Histamine in the Crosstalk Between Innate Immune Cells and Neurons: Relevance for Brain Homeostasis and Disease

Histamine is a biogenic amine playing a central role in allergy and peripheral inflammatory reactions and acts as a neurotransmitter and neuromodulator in the brain. In the adult, histamine is produced mainly by mast cells and hypothalamic neurons, which project their axons throughout the brain. Thus, histamine exerts a range of functions, including wakefulness control, learning and memory, neurogenesis, and regulation of glial activity. Histamine is also known to modulate innate immune responses induced by brain-resident microglia cells and peripheral circulating monocytes, and monocyte-derived cells (macrophages and dendritic cells). In physiological conditions, histamine per se causes mainly a pro-inflammatory phenotype while counteracting lipopolysaccharide-induced inflammation both in microglia, monocytes, and monocyte-derived cells. In turn, the activation of the innate immune system can profoundly affect neuronal survival and function, which plays a critical role in the onset and development of brain disorders. Therefore, the dual role of histamine/antihistamines in microglia and monocytes/macrophages is relevant for identifying novel putative therapeutic strategies for brain diseases. This review focuses on the effects of histamine in innate immune responses and the impact on neuronal survival, function, and differentiation/maturation, both in physiological and acute (ischemic stroke) and chronic neurodegenerative conditions (Parkinson's disease).