Combinatorial roles for histamine H 1-H 2 and H 3-H 4 receptors in autoimmune inflammatory disease of the central nervous system

Abstract

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system in which histamine (HA) and its receptors have been implicated in disease pathogenesis. HA exerts its effects through four different G protein-coupled receptors designated H 1-H 4. We previously examined the effects of traditional single HA receptor (HR) knockouts (KOs) in experimental allergic encephalomyelitis (EAE), the autoimmune model of MS. Our results revealed that H 1R and H 2R are propathogenic, while H 3R and H 4R are antipathogenic. This suggests that combinatorial targeting of HRs may be an effective disease-modifying therapy (DMT) in MS. To test this hypothesis, we generated H 1H 2RKO and H 3H 4RKO mice and studied them for susceptibility to EAE. Compared with wild-type (WT) mice, H 1H 2RKO mice developed a less severe clinical disease course, whereas the disease course of H 3H 4RKO mice was more severe. H 1H 2RKO mice also developed less neuropathology and disrupted blood brain barrier permeability compared with WT and H 3H 4RKO mice. Additionally, splenocytes from immunized H 1H 2RKO mice produced less interferon(IFN)-γ and interleukin(IL)-17. These findings support the concept that combined pharmacological targeting of HRs may be an appropriate ancillary DMT in MS and other immunopathologic diseases. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.