Histamine receptor agonism differentially induces immune and reparative healing responses in biomaterial-facilitated tissue repair

Tissue repair is a highly regulated process involving immune, stromal, vascular, and parenchymal cell responses. Mediators of cellular responses at different phases of the healing process stimulate transitions through the continuum of repair. Histamine is an early mediator of healing, which, in skin, is released by resident cells (e.g., mast cells) after cutaneous injury, and acts to stimulate diverse responses in multiple cell populations. Histamine signaling is regulated by four distinct cell surface G-protein coupled receptors (HRH1-4 in humans, Hrh1-4 in mice) which initiate different downstream signaling cascades upon activation, but the specific effect of each receptor on tissue repair is poorly understood. Here, we systematically investigated the effect of selective histamine receptor agonism in laser-activated sealing and tissue repair of incisional skin wounds in immunocompetent mice. Although all four histamine receptors exhibited wound responsiveness in the epidermis, we find that activation of Hrh1, Hrh2, and Hrh4 stimulate a pro-healing immune response characterized by increased pro-resolution macrophages, reduced pro-inflammatory macrophages, and suppressed neutrophil responses. Further, activation of Hrh1 and Hrh4 stimulate angiogenesis after injury. Lastly, although Hrh1 activation resulted in enhanced epidermal epithelial-to-mesenchymal transition (EMT) in vivo and epithelialization in vitro, activation of Hrh2 suppressed both epidermal EMT and epithelialization. Activation of Hrh3, primarily found on neuronal cells, had no effect on any measure in our study. Selective histamine receptor agonism, specifically of histamine receptors Hrh-1 and 4, is a potential reparative approach to promote the efficacy of biomaterial-mediated repair of tissues, including skin.