Histamine 4 receptor promotes expression of costimulatory B7.1/B7.2 molecules, CD28 signaling and cytokine production in stress-induced immune responses

• H4R modulates immune responses during chronic stress.
• H4R promotes CD80/CD86, and Th1/Th17 cytokines.
• H4R upregulates transcription factors such as NF-κB and STAT-3.
• H4R antagonist reverses H4R mediated immune responses.

Recently, the expression of histamine 4 receptor (H4R) on neurons was reported, however its function in cells within the central nervous system (CNS) remains poorly understood. To this end, we used the H4R agonist, 4-methylhistamine (4-MeH), and the H4R antagonist, JNJ77777120 (JNJ), to investigate the function of H4R signaling in immune cells in a murine model of chronic stress. Treatment of stressed mice with 4-MeH resulted in an increase in the proportion of lymphocyte subsets (CD3+, CD8+, CD28+, and CD4+ CD28+) and cells expressing the co-stimulatory molecules CD80+ (B7.1) and CD86+ (B7.2) in heparinized blood as compared to normal control (NC) and stressed control (SC) groups. We also observed that as compared to NC and SC mice, 4-MeH-treated mice showed greater production of IL-2+, IL-6+, IL-9+, IL-21+, and IL-27+ cytokines in the spleen and by splenic CD4+ T cells. Furthermore, 4-MeH treatment of stressed mice led to an increase in the levels of serum Th1/Th17 cytokines and corticosterone, and a decrease in Th2 cytokines. Treatment of chronically-stressed mice with 4-MeH also augmented expression of IL-6, IL-21, NF-κB p65, and STAT3 mRNA. Moreover, Western blot analyses confirmed increased protein expression of NF-κB, iNOS, and STAT3 expression following 4-MeH treatment of chronically-stressed mice as compared to controls. These proteins provide a novel relevant targets for the manipulation of chronic stress induced immune regulation. In striking contrast, treatment of stressed mice with the H4R antagonist, JNJ, resulted in a substantial reduction in all of the aforementioned effects upon immune cell percentages and cytokine production.

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