Monocyte/macrophage androgen receptor suppresses cutaneous wound healing in mice by enhancing local TNF-α expression
Jiann-Jyh Lai, … , Wen-Jye Lin, Chawnshang Chang
Jiann-Jyh Lai, … , Wen-Jye Lin, Chawnshang Chang
Published November 9, 2009
Citation Information: J Clin Invest. 2009;119(12):3739-3751. https://doi.org/10.1172/JCI39335.
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Research Article Dermatology

Monocyte/macrophage androgen receptor suppresses cutaneous wound healing in mice by enhancing local TNF-α expression

Abstract

Cutaneous wounds heal more slowly in elderly males than in elderly females, suggesting a role for sex hormones in the healing process. Indeed, androgen/androgen receptor (AR) signaling has been shown to inhibit cutaneous wound healing. AR is expressed in several cell types in healing skin, including keratinocytes, dermal fibroblasts, and infiltrating macrophages, but the exact role of androgen/AR signaling in these different cell types remains unclear. To address this question, we generated and studied cutaneous wound healing in cell-specific AR knockout (ARKO) mice. General and myeloid-specific ARKO mice exhibited accelerated wound healing compared with WT mice, whereas keratinocyte- and fibroblast-specific ARKO mice did not. Importantly, the rate of wound healing in the general ARKO mice was dependent on AR and not serum androgen levels. Interestingly, although dispensable for wound closure, keratinocyte AR promoted re-epithelialization, while fibroblast AR suppressed it. Further analysis indicated that AR suppressed wound healing by enhancing the inflammatory response through a localized increase in TNF-α expression. Furthermore, AR enhanced local TNF-α expression via multiple mechanisms, including increasing the inflammatory monocyte population, enhancing monocyte chemotaxis by upregulating CCR2 expression, and enhancing TNF-α expression in macrophages. Finally, targeting AR by topical application of a compound (ASC-J9) that degrades AR protein resulted in accelerated healing, suggesting a potential new therapeutic approach that may lead to better treatment of wound healing.

Authors

Jiann-Jyh Lai, Kuo-Pao Lai, Kuang-Hsiang Chuang, Philip Chang, I-Chen Yu, Wen-Jye Lin, Chawnshang Chang

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Figure 1

Cutaneous wound healing is accelerated in male GARKO mice due to loss of AR function.

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Cutaneous wound healing is accelerated in male GARKO mice due to loss of...
Excisional wounds were made by 4-mm-diameter punches. (A) Photographs of day 8 wounds. The arrowheads point out the location of wounds. (B) Wound areas were quantified for WT and GARKO mice. n = 7–10 (2 wounds/mouse). *P = 0.001. (C) H&E staining for day 3 wound sections. Black arrowheads indicate edges of wounds, red arrowheads indicate edges of epithelium, and white arrowheads indicate foci of infiltrating cells. Scale bars: 500 μm. (D) Higher magnification of the boxed region in C. The red arrowhead indicates the edge of epithelium. Scale bar: 100 μm. (E) The quantified data for re-epithelialization. n = 4 (6 wounds/mouse). *P = 0.001. (F) Day 10 wounds were subjected to Mason’s Trichrome staining to detect collagen fibers (blue). Arrowheads indicate the edges of wounds, and ovals indicate the areas of granulation tissue. Data are representative of 12–16 wounds (4 wounds/mouse) in each group. Scale bars: 500 μm. The quantitative data show relative collagen deposition in granulation tissues compared with the adjacent dermis. n = 3–4 (4 wounds/mouse). *P < 0.05. (G) DHT pellets or placebos were implanted into GARKO mice, and only placebo pellets were implanted into WT mice. Serum DHT levels were detected by ELISA after DHT restoration. n = 3–4 mice. *P = 0.023–0.025 versus GARKO placebo. (H) After DHT restoration, wounds were created, and wound areas were quantified on the days indicated. n = 3–4 (2 wounds/mouse). *P < 0.01 versus WT (placebo).