De Bondt Mirre, Renders Janne, Petit de Prado Paloma, Berghmans Nele, Pörtner Noëmie, Vanbrabant Lotte, de Oliveira Vívian Louise Soares, Duran Gayel, Baeten Paulien, Broux Bieke, Gouwy Mieke, Matthys Patrick, Hellings Niels, Struyf Sofie
Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
Neuro Immune Connections & Repair Lab, Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Agoralaan C, 3500 Hasselt, Belgium.
J Leukoc Biol. 2025 Mar 14;117(3). doi: 10.1093/jleuko/qiae160.
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 3 BTK inhibitors (evobrutinib, fenebrutinib, and tolebrutinib), and found that they reduce neutrophil activation by the bacterial peptide fMLF 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 toward CXCL8 in a Boyden chamber assay but not in a transendothelial setup. 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 in which BTK is crucial.
多发性硬化症（MS）是一种神经退行性自身免疫性疾病，目前仍无法治愈。如今，人们正在研发各种新药来预防过度炎症并阻止神经退行性变。其中包括布鲁顿酪氨酸激酶（BTK）抑制剂。这种酶对B细胞不可或缺，已成为自身免疫性疾病颇具吸引力的治疗靶点。鉴于BTK在髓系细胞中日益凸显的重要性，我们研究了即将问世的BTK抑制剂对中性粒细胞功能的影响。尽管MS中的适应性免疫已得到充分研究，但通过研究候选MS药物对中性粒细胞等先天性免疫细胞的影响（这些细胞在MS中此前一直被忽视），可以解决有关发病机制的一些未解决问题。在本研究中，我们使用了3种BTK抑制剂（依鲁替尼、非奈布替尼和托法替布），发现它们可降低细菌肽fMLF和趋化因子白细胞介素-8/CXCL8对中性粒细胞的激活作用。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。另外，对炎症刺激的反应中CXCL8和白细胞介素-1β的产生也减少了。这些药物对中性粒细胞激活的抑制作用与毒性无关。相反，BTK抑制剂可延长炎症环境中中性粒细胞的存活时间。最后，在Boyden小室试验中，BTK抑制剂处理可降低中性粒细胞向CXCL8的迁移，但在跨内皮实验装置中则不然。此外，体内CXCL1诱导的迁移不受BTK抑制剂影响。总体而言，本研究为BTK抑制剂对中性粒细胞功能的影响提供了新见解，从而对BTK至关重要的自身免疫性或血液学疾病具有重要意义。
