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 2

AR in monocytes/macrophages is critical for suppressing wound healing.

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AR in monocytes/macrophages is critical for suppressing wound healing. (...
(A) γ-Irradiated 6-week-old WT and GARKO mice were adoptively transplanted with WT or GARKO bone marrow cells. To confirm the bone marrow engraftment, various tissues from a WT recipient receiving GARKO bone marrow were subjected to AR genotyping. KO, truncated AR allele. (B) After bone marrow engraftment, wounds were created and the wound areas were quantified and compared among recipients. n = 3–4 (6 wounds/mouse). The numbers indicate the P values for each comparison. (C) Various tissues from MARKO mice were subjected to AR genotyping to confirm the efficiency and specificity of AR deletion. D3W, day 3 wound; Thy, thymus; Spln, spleen; Mus, muscle; Tes, testis; Bld, bladder. (D) Wound areas were compared between male MARKO mice and their WT littermates. n = 6–7 (2 wounds/mouse). (E) Day 8 wound tissues from WT and MARKO mice were subjected to Trichrome staining to detect collagen fibers (blue). Ovals indicate granulation tissues. Scale bars: 500 μm. The quantitative data show relative collagen deposition in granulation tissues compared with the adjacent dermis. n = 3 (4 wounds/mouse). (F) Day 3 wound tissues from WT and MARKO mice were subjected to H&E staining for analysis of re-epithelialization. n = 4 (6 wounds/mouse). (G) Excisional wounds were created and compared between KARKO mice and their WT littermates. n = 3–4 (6 wounds/mouse). (H) Excisional wounds were created and compared between FARKO mice and their WT littermates. n = 4–6 (6 wounds/mouse). Due to differences in genetic backgrounds among conditional ARKO lines, the WT controls among different experiments were not necessarily equivalent.