Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
Department of Medical Biotechnology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Pharmacol Ther. 2022 Oct;238:108282. doi: 10.1016/j.pharmthera.2022.108282. Epub 2022 Sep 18.
Efferocytosis (clearance of apoptotic cells by phagocytosis without inducing inflammation and autoimmunity) is an important mechanism in the resolution of inflammatory processes. Efficient efferocytosis inhibits the accumulation of apoptotic cells/debris and maintains homeostasis before the onset of necrosis (secondary necrosis), which promotes inflammation or injury. Moreover, the detection and clearance of apoptotic cells can promote anti-inflammatory responses. Defective efferocytosis is involved in the pathogenesis of several diseases, such as atherosclerosis, chronic inflammation, autoimmunity and cancer. Statins are 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors which exert cholesterol-lowering effects plus multiple pleiotropic properties, such as inhibition of inflammation and macrophage proliferation. Statins exhibit anti-inflammatory properties by reducing both the prenylation of signaling molecules with downregulation of gene expression and the expression of adhesion molecules, as well as the levels of cytokines and chemokines. Additionally, statins suppress the prenylation of GTPases, such as Rac-1, as a positive regulator of efferocytosis, and RhoA, as a negative regulator of efferocytosis. However, statins alter the membrane balance of Rho GTPases in efferocytosis toward Rac-1. Efferocytosis has modifiable targets, which can be exploited for the treatment of several diseases, although limited attention has been given to the mechanisms by which statins regulate efferocytosis and the resulting therapeutic implications. In this review, we will elaborate on the mechanisms underlying the modulation of apoptotic cell clearance by statins, which, in turn, inhibits uncontrolled inflammation and ensuing diseases.
吞噬作用（通过吞噬作用清除凋亡细胞而不引起炎症和自身免疫）是炎症过程消退的重要机制。有效的吞噬作用可抑制凋亡细胞/碎片的积累，并在坏死（继发性坏死）发生之前维持体内平衡，从而促进炎症或损伤。此外，凋亡细胞的检测和清除可促进抗炎反应。吞噬作用缺陷与多种疾病的发病机制有关，如动脉粥样硬化、慢性炎症、自身免疫和癌症。他汀类药物是 3-羟基-3-甲基戊二酰基辅酶 A 还原酶抑制剂，具有降低胆固醇作用以及多种多效性特性，如抑制炎症和巨噬细胞增殖。他汀类药物通过减少信号分子的prenylation 及其基因表达的下调，以及细胞因子和趋化因子的水平，发挥抗炎作用。此外，他汀类药物抑制 Rac-1 等 GTPases 的 prenylation，Rac-1 是吞噬作用的正调节剂，RhoA 是吞噬作用的负调节剂。然而，他汀类药物改变了吞噬作用中 Rho GTPases 的膜平衡，使其向 Rac-1 倾斜。吞噬作用有可调节的靶点，可以用于治疗多种疾病，尽管他汀类药物调节吞噬作用的机制及其治疗意义尚未得到充分关注。在这篇综述中，我们将详细阐述他汀类药物调节凋亡细胞清除的机制，这反过来又抑制了失控的炎症和随之而来的疾病。
