Histamine H4 Receptor Antagonist Ameliorates the Progression of Experimental Autoimmune Encephalomyelitis via Regulation of T-Cell Imbalance

被引:3
|
作者
Aldossari, Abdullah A. [1 ]
Assiri, Mohammed A. [1 ]
Ansari, Mushtaq A. [1 ]
Nadeem, Ahmed [1 ]
Attia, Sabry M. [1 ]
Bakheet, Saleh A. [1 ]
Albekairi, Thamer H. [1 ]
Alomar, Hatun A. [1 ]
Al-Mazroua, Haneen A. [1 ]
Almanaa, Taghreed N. [2 ]
Al-Hamamah, Mohammed A. [1 ]
Alwetaid, Mohammad Y. [2 ]
Ahmad, Sheikh F. [1 ]
机构
[1] King Saud Univ, Coll Pharm, Dept Pharmacol & Toxicol, Riyadh 11451, Saudi Arabia
[2] King Saud Univ, Coll Sci, Dept Bot & Microbiol, Riyadh 11451, Saudi Arabia
关键词
H4R antagonist; JNJ; 10191584; EAE; multiple sclerosis; inflammatory mediators transcription factors; CENTRAL-NERVOUS-SYSTEM; MULTIPLE-SCLEROSIS; H-4; RECEPTOR; TH17; CELLS; DIFFERENTIAL REGULATION; MOLECULAR-CLONING; HELPER TYPE-1; CUTTING EDGE; ACTIVATION; INFLAMMATION;
D O I
10.3390/ijms242015273
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-gamma and T-bet), Th9 (IL-9 and IRF4), Th17 (IL-17A and ROR gamma t), and regulatory T (Tregs; Foxp3 and TGF-beta 1) cells in the spleen. In this study, we further investigated the impact of JNJ on the mRNA expression levels of IFN-gamma, T-bet, IL-9, IRF4, IL-17A, ROR gamma t, Foxp3, and TGF-beta 1 in the brain. Daily treatment of JNJ effectively reduced the development of EAE in mice. The percentages of CD4+IFN-gamma+, CD4+T-bet+, CD4+IL-9+, CD4+IRF4+, CD4+IL-17A+, and CD4+ROR gamma t+ cells were shown to decrease, whereas the percentages of CD4+TGF-beta 1+ and CD4+Foxp3+ 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.
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页数:17
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