Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
Int J Mol Sci. 2023 Oct 17;24(20):15273. doi: 10.3390/ijms242015273.
Multiple sclerosis (MS) is a degenerative condition characterized by immune-mediated attacks on the central nervous system (CNS), resulting in demyelination and recurring T-cell responses. The histamine H4 receptor (H4R) is mainly expressed in cellular populations and plays a vital role in inflammation and immunological responses. The role of H4R in neurons of the CNS has recently been revealed. However, the precise role of H4R in neuronal function remains inadequately understood. The objective of this work was to investigate the impact of JNJ 10191584 (JNJ), a highly effective and specific H4R antagonist, on the development of experimental autoimmune encephalomyelitis (EAE) and to gain insight into the underlying mechanism involved. In this study, we examined the potential impact of JNJ therapy on the course of EAE in SJL/J mice. EAE mice were administered an oral dose of JNJ at a concentration of 6 mg/kg once a day, starting from day 10 and continuing until day 42. Afterward, the mice's clinical scores were assessed. In this study, we conducted additional research to examine the impact of JNJ on several types of immune cells, specifically Th1 (IFN-γ and T-bet), Th9 (IL-9 and IRF4), Th17 (IL-17A and RORγt), and regulatory T (Tregs; Foxp3 and TGF-β1) cells in the spleen. In this study, we further investigated the impact of JNJ on the mRNA expression levels of , , , , , , and in the brain. Daily treatment of JNJ effectively reduced the development of EAE in mice. The percentages of CD4IFN-γ, CD4T-bet, CD4IL-9, CD4IRF4, CD4IL-17A, and CD4RORγt cells were shown to decrease, whereas the percentages of CD4TGF-β1 and CD4Foxp3 cells were observed to increase in EAE mice treated with JNJ. Therefore, the HR4 antagonist positively affected the course of EAE by modulating the signaling of transcription factors. The identified results include possible ramifications in the context of MS treatment.
多发性硬化症（MS）是一种退行性疾病，其特征是免疫介导的中枢神经系统（CNS）攻击，导致脱髓鞘和反复的 T 细胞反应。组胺 H4 受体（H4R）主要在细胞群体中表达，在炎症和免疫反应中起着至关重要的作用。H4R 在中枢神经系统神经元中的作用最近已经被揭示。然而，H4R 在神经元功能中的精确作用仍未得到充分理解。这项工作的目的是研究高度有效的和特异性的 H4R 拮抗剂 JNJ 10191584（JNJ）对实验性自身免疫性脑脊髓炎（EAE）的发展的影响，并深入了解所涉及的潜在机制。在这项研究中，我们研究了 JNJ 治疗对 SJL/J 小鼠 EAE 病程的潜在影响。EAE 小鼠从第 10 天开始每天口服 6mg/kg 的 JNJ 一次，持续到第 42 天。之后，评估了小鼠的临床评分。在这项研究中，我们进行了进一步的研究，以检查 JNJ 对几种类型的免疫细胞的影响，特别是 Th1（IFN-γ 和 T-bet）、Th9（IL-9 和 IRF4）、Th17（IL-17A 和 RORγt）和调节性 T（Tregs；Foxp3 和 TGF-β1）细胞在脾中。在这项研究中，我们进一步研究了 JNJ 对脑内 、 、 、 、 、 和 的 mRNA 表达水平的影响。JNJ 的每日治疗可有效减轻 EAE 在小鼠中的发生发展。用 JNJ 治疗的 EAE 小鼠的 CD4IFN-γ、CD4T-bet、CD4IL-9、CD4IRF4、CD4IL-17A 和 CD4RORγt 细胞的百分比下降，而 CD4TGF-β1 和 CD4Foxp3 细胞的百分比增加。因此，HR4 拮抗剂通过调节转录因子的信号转导对 EAE 的病程产生积极影响。所确定的结果可能会对多发性硬化症的治疗产生影响。
