Combinatorial roles for histamine H1‐H2 and H3‐H4 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 H₁‐H₄. 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 H₁R and H₂R are propathogenic, while H₃R and H₄R 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 H₁H₂RKO and H₃H₄RKO mice and studied them for susceptibility to EAE. Compared with wild‐type (WT) mice, H₁H₂RKO mice developed a less severe clinical disease course, whereas the disease course of H₃H₄RKO mice was more severe. H₁H₂RKO mice also developed less neuropathology and disrupted blood brain barrier permeability compared with WT and H₃H₄RKO mice. Additionally, splenocytes from immunized H₁H₂RKO 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.