Cathepsin C exacerbates EAE by promoting the expansion of Tfh cells and the formation of TLSs in the CNS

IF 8.8 2区 医学 Q1 IMMUNOLOGY Brain, Behavior, and Immunity Pub Date : 2024-09-05 DOI:10.1016/j.bbi.2024.09.004
Shuang Liu , Xiaohan Yang , Henan Zhao , Xinnan Zhao , Kai Fan , Gang Liu , Xia Li , Cong Du , Jing Liu , Jianmei Ma
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Abstract

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) mediated by CD4+ T helper (Th) cells, and characterized by immune cell infiltration, demyelination and neurodegeneration, with no definitive cure available. Thus, it is pivotal and imperative to acquire more profound comprehension of the underlying mechanisms implicated in MS. Dysregulated immune responses are widely believed to play a primary role in the pathogenesis of MS. Recently, a plethora of studies have demonstrated the involvement of T follicular helper (Tfh) cells and tertiary lymphoid-like structures (TLSs) in the pathogenesis and progression of MS. Cathepsin C (CatC) is a cysteine exopeptidase which is crucial for the activation of immune-cell-associated serine proteinases in many inflammatory diseases in peripheral system, such as rheumatoid arthritis and septicemia. We have previously demonstrated that CatC is involved in neuroinflammation and exacerbates demyelination in both cuprizone-induced and experimental autoimmune encephalomyelitis (EAE) mouse models. However, the underlying immunopathological mechanism remains elusive. In the present study, we established a recombinant myelin oligodendrocyte glycoprotein 35–55 peptide-induced EAE model using conditional CatC overexpression mice to investigate the effects of CatC on the alteration of CD4+ Th subsets, including Th1, Th2, Th17, Tfh and T regulatory cells. Our findings demonstrated that CatC particularly enhanced the population of Tfh cell in the brain, resulting in the earlier onset and more severe chronic syndrome of EAE. Furthermore, CatC promoted the formation of TLSs in the brain, leading to persistent neuroinflammation and exacerbating the severity of EAE in the chronic phase. Conversely, treatment with AZD7986, a specific inhibitor of CatC, effectively attenuated the syndrome of EAE and its effects caused by CatC both in vivo and in vitro. These findings provide a novel insight into the critical role of CatC in innate and adaptive immunity in EAE, and specific inhibitor of CatC, AZD7986, may contribute to potential therapeutic strategies for MS.

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Cathepsin C能促进中枢神经系统中Tfh细胞的扩增和TLS的形成,从而加剧EAE。
多发性硬化症(MS)是一种由 CD4+ T 辅助细胞(Th)介导的中枢神经系统(CNS)慢性自身免疫性疾病,以免疫细胞浸润、脱髓鞘和神经变性为特征,目前尚无根治方法。因此,更深入地了解多发性硬化症的内在机制至关重要,势在必行。人们普遍认为,失调的免疫反应在多发性硬化症的发病机制中起着主要作用。最近,大量研究表明,T 滤泡辅助细胞(Tfh)和三级淋巴样结构(TLSs)参与了多发性硬化症的发病和进展。Cathepsin C(CatC)是一种半胱氨酸外肽酶,在类风湿性关节炎和败血症等许多外周系统炎症性疾病中,它是激活免疫细胞相关丝氨酸蛋白酶的关键。我们之前已经证明,CatC 参与了铜绿素诱导的神经炎症,并加剧了实验性自身免疫性脑脊髓炎(EAE)小鼠模型的脱髓鞘。然而,其潜在的免疫病理机制仍然难以捉摸。在本研究中,我们利用条件性CatC过表达小鼠建立了重组髓鞘少突胶质细胞糖蛋白35-55肽诱导的EAE模型,研究了CatC对CD4+ Th亚群(包括Th1、Th2、Th17、Tfh和T调节细胞)改变的影响。我们的研究结果表明,CatC特别增强了脑内Tfh细胞的数量,导致EAE慢性综合征发病更早、更严重。此外,CatC还能促进脑内TLS的形成,导致持续性神经炎症,加重慢性期EAE的严重程度。相反,CatC的特异性抑制剂AZD7986能有效减轻EAE综合征及其在体内和体外由CatC引起的影响。这些研究结果提供了一个新的视角,让我们了解到CatC在EAE的先天性免疫和适应性免疫中的关键作用,而CatC的特异性抑制剂AZD7986可能有助于多发性硬化症的潜在治疗策略。
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来源期刊
CiteScore
29.60
自引率
2.00%
发文量
290
审稿时长
28 days
期刊介绍: Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals. As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.
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