The role of the activating versus inhibitory classes of G protein coupled histamine receptors on experimental allergic encephalomyelitis susceptibility. (47.2)

Abstract

Abstract Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) augmented by histamine (HA) and histamine receptor (HR) signaling. To help elucidate the mechanism behind HA and HR signaling on MS susceptibility, we utilize the experimental allergic encephalomyelitis (EAE) mouse model for MS and implement the use of traditional gene knockout studies. HA is known to exert its effects through four different G protein coupled receptors (GPCRs) designated as H1R, H2R, H3R and H4R. H1R and H2R couples to the Gαq/11 and Gs class of activating G proteins, respectively, whereas H3R and H4R couples to the Gi/o class of inhibitory G proteins. Each individual HR has been shown to influence EAE pathogenesis. Here we assessed the overall contribution to EAE susceptibility imposed by the two classes of GPCRs by generating C57BL6/J mice deficient for both H1R and H2R (H1H2RKO), as well as mice deficient for both H3R and H4R (H3H4RKO). The results of our study show that H1H2RKO mice exhibit decreased susceptibility to EAE, less severe neuroinflammation with a higher infiltration of T regulatory cells into the CNS, and decreased blood brain barrier permeability compared to H3H4RKO mice. Moreover, we show that splenocytes from immunized H1H2RKO mice produce significantly less IFN-γ and IL-17, which are cytokines known to exacerbate disease. Therefore, the activating class of GPCRs enhances EAE susceptibility compared to the inhibitory class of HRs.