The Role of Histamine and Histamine Receptors in Mast Cell-Mediated Allergy and Inflammation: The Hunt for New Therapeutic Targets

Abstract

Histamine and its receptors (H1R-H4R) play a crucial and significant role in the development of various allergic diseases. Mast cells are multifunctional bone marrow-derived tissue-dwelling cells that are the major producer of histamine in the body. H1R are expressed in many cells, including mast cells, and are involved in Type 1 hypersensitivity reactions. H2R are involved in Th1 lymphocyte cytokine production. H3R are mainly involved in blood-brain barrier function. H4R are highly expressed on mast cells where their stimulation exacerbates histamine and cytokine generation. Both H1R and H4R have important roles in the progression and modulation of histamine-mediated allergic diseases. Antihistamines that target H1R alone are not entirely effective in the treatment of acute pruritus, atopic dermatitis, allergic asthma, and other allergic diseases. However, antagonists that target H4R have shown promising effects in preclinical and clinical studies in the treatment of several allergic diseases. In the present review, we examine the accumulating evidence suggesting novel therapeutic approaches that explore both H1R and H4R as therapeutic targets for histamine-mediated allergic diseases.

Keywords: allergy; antihistamines; histamine; histamine receptors; inflammation; mast cells.

Figure 1

Schematic representation of the expression of histamine receptors on mast cells and their potential response to histamine: binding of histamine to H1R induces vasodilatation, bronchoconstriction, platelet aggregation, and mucus hyper-secretion. Stimulation of H2R by histamine causes gastric acid secretion, increase heart rate, and cardiac output. Activation of H3R is involved in sleep-wake cycle, cognition, homeostatic regulation of energy levels, and neurotransmission. H4R activation leads to Ca⁺⁺ release from endoplasmic reticulum, degranulation, chemotaxis, and immuno-modulation whereas inhibitors of histamine receptors (H1R–H4R) inhibit specific responses.