Kaufmann Thomas, Simon Hans-Uwe
Institute of Pharmacology, University of Bern, Bern, Switzerland; email:
Department of Clinical Immunology and Allergology, Sechenov University, Moscow, Russia.
Annu Rev Pharmacol Toxicol. 2023 Jan 20;63:231-247. doi: 10.1146/annurev-pharmtox-051921-115130. Epub 2022 Aug 26.
Apoptosis is central for the maintenance of health. In the immune system, apoptosis guarantees proper development of immune cells and shutdown of immune reactions by the coordinated elimination of activated immune cells. Limitation of the life span of granulocytes is important, as overactivation of these cells is associated with chronic inflammation and collateral tissue damage. Consequently, targeted induction of granulocyte apoptosis may be beneficial in the course of respective immune disorders. Anti-inflammatory drugs such as glucocorticoids and monoclonal antibodies against IL-5Rα exert their function in part by triggering eosinophil apoptosis. Agonistic antibodies targeting Siglec-8 or death receptors are tested (pre)clinically. Moreover, a new class of inhibitors targeting antiapoptotic BCL-2 proteins shows great promise for anticancer treatments. Because of their specificity and tolerable side effects, these so-called BH3 mimetics may be worthwhile to evaluate in inflammatory disorders. Here, we review past and recent data on pharmacological apoptosis induction of granulocytes and highlight respective therapeutic potential.
细胞凋亡对于维持健康至关重要。在免疫系统中，细胞凋亡通过协调清除活化的免疫细胞来保证免疫细胞的正常发育并终止免疫反应。限制粒细胞的寿命很重要，因为这些细胞的过度活化与慢性炎症和附带的组织损伤有关。因此，在相应的免疫紊乱过程中，靶向诱导粒细胞凋亡可能有益。抗炎药物如糖皮质激素和抗IL-5Rα单克隆抗体部分通过触发嗜酸性粒细胞凋亡发挥作用。靶向Siglec-8或死亡受体的激动性抗体正在进行临床前或临床测试。此外，一类新型的靶向抗凋亡BCL-2蛋白的抑制剂在抗癌治疗中显示出巨大潜力。由于其特异性和可耐受的副作用，这些所谓的BH3模拟物可能值得在炎症性疾病中进行评估。在此，我们回顾过去和最近关于粒细胞药理学诱导凋亡的数据，并强调各自的治疗潜力。
