{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The histamine H₄ receptor (HRH4) is a G protein–coupled receptor that mediates a wide spectrum of immunomodulatory and inflammatory responses across multiple cell types and tissues. HRH4 activation in mast cells triggers Gi/o‐coupled signaling cascades that induce intracellular calcium mobilization and drive chemotaxis and cytokine production, thereby contributing to cell activation without necessarily promoting degranulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " In immune cells, HRH4 is expressed on CD4⁺ T lymphocytes where its expression is upregulated under Th2 conditions, leading to the induction of transcription factors (such as AP‐1) and cytokines (including IL‑31) that help skew immune responses; activation of HRH4 in these cells also promotes the recruitment of regulatory T cells, thereby dampening allergic inflammation in models of asthma and atopic dermatitis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "7"}]}, {"type": "t", "text": " In antigen‐presenting cells such as Langerhans cells and plasmacytoid dendritic cells, HRH4 activation leads to a downregulation of chemokines (for example, CCL2 and IL‑12), thereby modulating cell migration and reducing pro‐inflammatory signals in allergic skin disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Similarly, in monocytes, HRH4 engagement results in Ca²⁺ mobilization and decreased expression of CCL2, which limits the recruitment of additional inflammatory cells"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", whereas in eosinophils, HRH4 mediates chemotactic responses to ligands such as CCL16."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Within the central nervous system, HRH4 is expressed on both neurons and microglia; receptor activation modulates neuronal excitability and directly influences microglial migration and cytokine release, thereby contributing to neuroinflammatory regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "14"}]}, {"type": "t", "text": " Moreover, HRH4 plays a role in autoimmune and inflammatory diseases. In experimental arthritis models, for instance, antagonism of HRH4 results in decreased Th17 cell development and lower production of pro‐inflammatory cytokines"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "; genetic studies also implicate HRH4 in atopic dermatitis and systemic lupus erythematosus, while altered HRH4 expression is observed in colorectal and breast cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "19"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n HRH4 also exhibits biased signaling properties that have been leveraged in the development of selective agonists, antagonists, and inverse agonists with anti‐inflammatory effects."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": " In addition, alternative splicing of HRH4 transcripts generates variants that act as dominant negatives by sequestering full‐length receptors intracellularly, thereby modulating overall receptor function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": " Collectively, these diverse signaling and regulatory functions underscore the therapeutic potential of targeting HRH4 in a broad range of inflammatory, allergic, and autoimmune conditions.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Claudia L Hofstra, Pragnya J Desai, Robin L Thurmond, et al. 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