Sustained Inflammasome Activity in Macrophages Impairs Wound Healing in Type 2 Diabetic Humans and Mice
- Rita E. Mirza1,
- Milie M. Fang1,
- Eileen M. Weinheimer-Haus1,3,
- William J. Ennis2,3 and
- Timothy J. Koh1,3⇑
- 1Department of Kinesiology and Nutrition
- 2Department of Surgery
- 3Center for Tissue Repair and Regeneration, University of Illinois at Chicago
- corresponding author: Timothy J. Koh, Email:
The hypothesis of this study was that sustained activity of the Nod-like receptor protein (NLRP)-3 inflammasome in wounds of diabetic humans and mice contributes to the persistent inflammatory response and impaired healing characteristic of these wounds. Macrophages (Mp) isolated from wounds on diabetic humans and db/db mice exhibited sustained inflammasome activity associated with low level of expression of endogenous inflammasome inhibitors. Soluble factors in the biochemical milieu of these wounds are sufficient to activate the inflammasome, as wound conditioned medium activates caspase-1 and induces release of IL-1β and IL-18 in cultured Mp via a reactive oxygen species-mediated pathway. Importantly, inhibiting inflammasome activity in wounds of db/db mice using topical application of pharmacological inhibitors improved healing of these wounds, induced a switch from pro-inflammatory to healing-associated Mp phenotypes and increased levels of pro-healing growth factors. Furthermore, data generated from bone marrow transfer experiments from NLRP-3 or caspase-1 knockout to db/db mice indicated that blocking inflammasome activity in bone marrow cells is sufficient to improve healing. Our findings indicate that sustained inflammasome activity in wound macrophages contributes to impaired early healing responses of diabetic wounds and that the inflammasome may represent a new therapeutic target for improving healing in diabetic individuals.
- Received June 13, 2013.
- Accepted October 31, 2013.
- © 2013 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.