Reduced Iron in Diabetic Wounds: An Oxidative Stress-Dependent Role for STEAP3 in Extracellular Matrix Deposition and Remodeling

Wilkinson, Holly N.; Upson, Sophie E.; Banyard, Kayleigh L.; Knight, Robert; Mace, Kimberly A.; Hardman, Matthew J.

Abstract

Iron is crucial for maintaining normal bodily function with well-documented roles in erythropoiesis, hemostasis, and inflammation. Despite this, little is known about the temporal regulation of iron during wound healing, or how iron contributes to wound biology and pathology. In this study, we profiled tissue iron levels across a healing time-course, identifying iron accumulation during late-stage repair. Diabetic murine wounds displayed significantly reduced iron levels, delayed extracellular matrix deposition, and dysregulation of iron gene expression. In vitro studies revealed important cellular roles for iron, promoting both the deposition and remodeling of extracellular proteins. Functional studies identified oxidative stress-dependent upregulation of the iron-converting metalloreductase, STEAP3, as a key mediator of extracellular matrix production. Taken together, these data reveal a mechanistic role for iron in facilitating the remodeling stage of wound healing. Indeed, targeting tissue iron could be a promising future strategy to tackle the development and progression of chronic wounds.

Citation

Wilkinson, H. N., Upson, S. E., Banyard, K. L., Knight, R., Mace, K. A., & Hardman, M. J. (2019). Reduced Iron in Diabetic Wounds: An Oxidative Stress-Dependent Role for STEAP3 in Extracellular Matrix Deposition and Remodeling. Journal of Investigative Dermatology, 139(11), 2368-2377.e7. https://doi.org/10.1016/j.jid.2019.05.014

• Journal Article Type: Article
• Acceptance Date: May 23, 2019
• Online Publication Date: Jun 7, 2019
• Publication Date: Nov 1, 2019
• Deposit Date: Jun 20, 2019
• Publicly Available Date: Dec 8, 2019
• Journal: Journal of Investigative Dermatology
• Print ISSN: 0022-202x
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 139
• Issue: 11
• Pages: 2368-2377.e7
• DOI: https://doi.org/10.1016/j.jid.2019.05.014
• Keywords: Cell Biology; Biochemistry; Molecular Biology; Dermatology
• Public URL: https://hull-repository.worktribe.com/output/2018862
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0022202X19316331
• Contract Date: Jun 20, 2019