Wound Healing Macrophages: The Intervention Of ATP To Stimulate Pro-wound Healing Phenotypes
Harshini Sarojini, Sarah Eichenberger, Sufan Chien.
University of Louisville, Louisville, KY, USA.
BACKGROUND: Macrophage phenotype changes occurs in accordance to the intracellular signaling during wound healing but the mechanisms are complex and some are still unknown. We have found that the use of intracellular ATP delivery (ATP-vesicles) enhances wound healing by transition of infiltrated circulating and resident macrophages from pro-inflammatory (M1) to anti-inflammatory (M2) resulting in extremely rapid tissue regeneration. This study was designed to explore the cellular mechanism in this process.
METHODS: Twenty-seven rabbits were used and four wounds were created on each ear. Two were treated with ATP-vesicles (10 mM Mg-ATP) and the other two were treated with controls (normal saline or RegranexTM). They were sacrificed at 5h, 12h, and days 1, 2, 3, 4, 6, 9, and 15 post-surgery.
RESULTS: ATP-vesicle-treated wounds showed increase of platelets, neutrophils and cytokines as early as 5-12h by immunohistochemical analysis. Massive macrophage accumulation was detected by CD68, CD16 and Anti-Mac by 24h. The activation of BRG1/Brm, the subunits of SWI/SNF ATP-dependent chromatin remodeling complex, in the ATP-Vesicle-treated wounds, may be responsible for this effect. Peroxisome proliferator-activated receptors (PPARα and PPARγ) are also involved in macrophage polarization. As early as day two, CD36, arginase and collagen type 1 immunoreactivity were detected along with early neovascularization. Double immunostaining with M1 and M2 macrophage markers showed massive early M2 macrophage polarization and double staining of macrophages with pre-collagen markers showed their active collagen synthesis as early as day 3. The control wounds treated by normal saline or RegranexTM did not show similar changes.
CONCLUSIONS: We conclude that intracellular ATP delivery causes rapid tissue regeneration by initiating the subunits of SWI/SNF ATP-dependent chromatin remodeling complex in the macrophages. All the cellular events associated with this healing process may provide a new strategy for wound healing.
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