Histamine Receptor Agonists Differentially Modulate Wound Closure and Tissue Repair in Diabetic and Obese Mice

Wound healing in diabetes is impaired, in part, because of poor angiogenesis as well as poor recruitment and dysfunction of immune cells. As a consequence, diabetic patients are at a higher risk of wound infections, dehiscence, and abnormal scarring, and these complications contribute to significant medical and economic burden globally. In early stages of healthy injury repair, mast cells release histamine, which acts via four histamine receptors (HRH) 1‐4, and induces vascular permeability, thereby facilitating migration of immune cells into the wound microenvironment. In our previous studies, we have shown that individual agonism of histamine receptors in incisional, acute wounds differentially modulates healing. In the current study, we investigated the efficacy of selective small‐molecule, histamine receptor agonists for wound closure and tissue repair in diabetic, obese mice. Here, topical delivery of HRH1 and HRH4 agonists, 2‐pyridylethylamine and 4‐methylhistamine, respectively, significantly accelerated wound closure, reduced epidermal gap, and enhanced skin barrier function compared to saline in full‐thickness, splinted wounds in db/db diabetic, obese mice. Immunohistochemical (IHC) analyses of the wound tissue indicated that HRH1 and HRH 4 agonists promoted macrophage polarization, epithelial‐to‐mesenchymal transition, myofibroblast activation, and angiogenesis, thus activating a comprehensive pro‐reparative tissue response. Overall, histamine receptor modulation demonstrated a multipronged effect on tissue repair, which offers a translationally promising therapeutic approach for diabetic wound healing.