Histamine induces microglia activation and dopaminergic neuronal toxicity via H1 receptor activation.
Histamine is an amine widely known as a peripheral inflammatory mediator and as a neurotransmitter in the central nervous system. Recently, it has been suggested that histamine acts as an innate modulator of microglial activity. Herein, we aimed to disclose the role of histamine in microglial phagocytic activity and reactive oxygen species (ROS) production and to explore the consequences of histamine-induced neuroinflammation in dopaminergic (DA) neuronal survival.



The effect of histamine on phagocytosis was assessed both in vitro by using a murine N9 microglial cell line and primary microglial cell cultures and in vivo. Cells were exposed to IgG-opsonized latex beads or phosphatidylserine (PS) liposomes to evaluate Fcγ or PS receptor-mediated microglial phagocytosis, respectively. ROS production and protein levels of NADPH oxidases and Rac1 were assessed as a measure of oxidative stress. DA neuronal survival was evaluated in vivo by counting the number of tyrosine hydroxylase-positive neurons in the substantia nigra (SN) of mice.



We found that histamine triggers microglial phagocytosis via histamine receptor 1 (H1R) activation and ROS production via H1R and H4R activation. By using apocynin, a broad NADPH oxidase (Nox) inhibitor, and Nox1 knockout mice, we found that the Nox1 signaling pathway is involved in both phagocytosis and ROS production induced by histamine in vitro. Interestingly, both apocynin and annexin V (used as inhibitor of PS-induced phagocytosis) fully abolished the DA neurotoxicity induced by the injection of histamine in the SN of adult mice in vivo. Blockade of H1R protected against histamine-induced Nox1 expression and death of DA neurons in vivo.



Overall, our results highlight the relevance of histamine in the modulation of microglial activity that ultimately may interfere with neuronal survival in the context of Parkinson's disease (PD) and, eventually, other neurodegenerative diseases which are accompanied by microglia-induced neuroinflammation. Importantly, our results also open promising new perspectives for the therapeutic use of H1R antagonists to treat or ameliorate neurodegenerative processes.
Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal.
Sandra M
SM
Rocha
Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal.
Tatiana
T
Saraiva
Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal.
Ana C
AC
Cristóvão
Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal.
Raquel
R
Ferreira
Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal.
Tiago
T
Santos
Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal.
Marta
M
Esteves
Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal.
Cláudia
C
Saraiva
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA.
Goun
G
Je
Center for Neuroscience and Cell Biology, Coimbra, Portugal.
Luísa
L
Cortes
Center for Neuroscience and Cell Biology, Coimbra, Portugal.
Jorge
J
Valero
Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal.
Gilberto
G
Alves
Division of Cardiovascular Medicine and Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
Alexander
A
Klibanov
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA.
Yoon-Seong
YS
Kim
Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal. libernardino@fcsaude.ubi.pt.|Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506, Covilhã, Portugal. libernardino@fcsaude.ubi.pt.
Liliana
L
Bernardino
D000818:Animals; D000831:Animals, Newborn; D017304:Annexin A5 / Q000378:metabolism; D001921:Brain / Q000166:cytology; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects / Q000473:pathology; D059290:Dopaminergic Neurons / Q000187:drug effects*; D006632:Histamine / Q000633:toxicity*; D018494:Histamine Agents / Q000494:pharmacology; D017442:Histamine Agonists / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects*; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000074624:NADPH Oxidase 1; D010587:Phagocytosis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D017304:Annexin A5; D039481:CD11b Antigen; D018494:Histamine Agents; D017442:Histamine Agonists; D017382:Reactive Oxygen Species; D011969:Receptors, Histamine H1; D006632:Histamine; D014446:Tyrosine 3-Monooxygenase; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse
Dopaminergic neurons; Histamine; Microglia; NADPH oxidase; Neurotoxicity; Phagocytosis