Androgens modulate the inflammatory response during acute wound healing

Gilliver, Stephen C.; Ashworth, Jason J.; Mills, Stuart J.; Hardman, Matthew J.; Ashcroft, Gillian S.

doi:10.1242/jcs.02786

Cited by 122 publications

(91 citation statements)

References 59 publications

(69 reference statements)

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“…However, there is also evidence suggesting that hyperinsulinemia drives androgen production (5). Irrespective of the cause, higher testosterone levels could drive inflammation (4,25). Given that adipocyte and muscle insulin resistance was observed only in male mice, we determined whether these defects were related to differences in testosterone levels.…”

Section: Resultsmentioning

confidence: 99%

Abdominal obesity in BTBR male mice is associated with peripheral but not hepatic insulin resistance

Flowers¹,

Oler²,

Nadler³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Insulin resistance is a common feature of obesity. BTBR mice have more fat mass than most other inbred mouse strains. On a chow diet, BTBR mice have elevated insulin levels relative to the C57BL/6J (B6) strain. Male F1 progeny of a B6 × BTBR cross are insulin resistant. Previously, we reported insulin resistance in isolated muscle and in isolated adipocytes in this strain. Whereas the muscle insulin resistance was observed only in male F1 mice, adipocyte insulin resistance was also present in male BTBR mice. We examined in vivo mechanisms of insulin resistance with the hyperinsulinemic euglycemic clamp technique. At 10 wk of age, BTBR and F1 mice had a >30% reduction in whole body glucose disposal primarily due to insulin resistance in heart, soleus muscle, and adipose tissue. The increased adipose tissue mass and decreased muscle mass in BTBR and F1 mice were negatively and positively correlated with whole body glucose disposal, respectively. Genes involved in focal adhesion, actin cytoskeleton, and inflammation were more highly expressed in BTBR and F1 than in B6 adipose tissue. The BTBR and F1 mice have higher levels of testosterone, which may be related to the pathological changes in adipose tissue that lead to systemic insulin resistance. Despite profound peripheral insulin resistance, BTBR and F1 mice retained hepatic insulin sensitivity. These studies reveal a genetic difference in body composition that correlates with large differences in peripheral insulin sensitivity.

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Section: Resultsmentioning

confidence: 99%

Abdominal obesity in BTBR male mice is associated with peripheral but not hepatic insulin resistance

Flowers¹,

Oler²,

Nadler³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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“…Earlier studies by Ashcroft and colleagues, using surgical or chemical castration, have found that androgens were able to inhibit cutaneous wound healing, possibly by modulating inflammatory responses, matrix deposition, and keratinocyte function (1,(8)(9)(10). However, the in vivo role of androgens/AR signals in different cell types involved in the wound-healing process remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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

Lai¹,

Lai²,

Chuang³

et al. 2009

J. Clin. Invest.

174

182

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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.

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“…In males, testosterone and its more potent metabolite 5␣-dihydrotestosterone inhibit repair 1,4 ; in females, estrogens such as 17␤-estradiol accelerate healing. 5,6 Although the effects of estrogens on female cutaneous physiology are well characterized, their roles in males are poorly understood.…”

mentioning

confidence: 99%

17β-Estradiol Inhibits Wound Healing in Male Mice via Estrogen Receptor-α

Gilliver

Emmerson

Campbell

et al. 2010

The American Journal of Pathology

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Although estrogens have long been known to accelerate healing in females, their roles in males remain to be established. To address this, we have investigated the influence of 17␤-estradiol on acute wound repair in castrated male mice. We report that sustained exposure to estrogen markedly delays wound re-epithelialization. Our use of hairless mice revealed this response to be largely independent of hair follicle cycling, whereas other studies demonstrated that estrogen minimally influences wound inflammation in males. Additionally , we report reduced collagen accumulation and increased gelatinase activities in the wounds of estrogen-treated mice. Increased wound matrix metalloproteinase (MMP)-2 activity in these animals may i) contribute to their inability to heal skin wounds optimally and ii) stem , at least in part , from effects on the overall levels and spatial distribution of membrane-type 1-MMP and tissue inhibitor of MMP (TIMP)-3 , which respectively facilitate and prevent MMP-2 activation. Using mice rendered null for either the ␣ or ␤ isoform of the estrogen receptor , we identified estrogen receptor-␣ as the likely effector of estrogen's inhibitory effects on healing.

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Androgens modulate the inflammatory response during acute wound healing

Cited by 122 publications

References 59 publications

Abdominal obesity in BTBR male mice is associated with peripheral but not hepatic insulin resistance

Abdominal obesity in BTBR male mice is associated with peripheral but not hepatic insulin resistance

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

17β-Estradiol Inhibits Wound Healing in Male Mice via Estrogen Receptor-α

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