质负载细胞的胞葬作用，并增强凋亡细胞的持续胞葬作用。与硫利达嗪对多巴胺能信号传导的抑制作用一致，多巴胺以一种仅被硫利达嗪部分逆转的方式强烈抑制胞葬作用。硫利达嗪在小鼠巨噬细胞中的促吞噬作用依赖于编码视黄醇结合蛋白受体Stra6L的基因表达增加，这反过来又促进了持续胞葬作用刺激物精氨酸酶1的产生。我们的研究结果表明，多巴胺抑制巨噬细胞的胞葬作用，并确定硫利达嗪是一种已使用超过50年的通用FDA批准的抗精神病药物，是促进持续胞葬作用和清除病变组织的有希望的候选药物。
