title: Histamine H3 receptor in primary mouse microglia inhibits chemotaxis, phagocytosis, and cytokine secretion.
abstract: Histamine is a physiological amine which initiates a multitude of physiological responses by binding to four known G-protein coupled histamine receptor subtypes as follows: histamine H1 receptor (H1 R), H2 R, H3 R, and H4 R. Brain histamine elicits neuronal excitation and regulates a variety of physiological processes such as learning and memory, sleep-awake cycle and appetite regulation. Microglia, the resident macrophages in the brain, express histamine receptors; however, the effects of histamine on critical microglial functions such as chemotaxis, phagocytosis, and cytokine secretion have not been examined in primary cells. We demonstrated that mouse primary microglia express H2 R, H3 R, histidine decarboxylase, a histamine synthase, and histamine N-methyltransferase, a histamine metabolizing enzyme. Both forskolin-induced cAMP accumulation and ATP-induced intracellular Ca(2+) transients were reduced by the H3 R agonist imetit but not the H2 R agonist amthamine. H3 R activation on two ubiquitous second messenger signalling pathways suggests that H3 R can regulate various microglial functions. In fact, histamine and imetit dose-dependently inhibited microglial chemotaxis, phagocytosis, and lipopolysaccharide (LPS)-induced cytokine production. Furthermore, we confirmed that microglia produced histamine in the presence of LPS, suggesting that H3 R activation regulate microglial function by autocrine and/or paracrine signalling. In conclusion, we demonstrate the involvement of histamine in primary microglial functions, providing the novel insight into physiological roles of brain histamine.
authors.affiliation: Department of Pharmacology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-Machi, Aoba-Ku, Sendai, Japan; Cyclotron Radioisotope Center, Tohoku University, 6-3 Aoba, Aramaki, Aoba-Ku, Sendai, Japan.
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Iida
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Takuro
authors.initials: T
authors.lastname: Matsuzawa
authors.forename: Fumito
authors.initials: F
authors.lastname: Naganuma
authors.forename: Tadaho
authors.initials: T
authors.lastname: Nakamura
authors.forename: Yamato
authors.initials: Y
authors.lastname: Miura
authors.forename: Attayeb S
authors.initials: AS
authors.lastname: Mohsen
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Harada
authors.forename: Ren
authors.initials: R
authors.lastname: Iwata
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yanai
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D006632:Histamine / Q000378:metabolism; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000502:physiology*; D010587:Phagocytosis / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D011970:Receptors, Histamine H2 / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3; D014409:Tumor Necrosis Factor-alpha; D006632:Histamine; D000242:Cyclic AMP; D015232:Dinoprostone; D002118:Calcium
keywords: H3R; chemotaxis; cytokine secretion; histamine secretion; phagocytosis