Histamine H(3) receptor-mediated signaling protects mice from cerebral malaria.
BACKGROUND
Histamine 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.


RESULTS
In 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.


CONCLUSIONS
Our 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.
Beghdadi
Walid
W
Unité des Réponses Précoces aux Parasites et Immunopathologie, Institut Pasteur, Paris, France.
Porcherie
Adeline
A
Schneider
Bradley S
BS
Morisset
Séverine
S
Dubayle
David
D
Peronet
Roger
R
Dy
Michel
M
Louis
Jacques
J
Arrang
Jean-Michel
JM
Mécheri
Salaheddine
S
D000818:Animals; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000469:parasitology*; D018450:Disease Progression; D005260:Female; D006632:Histamine / Q000378:metabolism; D007107:Immune System; D007249:Inflammation; D016779:Malaria, Cerebral / Q000378:metabolism* / Q000469:parasitology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D010962:Plasmodium berghei / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D015398:Signal Transduction
D018100:Receptors, Histamine H3; D006632:Histamine