Monocyte/macrophage androgen receptor suppresses cutaneous wound healing in mice by enhancing local TNF-α expression
Monocyte/macrophage androgen receptor suppresses cutaneous wound healing in mice by enhancing local TNF-α expression
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DOI：
10.1172/jci39335
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发表时间：
2009-12-01
影响因子：
15.9
通讯作者：
Chang, Chawnshang
中科院分区：
文献类型：
--
作者：
Lai, Jiann-Jyh;Lai, Kuo-Pao;Chang, Chawnshang
老年男性的皮肤伤口愈合速度比老年女性的要慢，这表明性激素在愈合过程中发挥了作用。事实上，雄激素/雄激素受体(AR)信号已被证明抑制皮肤伤口愈合。AR在愈合皮肤中表达于多种细胞类型，包括角质形成细胞、真皮成纤维细胞和浸润性巨噬细胞，但雄激素/AR信号在这些不同细胞类型中的确切作用尚不清楚。为了解决这个问题，我们建立并研究了细胞特异性AR基因敲除(ARKO)小鼠的皮肤伤口愈合。与WT小鼠相比，普通和髓系特异性ARKO小鼠的伤口愈合速度更快，而角质形成细胞和成纤维细胞特异性ARKO小鼠则没有。重要的是，普通ARKO小鼠的伤口愈合率取决于AR，而不是血清雄激素水平。有趣的是，尽管角质形成细胞AR对于伤口闭合是必不可少的，但它促进了再上皮化，而成纤维细胞AR抑制了再上皮化。进一步的分析表明，AR通过局部增加肿瘤坏死因子-α的表达来增强炎症反应，从而抑制伤口愈合。此外，AR通过多种机制促进局部肿瘤坏死因子-α的表达，包括增加炎症单核细胞的数量，通过上调CCR2的表达来增强单核细胞的趋化作用，以及增强巨噬细胞中的肿瘤坏死因子-α的表达。最后，通过局部应用一种能降解AR蛋白的化合物(ASC-J9)来靶向AR可以加速愈合，这表明一种潜在的新的治疗方法可能会导致更好地治疗伤口愈合。
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-alpha expression. Furthermore, AR enhanced local TNF-alpha expression via multiple mechanisms, including increasing the inflammatory monocyte population, enhancing monocyte chemotaxis by upregulating CCR2 expression, and enhancing TNF-alpha 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.