Novel insights on the biology and immunologic effects of histamine: A road map for allergists and mast cell biologists

Histamine (C5H9N3, molecular weight 111.15 g/mol) is a well-studied endogenous biogenic amine composed of an imidazole ring attached to an ethylamine side chain. It has a limited half-life of a few minutes within tissues and in circulation. Several cell types including mast cells (MCs), basophils, platelets, histaminergic neurons, and enterochromaffin cells produce varying amounts of histamine using histidine decarboxylase. However, only MCs and basophils have complex mechanisms to pack and store histamine in granules along with other mediators using serglycin and its carried glycosaminoglycan side chains. Relatively low granule pH (∼5.5) supports the binding of stored histamine to heparin, whereas exposure to neutral pH after degranulation weakens the binding and histamine becomes liberated. Histamine exerts multifaceted regulatory biofunctions by engaging its 4 types of heptahelical G protein–coupled receptors (H1R-H4R), which have different expression profiles and functions. MCs express H1R, H2R, and H4R, which gives them a dual role in histamine biology as producers and responsive target cells. Histamine plays a role in a variety of physiologic and pathologic processes such as cell proliferation, differentiation, hematopoiesis, vascular permeability, embryogenesis, tissue regeneration, and wound healing. The emergence of histamine receptor–deficient mouse models and the development of multiple histamine receptor agonists and antagonists have helped researchers better understand these physiologic and pathogenic functions of histamine. We review the biology of histamine with a focus on immunologic aspects and the role of histamine in allergy and MC biology. © 2025 Elsevier B.V., All rights reserved.