Histamine H3 Receptor-Mediated Signaling Protects Mice from Cerebral Malaria

Walid Beghdadi,Jacques Louis,David Dubayle,Jean-Michel Arrang,Séverine Morisset,Michel Dy,Roger Peronet,Salaheddine Mécheri,Adeline Porcherie,Bradley S Schneider,Mauricio Martins Rodrigues

doi:10.1371/journal.pone.0006004

Abstract

BackgroundHistamine is a biogenic amine that has been shown to contribute to several pathological conditions, such as allergic conditions, experimental encephalomyelitis, and malaria. In humans, as well as in murine models of malaria, increased plasma levels of histamine are associated with severity of infection. We reported recently that histamine plays a critical role in the pathogenesis of experimental cerebral malaria (CM) in mice infected with Plasmodium berghei ANKA. Histamine exerts its biological effects through four different receptors designated H1R, H2R, H3R, and H4R.Principal FindingsIn the present work, we explored the role of histamine signaling via the histamine H3 receptor (H3R) in the pathogenesis of murine CM. We observed that the lack of H3R expression (H3R−/− mice) accelerates the onset of CM and this was correlated with enhanced brain pathology and earlier and more pronounced loss of blood brain barrier integrity than in wild type mice. Additionally tele-methylhistamine, the major histamine metabolite in the brain, that was initially present at a higher level in the brain of H3R−/− mice was depleted more quickly post-infection in H3R−/− mice as compared to wild-type counterparts.ConclusionsOur data suggest that histamine regulation through the H3R in the brain suppresses the development of CM. Thus modulating histamine signaling in the central nervous system, in combination with standard therapies, may represent a novel strategy to reduce the risk of progression to cerebral malaria.

Highlights

The main cellular reserves of histamine in peripheral tissues are mast cells and basophils
Modulating histamine signaling in the central nervous system, in combination with standard therapies, may represent a novel strategy to reduce the risk of progression to cerebral malaria
Lack of H3 receptor (H3R) expression accelerates the onset of cerebral malaria (CM) Wild type C57BL/6 mice display neurological signs characteristic of CM within 6–11 days after infection with parasites from the Plasmodium berghei ANKA strain (Pb ANKA) strain, and death usually occurs within 24 h after the onset of these signs [29]

Summary

Introduction

The main cellular reserves of histamine in peripheral tissues are mast cells and basophils. Histamine release is involved in the pathogenesis of various inflammatory reactions [1,2]. The H1 receptor (H1R) mediates most of the proinflammatory effects of histamine. Anti-inflammatory and immunosuppressive effects of histamine, such as inhibition of polymorphonuclear chemotaxis [8], and interleukin (IL)-12 secretion by monocytes, and induction of IL-10 production [9], are mainly dependent on stimulation of the H2 receptor (H2R), which is positively coupled to the adenylyl cyclase pathway. Unlike the other histamine receptors, H4 receptor (H4R) is predominantly expressed on hematopoietic cells [10,11,12], and H4R agonists were shown to induce chemotaxis of mast cells and eosinophils [13] as well as the production of IL-16 by T cells [14]. We reported recently that histamine plays a critical role in the pathogenesis of experimental cerebral malaria (CM) in mice infected with Plasmodium berghei ANKA. Histamine exerts its biological effects through four different receptors designated H1R, H2R, H3R, and H4R

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Conclusion