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.

Interaction of peripheral nerves and mast cells, eosinophils, and basophils in the development of pruritus

“…H1R and H4R play essential roles in peripheral histamine‐induced pruritus. H1R is ubiquitously expressed in many tissues, including peripheral nerves, airway and vascular smooth muscle cells, epithelial cells, endothelial cells, hepatocytes, dendritic cells, lymphocytes, eosinophils and basophils . Mast cells, eosinophils and basophils express H4R (Table ).…”

“…Mast cells, eosinophils and basophils express H4R (Table ). Peripheral nerves in the skin express H1R, H3R and H4R …”

Mast cell quantification in the skin of dogs with hormonal dermatosis

“…The elevated infiltration of mast cells in hypothyroid animals therefore agrees with an ongoing inflammatory process. There is evidence that mast cells can synthesize and store hormones among which are thyroid stimulating hormone (TSH) and the thyroid hormone (T3) (Csaba and Pállinger, 2009a, b;Thangam et al, 2018). Furthermore, evidence also indicates that mast cells express T3 receptors and that tissue mast cells population increased in hypothyroidism (Siebler et al, 2002), thus suggesting that the health or sick thyroid could condition mast cell hormone levels and/or that mast cells may represent an alternative source of packaged T3 locally deliverable (Thangam et al, 2018).…”

SG-SP1 Suppresses Mast Cell-Mediated Allergic Inflammation via Inhibition of FcεRI Signaling

“…Mast cells are important sources of histamine, which plays a key role in allergic symptoms (17). Attenuation of mast cell degranulation could be a therapeutic strategy to regulate allergic responses.…”