Histamine Induces Upregulated Expression of Histamine Receptors and Increases Release of Inflammatory Mediators from Microglia

Abstract

Histamine is a potent mediator of inflammation and a regulator of innate and adaptive immune responses. However, the influence of histamine on microglia, the resident immune cells in the brain, remains uninvestigated. In the present study, we found that microglia can constitutively express all four histamine receptors (H1R, H2R, H3R, and H4R), and the expression of H1R and H4R can be selectively upregulated in primary cultured microglia in a dose-dependent manner by histamine. Histamine can also dose-dependently stimulate microglia activation and subsequently production of proinflammatory factors tumor necrosis factor (TNF)-alpha and interleukin-6 (IL-6). The antagonists of H1R and H4R but not H2R and H3R reduced histamine-induced TNF-alpha and IL-6 production, MAPK and PI3K/AKT pathway activation, and mitochondrial membrane potential loss in microglia, suggesting that the actions of histamine are via H1R and H4R. On the other hand, inhibitors of JNK, p38, or PI3K suppressed histamine-induced TNF-alpha and IL-6 release from microglia. Histamine also activated NF-kappa B and ammonium pyrrolidinedithiocarbamate, an inhibitor of NF-kappa B, and reduced histamine-induced TNF-alpha and IL-6 release. In summary, the present study identifies the expression of histamine receptors on microglia. We also demonstrate that histamine induced TNF-alpha and IL-6 release from activated microglia via H1R and H4R-MAPK and PI3K/AKT-NF-kappa B signaling pathway, which will deepen the understanding of microglia-mediated neuroinflammatory symptoms of chronic neurodegenerative disease.

Histamine Induces Bovine Rumen Epithelial Cell Inflammatory Response via NF-κB Pathway

“…Elevated NF-κB activity has been recognized as a hallmark of inflammation [29]. Dong et al reported that the activity of NF-κB was significantly increased in the microglia of histaminetreated rats [25]. Taken together, previous studies and our results indicate that histamine over activates the NF-κB inflammatory pathway in bovine rumen epithelial cells.…”

“…The NF-κB pathway plays a crucial role in the inflammatory responses that mediate the histamine challenge in rat microglia [25]. Aberrant constitutive NF-κB activation is associated with inflammatory diseases [26].…”

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…Recently, the expression of all four histamine receptors has been demonstrated on microglia, which represents resident immune cells in the brain (Ferreira et al, 2012;Dong et al, 2014). Histamine induced microglia migration and inhibited LPS-induced IL-1b production via the H 4 receptor in one study (Ferreira et al, 2012).…”

“…Histamine induced microglia migration and inhibited LPS-induced IL-1b production via the H 4 receptor in one study (Ferreira et al, 2012). In another study, histamine induced TNFa and IL-6 production, which could be blocked by H 1 receptor and H 4 receptor antagonists (Dong et al, 2014). Thus, neuronal functions could also be indirectly affected via histamine influence on microglia.…”

Current Knowledge and Perspectives on Histamine H1and H2Receptor Pharmacology: Functional Selectivity, Receptor Crosstalk, and Repositioning of Classic Histaminergic Ligands

“…H 1 R antagonists are also proposed to be beneficial in the treatment of neurodegenerative disorders that have a neuroinflammatory component, such as Parkinson disease and amyotrophic lateral sclerosis (Dong et al, 2014;Rocha et al, 2014). Chronic treatment with clemastine enhances neuronal survival and modulates the expression of inflammatory genes in microglia (Apolloni et al, 2016).…”