Abstract
Objectives Diabetic wound inflammation deficiencies lead to ulcer development and eventual amputation and disability. Our previous research demonstrates that myeloid-derived suppressor cells (MDSCs) accumulate during inflammation and promote chronic wound healing via the regulation of Kruppel-like factor 4 (KLF4). In this study, we aimed to investigate the potential roles of MDSCs and KLF4 in diabetic wound healing. Methods An ob/ob mouse pressure ulcer (PU) model was used to evaluate the process of wound healing. The expression levels of KLF4 and IL-17A were measured by real-time PCR, and the population of MDSCs and Th17 cells was measured by flow cytometry. The levels of cytokines were determined by an immunosuppression assay. Results KLF4 deficiency in the diabetic PU model resulted in decreased accumulation of MDSCs, increased expansion of Th17 cells, and significantly delayed wound healing. Conversely, KLF4 activation by APTO-253 accelerated wound healing accompanied by increased MDSC populations and decreased numbers of Th17 cells. MDSCs have been proven to mediate Th17 differentiation via cytokines, and our in vitro data showed that elevated KLF4 expression in MDSCs resulted in reduced Th17 cell numbers and, thus, decreased levels of cytokines indispensable for Th17 differentiation. Conclusions Our study revealed a previously unreported function of KLF4-regulated MDSCs in diabetic wound healing and identified APTO-253 as a potential agent to improve the healing of pressure ulcers.
Highlights
Wound healing is a multifactorial, pathophysiologic process characterized by four discrete temporal phases that overlap: hemostasis, inflammation, proliferation, and remodeling [1]
We examined the expression of Kruppel-like factor 4 (KLF4) and IL-17A in ob/ob mice on day 3 by qRT-PCR, and a substantial decrease of KLF4 expression in the peripheral blood and granule tissue of the skin was detected while IL-17A expression was significantly elevated in both blood and skin (Figure 1(b))
The results revealed that Myeloid-derived suppressor cells (MDSCs) from ob/ob mice efficiently enhanced the differentiation of Th17 cells (p < 0:001), but this was significantly reduced when KLF4 expression was upregulated by APTO-253 (p < 0:05, Figure 4(c)), indicating that KLF4 expression in MDSCs is the key to Th17 differentiation
Summary
Wound healing is a multifactorial, pathophysiologic process characterized by four discrete temporal phases that overlap: hemostasis, inflammation, proliferation, and remodeling [1]. Wounds in diabetics will usually stall in a sustained inflammatory state resulting in nonhealing ulcers. Management of inflammation in nonhealing wounds, will open the way for the development of therapies that improve both prognosis and quality of life for such patients. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of bone marrow-derived cells possessing phenotypic plasticity, carrying monocyte markers [5], and contributing to wound healing [6]. Our previous study showed that KLF4 facilitates the healing of wounds via the mediation of both monocytic MDSC recruitment and differentiation of these cells into fibrocytes [7], but the effects of KLF4-mediated MDSCs on diabetic wounds still remain unknown
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