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.

Clemastine Confers Neuroprotection and Induces an Anti-Inflammatory Phenotype in SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis

“…In the experimental autoimmune encephalitis mice model of multiple sclerosis, histamine H1 (H1R) and H2 receptor knockout mice develop a less severe clinical disease course and neuropathology. This would support the hypothesis that pharmacological targeting of histamine receptors is an appropriate diseasemodifying therapeutic approach against neuroinflammatory and autoimmune diseases [8,9]. Among several inflammatory mediators, rat and mouse microglia appears sensitive to histamine challenge [10][11][12].…”

Histamine Promotes the Development of Monocyte-Derived Dendritic Cells and Reduces Tumor Growth by Targeting the Myeloid NADPH Oxidase

“…The altered cytokine expression was reportedly dependent, in part, on the agonistic action of histamine at H 2 Rs, and it favored the development of Th2-polarized (30,32) or regulatory T cell-polarized (33) T cells in cultures of DCs and allogeneic T cells. These findings are challenged by results showing that H 2 R-KO mice are characterized by blunted Th1 responses and resistance to induction of Th1-dependent autoimmunity (34)(35)(36). In addition, the administration of histamine for therapeutic purposes in humans reportedly favors the maturation of Th1 cell, rather than Th2 or regulatory T cell, responses (37).…”

Analysis of Histamine Receptor Knockout Mice in Models of Inflammation

“…They found an upregulated expression of H 4 R mRNA in H 1 R/H 2 R 2/2 T cells and an upregulated expression of H 1 R and H 2 R mRNAs in H 3 R/H 4 R 2/2 T cells compared with the respective single-knockout T cells (Saligrama et al, 2012a). Whether these findings account for compensatory mechanisms is questionable, because in terms of disease activity, the absence of propathogenic signaling in H 1 R/H 2 R 2/2 mice enhances antipathogenic signaling via enhanced H 4 R expression and vice versa in H 3 R/H 4 R 2/2 mice, probably leading to additive or synergistic effects.…”

“…In addition, also in invariant natural killer T cells, cells, which in contrast to dendritic cells, recognize selective antigens out of the context of the major histocompatibility by complex; histamine via the H 4 R regulates production of Th-associated cytokine and, therefore, the adaptive immune response (Leite-de-Moraes et al, 2009 (Saligrama et al, 2012a). Disease symptoms in the double knockouts were reduced in H 1 R/H 2 R 2/2 and enhanced in H 3 R/H 4 R 2/2 mice.…”