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.
View: Text | PDF
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

×

Figure 3

AR in keratinocytes and fibroblasts is involved in regulating re-epithelialization.

Options: View larger image (or click on image) Download as PowerPoint
AR in keratinocytes and fibroblasts is involved in regulating re-epithel...
(A) Day 4 wounds from KARKO and WT mice were subjected to paraffin sectioning and H&E staining to determine the re-epithelialization rate. n = 4–6 (6 wounds/mouse). (B and C) Day 3 wounds were harvested from mice that had been injected with BrdU (150 μg/g body weight) 2 hours before harvest. The wounds were subjected to paraffin sectioning and subsequent immunohistochemistry to detect BrdU incorporation. BrdU+ epithelial cells in each wound section of (B) KARKO and (C) GARKO mice and their WT littermates were counted. n = 5–6 (6 wounds/mouse). (D) Re-epithelialization rates of day 3 wounds were compared between FARKO and WT mice. n = 4–6 (6 wounds/mouse). (E) Day 3 wounds were harvested from FARKO and WT mice injected with BrdU and subjected to immunohistochemistry as described in B and C. The proliferating (BrdU+) epithelial cells were counted in each wound section. n = 4–6 (4 wounds/mouse).