Opportunities and challenges in the therapeutic exploitation of histamine and histamine receptor pharmacology in inflammation-driven disorders

Inflammation-driven diseases encompass a wide array of pathological conditions characterised by immune system dysregulation leading to tissue damage and dysfunction. Among the myriad of mediators involved in the regulation of inflammation, histamine has emerged as a key modulatory player. Histamine elicits its actions through four rhodopsin-like G-protein-coupled receptors (GPCRs), named chronologically in order of discovery as histamine H₁, H₂, H₃ and H₄ receptors (H_1–4R). The relatively low affinity H₁R and H₂R play pivotal roles in mediating allergic inflammation and gastric acid secretion, respectively, whereas the high affinity H₃R and H₄R are primarily linked to neurotransmission and immunomodulation, respectively. Importantly, however, besides the H₄R, both H₁R and H₂R are also crucial in driving immune responses, the H₂R tending to promote yet ill-defined and unexploited suppressive, protective and/or resolving processes. The modulatory action of histamine via its receptors on inflammatory cells is described in detail. The potential therapeutic value of the most recently discovered H₄R in inflammatory disorders is illustrated via a selection of preclinical models. The clinical trials with antagonists of this receptor are discussed and possible reasons for their lack of success described.