Department of Hematology, Medical Oncology, & Pneumology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Sci Rep. 2018 Apr 3;8(1):5558. doi: 10.1038/s41598-018-23808-2.
Triggering receptor expressed on myeloid cells (TREM)-1 on polymorphonuclear neutrophils (PMN) regulates innate immune activation in infectious and non-infectious conditions. TREM-1 ligation activates phosphatidyl-inositol 3 kinase (PI3K) triggering all neutrophil effector functions. As idelalisib is a PI3K inhibitor in clinical use for the treatment of non-Hodgkin lymphomas, we asked whether this inhibitor affects PMN functionalities. We analyzed PMNs from healthy donors or lymphoma patients for oxidative burst, phagocytosis, activation markers and IL-8 release upon TREM-1 or TLR ligation ex vivo. In addition, we performed western blot analyses to characterize the signaling events inhibited by idelalisib and other PI3K inhibitors. Upon TREM-1 ligation, the oxidative burst, degranulation, L-selectin shedding and cytokine release were all strongly reduced in the presence of idelalisib along impaired phosphorylation of P38, AKT and ERK by western blot analyses. In line with this, PMNs from patients receiving idelalisib also displayed an impaired TREM-1 mediated PMN activation ex vivo. In conclusion, PI3K inhibitors might cause a neutropenia-like susceptibility to infections in patients by leading to impaired PMN functionality. This should be considered when evaluating patients for infections treated with such inhibitors in daily clinical routine.
髓系细胞触发受体-1（TREM-1）在多形核粒细胞（PMN）上的表达调节感染和非感染情况下的固有免疫激活。TREM-1 的配体激活磷脂酰肌醇 3 激酶（PI3K），触发所有中性粒细胞效应功能。由于idelalisib 是一种临床用于治疗非霍奇金淋巴瘤的 PI3K 抑制剂，我们想知道这种抑制剂是否会影响 PMN 的功能。我们分析了来自健康供体或淋巴瘤患者的 PMN，以检测在体外 TREM-1 或 TLR 配体结合后氧化爆发、吞噬作用、激活标志物和 IL-8 释放的情况。此外，我们还进行了 Western blot 分析，以表征 idelalisib 和其他 PI3K 抑制剂抑制的信号事件。在 TREM-1 配体的作用下，在 idelalisib 存在的情况下，氧化爆发、脱颗粒、L-选择素脱落和细胞因子释放均显著减少，Western blot 分析显示 P38、AKT 和 ERK 的磷酸化受损。与此一致的是，正在接受 idelalisib 治疗的患者的 PMN 也表现出体外 TREM-1 介导的 PMN 激活受损。总之，PI3K 抑制剂可能通过导致 PMN 功能受损，使接受此类抑制剂治疗的患者出现类似中性粒细胞减少的感染易感性。在日常临床实践中评估接受此类抑制剂治疗的感染患者时，应考虑这一点。
