Anastasia Geladaris, Sebastian Torke, Darius Saberi, Yasemin B. Alankus, Frank Streit, Sabrina Zechel, Christine Stadelmann-Nessler, Andreas Fischer, Ursula Boschert, Darius Häusler, Martin S. Weber
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引用次数: 0
摘要
在多发性硬化症(MS)中,持续性残疾的发生可能与复发活动或新的中枢神经系统(CNS)炎性病变的发展无关,这被称为慢性进展。这一过程发生较早,主要由中枢神经系统内的细胞驱动。抑制布鲁顿酪氨酸激酶(BTK)是控制多发性硬化症进展的一种很有前景的策略,该酶主要参与 B 细胞和骨髓细胞(如巨噬细胞和小胶质细胞)的活化。在治疗慢性实验性自身免疫性脑脊髓炎(EAE)或活化T细胞收养性转移后,我们观察到小胶质细胞的促炎性活化减少,这证明了evobrutinib抑制BTK的益处。此外,在毒性脱髓鞘模型中,evobrutinib介导的BTK抑制促进了小胶质细胞对髓鞘碎片的清除,从而加速了髓鞘再形成。这些发现突出表明,抑制 BTK 有可能抵消多发性硬化症潜在的慢性进展。
BTK inhibition limits microglia-perpetuated CNS inflammation and promotes myelin repair
In multiple sclerosis (MS), persisting disability can occur independent of relapse activity or development of new central nervous system (CNS) inflammatory lesions, termed chronic progression. This process occurs early and it is mostly driven by cells within the CNS. One promising strategy to control progression of MS is the inhibition of the enzyme Bruton's tyrosine kinase (BTK), which is centrally involved in the activation of both B cells and myeloid cells, such as macrophages and microglia. The benefit of BTK inhibition by evobrutinib was shown as we observed reduced pro-inflammatory activation of microglia when treating chronic experimental autoimmune encephalomyelitis (EAE) or following the adoptive transfer of activated T cells. Additionally, in a model of toxic demyelination, evobrutinib-mediated BTK inhibition promoted the clearance of myelin debris by microglia, leading to an accelerated remyelination. These findings highlight that BTK inhibition has the potential to counteract underlying chronic progression of MS.
期刊介绍:
Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.