Elevated local senescence in diabetic wound healing is linked to pathological repair via CXCR2.

Wilkinson, Holly N.; Clowes, Christopher; Banyard, Kayleigh L.; Matteuci, Paolo; Mace, Kimberly; Hardman, Matthew J.

Abstract

© 2019 The Authors Cellular senescence can be broadly defined as a stable, but essentially irreversible, loss of proliferative capacity. Historically, senescence has been described as a negative outcome of advanced cellular age. It is now clear, however, that senescence represents a dynamic autonomous stress response, integral to long-term tumor suppression. Transient induction of a senescent phenotype has actually been suggested to promote regeneration in both liver and skin. Here, we explored the role of senescence in pathological aged and diabetic murine wound healing. Aged and diabetic wounds had greater numbers of senescent cells, and diabetic macrophages maintained altered retention of polarization and produced a CXCR2-enriched senescence-associated secretory phenotype (i.e., SASP). Of translational relevance, targeted expression of CXCR2 in primary human dermal fibroblasts led to paracrine induction of nuclear p21. Furthermore, a selective agonist to CXCR2 was able to reverse delayed healing in diabetic mice and accelerate ex vivo human skin wound healing. Collectively, these data suggest a hitherto unappreciated role for CXCR2 in mediating cellular senescence in pathological wound repair.

Citation

Wilkinson, H. N., Clowes, C., Banyard, K. L., Matteuci, P., Mace, K., & Hardman, M. J. (2019). Elevated local senescence in diabetic wound healing is linked to pathological repair via CXCR2. Journal of Investigative Dermatology, 139(5), 1171-1181.e6. https://doi.org/10.1016/j.jid.2019.01.005

• Journal Article Type: Article
• Acceptance Date: Jan 8, 2019
• Online Publication Date: Jan 23, 2019
• Publication Date: 2019-05
• Deposit Date: Jan 30, 2019
• Publicly Available Date: Jul 24, 2019
• Journal: Journal of Investigative Dermatology
• Print ISSN: 0022-202x
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 139
• Issue: 5
• Pages: 1171-1181.e6
• DOI: https://doi.org/10.1016/j.jid.2019.01.005
• Keywords: Senescence; Wound healing; Ageing; Diabetes; Macrophage polarisation
• Public URL: https://hull-repository.worktribe.com/output/1250509
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0022202X19300211?via%3Dihub#kwrds0010
• Additional Information: This is the accepted manuscript of an article published in Journal of investigative dermatology, 2019. The version of record is available at the DOI link in this record.
• Contract Date: Feb 1, 2019