Immethridine, histamine H3-receptor (H3R) agonist, alleviated experimental autoimmune encephalomyelitis via inhibiting the function of dendritic cells

Abstract

Multiple sclerosis (MS) is an inflammatory disease that is characterized by immune-mediated demyelination and degeneration of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is the preferential experimental rodent model for MS. Previous study demonstrated histamine H3 receptor (H3R) was an important factor in pathophysiology of EAE and immethridine was the most selective agonist of H3R. However, whether immethridine has therapeutic effect on EAE and its mechanism remained to be defined. Here we constructed EAE mouse model by immunization of MOG35-55 peptides with complete Freund's adjuvant, immethridine was used to treat EAE and its therapeutic effect was evaluated. The results showed that the treatment of immethridine could alleviate EAE. The percentage of Th1 and Th17 in the spleen from the treated EAE mice decreased and the surface molecules such as CD40, CD86 or MHCII on dendritic cells (DCs) were also down-regulated. To understand the effect of immethridine on DCs, bone marrow-derived DCs were prepared and the immunological functions were analyzed. The data demonstrated that immethridine could change the expression profiles of cytokines in DCs and inhibit the expression of the co-stimulatory molecules such as CD40 and CD86. Furthermore, immethridine also inhibited the antigen-presenting function of DCs and T cell differentiation induced by DCs. Signaling pathway analysis demonstrated that the phosphorylation of NF-κB p65 but not ERK1/2 in DCs was inhibited after the treatment of immethridine. These data strongly suggested that immethridine could inhibit the function of DCs and indicated the therapeutic potential on EAE.