HISTAMINE H3 AND H4 RECEPTORS AS A NEUROIMMUNE CONTROL AXIS: INTEGRATING SYNAPTIC SIGNALING WITH IMMUNE INFLAMMATION

Abstract

Histamine is classically associated with inflammation and gastric acid release in the histamine H1 and H2 receptors. Conversely, the new data indicate the pressing role of non-classical histamine H3 and H4 receptors in neuro-inflammation process and immune regulation. H3 receptor is found primarily in the central nervous system, where it regulates the secretion of neurotransmitters, synaptic activity, and microglial functionality, and H4 receptor is found on immune cells, and regulates the chemotaxis of immune cells, generation of cytokines, and inflammatory reactions of chronic inflammation. The clinical and preclinical data indicate that the neuroimmune bi-directional communication between the H3 and H4 receptors is achieved through the processes that entail neuronal signaling, peripheral immune stimulation, and blood-brain barrier interaction. The disruption in the functioning of these pathways has been identified with neuroinflammatory and neurodegenerative diseases. Although pharmacological targeting of H3 and H4 receptors has potential therapeutic utility, receptor specificity, penetration into the central nervous system, and biomarker discovery remain problematic. To achieve the full therapeutic capabilities of H3Rs and H4Rs modulation of neuroinflammatory and neurodegenerative disease, it may be necessary to integrate biomarker-guided strategies that deal with neuronal and immune components be integrated. This review summarizes the existing body of knowledge in the expression pattern, functional roles of H3R & H4R, and special attention is paid to their contribution to neuroimmune cross-talk. We also assess the advancement and constraints of therapeutic approaches to these receptors in clinical development, as well as treatment of neuroinflammatory and immune-mediated disease interventions.