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

Jordan R Yaron; Shubham Pallod; Nicole Grigaitis-Esman; Vanshika Singh; Samantha Rhodes; Dirghau Manishbhai Patel; Deepanjan Ghosh; Kaushal Rege

doi:10.1016/j.biomaterials.2024.122967

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

Biomaterials. 2024 Nov 15:315:122967. doi: 10.1016/j.biomaterials.2024.122967. Online ahead of print.

Authors

Jordan R Yaron¹, Shubham Pallod², Nicole Grigaitis-Esman², Vanshika Singh³, Samantha Rhodes², Dirghau Manishbhai Patel³, Deepanjan Ghosh², Kaushal Rege⁴

Affiliations

¹ Center for Biomaterials Innovation and Translation, The Biodesign Institute, Arizona State University, Tempe, AZ, 85287, USA; Chemical Engineering, School for Engineering of Matter, Transport, and Energy, Ira A. Fulton Schools of Engineering, Arizona State University, Tempe, AZ, 85287, USA.
² Center for Biomaterials Innovation and Translation, The Biodesign Institute, Arizona State University, Tempe, AZ, 85287, USA; Biological Design Graduate Program, School for Engineering of Matter, Transport, and Energy, Ira A. Fulton Schools of Engineering, Arizona State University, Tempe, AZ, 85287, USA.
³ Center for Biomaterials Innovation and Translation, The Biodesign Institute, Arizona State University, Tempe, AZ, 85287, USA; Biomedical Engineering, School for Biological and Health Systems Engineering, Ira A. Fulton Schools of Engineering, Arizona State University, Tempe, AZ, 85287, USA.
⁴ Center for Biomaterials Innovation and Translation, The Biodesign Institute, Arizona State University, Tempe, AZ, 85287, USA; Chemical Engineering, School for Engineering of Matter, Transport, and Energy, Ira A. Fulton Schools of Engineering, Arizona State University, Tempe, AZ, 85287, USA; Biological Design Graduate Program, School for Engineering of Matter, Transport, and Energy, Ira A. Fulton Schools of Engineering, Arizona State University, Tempe, AZ, 85287, USA. Electronic address: kaushal.rege@asu.edu.

PMID: 39586217
DOI: 10.1016/j.biomaterials.2024.122967

Abstract

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.