多发性硬化症(MS)是一种神经退行性疾病,自身免疫性疾病仍然无法治愈。如今,正在开发各种新药来防止过度炎症和停止神经变性。其中包括布鲁顿酪氨酸激酶(BTK)抑制剂。对B细胞来说是不可或缺的,这种酶成为自身免疫性疾病的一个有吸引力的治疗靶点。认识到BTK在骨髓细胞中的重要性,我们研究了即将推出的BTK抑制剂对中性粒细胞功能的影响.尽管已经对MS的适应性免疫进行了深入的研究,关于发病机制的悬而未决的问题可以通过研究候选MS药物对先天免疫细胞如中性粒细胞的影响来解决,以前在女士中被忽视在这项研究中,我们使用了三种BTK抑制剂(evobrutinib,非内布替尼和托莱布替尼),并发现它们通过细菌肽N-甲酰甲硫氨酰-亮氨酰-苯丙氨酸和趋化因子白介素8/CXCL8减少中性粒细胞的激活。此外,它们减少了活性氧的产生和中性粒细胞胞外陷阱的释放。此外,响应炎症刺激的CXCL8和白介素-1β的产生减少.药物对中性粒细胞活化的抑制作用与毒性无关。相反,BTK抑制剂延长了中性粒细胞在炎症环境中的存活。最后,在Boyden小室试验中,BTK抑制剂治疗降低了中性粒细胞向CXCL8的迁移,但在跨内皮设置中未降低.此外,体内CXCL1诱导的迁移不受BTK抑制剂的影响。总的来说,这项研究为BTK抑制剂对中性粒细胞功能的影响提供了新的见解,从而对BTK至关重要的自身免疫或血液学疾病具有重要意义。
Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease that is still incurable. Nowadays, a variety of new drugs are being developed to prevent excessive inflammation and halt neurodegeneration. Among these are the inhibitors of Bruton\'s tyrosine kinase (BTK). Being indispensable for B cells, this enzyme became an appealing therapeutic target for autoimmune diseases. Recognizing the emerging importance of BTK in myeloid cells, we investigated the impact of upcoming BTK inhibitors on neutrophil functions. Although adaptive immunity in MS has been thoroughly studied, unanswered questions about the pathogenesis can be addressed by studying the effects of candidate MS drugs on innate immune cells such as neutrophils, previously overlooked in MS. In this study, we used three BTK inhibitors (evobrutinib, fenebrutinib and tolebrutinib), and found that they reduce neutrophil activation by the bacterial peptide N-formylmethionyl-leucyl-phenylalanine and the chemokine interleukin 8/CXCL8. Furthermore, they diminished the production of reactive oxygen species and release of neutrophil extracellular traps. Additionally, the production of CXCL8 and interleukin-1β in response to inflammatory stimuli was decreased. Inhibitory effects of the drugs on neutrophil activation were not related to toxicity. Instead, BTK inhibitors prolonged neutrophil survival in an inflammatory environment. Finally, treatment with BTK inhibitors decreased neutrophil migration towards CXCL8 in a Boyden chamber assay but not in a trans endothelial set-up. Also, in vivo CXCL1-induced migration was unaffected by BTK inhibitors. Collectively, this study provides novel insights into the impact of BTK inhibitors on neutrophil functions, thereby holding important implications for autoimmune or hematological diseases where BTK is crucial.