Neutropenia with impaired host defense against microbial infection in mice lacking androgen receptor

Chuang, Kuang-Hsiang; Altuwaijri, Saleh; Li, Gonghui; Lai, Jiann–Jyh; Chu, Chin-Yi; Lai, Kuo-Pao; Lin, Hung-Yun; Hsu, Jong-Wei; Keng, Peter C.; Wu, Ming‐Chi; Chang, Chawnshang

doi:10.1084/jem.20082521

Cited by 119 publications

(114 citation statements)

References 73 publications

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“…Furthermore, studies of Ar KO mice have indicated that the immune system is regulated by androgens. For example, Chuang et al (19) found reduced neutrophil counts in castrated males that could be restored to normal levels through androgen supplementation, implicating the innate immune system. Our evidence that testosterone acts indirectly to promote colonic adenomagenesis opens the possibility of testing these indirect mechanisms, using the power of the molecular genetics of the mouse and rat to ablate the Ar gene in somatic lineages that are candidates for the site of testosterone action (20).…”

Section: Discussionmentioning

confidence: 99%

Sex disparity in colonic adenomagenesis involves promotion by male hormones, not protection by female hormones

Amos‐Landgraf

Heijmans

Wielenga

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

103

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It recently has been recognized that men develop colonic adenomas and carcinomas at an earlier age and at a higher rate than women. In the Apc Pirc/+ (Pirc) rat model of early colonic cancer, this sex susceptibility was recapitulated, with male Pirc rats developing twice as many adenomas as females. Analysis of large datasets revealed that the Apc Min/+ mouse also shows enhanced male susceptibility to adenomagenesis, but only in the colon. In addition, WT mice treated with injections of the carcinogen azoxymethane (AOM) showed increased numbers of colonic adenomas in males. The mechanism underlying these observations was investigated by manipulation of hormonal status. The preponderance of colonic adenomas in the Pirc rat model allowed a statistically significant investigation in vivo of the mechanism of sex hormone action on the development of colonic adenomas. Females depleted of endogenous hormones by ovariectomy did not exhibit a change in prevalence of adenomas, nor was any effect observed with replacement of one or a combination of female hormones. In contrast, depletion of male hormones by orchidectomy (castration) markedly protected the Pirc rat from adenoma development, whereas supplementation with testosterone reversed that effect. These observations were recapitulated in the AOM mouse model. Androgen receptor was undetectable in the colon or adenomas, making it likely that testosterone acts indirectly on the tumor lineage. Our findings suggest that indirect tumor-promoting effects of testosterone likely explain the disparity between the sexes in the development of colonic adenomas.colon cancer | animal models | androgens | estrogens | intestinal regionality E pidemiologic studies have identified a number of factors that influence the risk of sporadic adenomas and colorectal cancer (CRC). Age, familial predisposition, racial background, diet, physical activity, obesity and the metabolic syndrome, smoking, and heavy alcohol use are all established risk factors for the development of CRC. In addition, the risk of CRC also shows sexual dimorphism, with a lower incidence and delayed onset in women (1, 2). Colonoscopic screening of asymptomatic individuals has corroborated male sex as a risk factor for the development of both adenomas and CRC in all age groups (3, 4); however, whether this disparity depends on protective factors in women, tumor-promoting factors in males, or both is unknown.A protective role of female hormones against the development of frank CRC is suggested by data from the Women's Health Initiative (WHI). In the WHI, two large randomized controlled trials examined the effects of hormonal replacement therapy on postmenopausal women over a 5-y period, using CRC development as one of the endpoints. The first study showed that combined treatment with both equine estrogen (E2) and medroxyprogesterone acetate (MPA) substantially reduced the risk of colorectal cancer compared with placebo (odds ratio, 0.63) after a 5-y follow-up (5). However, protection was not found in a second randomized cont...

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Section: Discussionmentioning

confidence: 99%

Sex disparity in colonic adenomagenesis involves promotion by male hormones, not protection by female hormones

Amos‐Landgraf

Heijmans

Wielenga

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

103

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“…The predominant hematological phenotype of male mice genetically engineered to lack the androgen receptor (androgen receptor knockout mice) was neutropenia with increased susceptibility to microbial infection. 63 Surprisingly, androgen receptor knockout mice did not have reduced hemoglobin levels compared to wild-type mice, although there was a significant reduction in hematocrit. 63 In contrast to the marked neutropenia observed in androgen receptor knockout mice, castration of male mice resulted in only moderate neutrophil reduction in mice indicating that it is the androgen receptor itself rather than testosterone which is critical for neutrophil development and maturation.…”

Section: Effects Of Androgens On White Blood Cells and Plateletsmentioning

confidence: 96%

“…63 Surprisingly, androgen receptor knockout mice did not have reduced hemoglobin levels compared to wild-type mice, although there was a significant reduction in hematocrit. 63 In contrast to the marked neutropenia observed in androgen receptor knockout mice, castration of male mice resulted in only moderate neutrophil reduction in mice indicating that it is the androgen receptor itself rather than testosterone which is critical for neutrophil development and maturation. 63 Consistent with this, neutropenia or increased susceptibility to infection is not recognized in hypogonadal men or men receiving ADT.…”

Section: Effects Of Androgens On White Blood Cells and Plateletsmentioning

confidence: 96%

Hematological changes during androgen deprivation therapy

Grossmann¹,

Zajac²

2012

Asian J Androl

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Androgen deprivation therapy (ADT) has been associated with a plethora of adverse effects, consistent with the androgen dependency of multiple reproductive and somatic tissues. One such tissue is the hemopoietic system, and one of the most predictable consequences of ADT is the development of anemia. Although anemia caused by ADT is rarely severe, ADT is often given to frail, elderly men with increased susceptibility to anemia due to multiple other causes. ADT-associated anemia may contribute to fatigue and reduced quality of life (QoL) in such men, although this requires further study. While anemia is an independent risk factor of mortality in men with prostate cancer, it is not known whether treatment of ADT-associated anemia alters clinically important outcomes, or whether treatment affects mortality. Awareness of the phenomenon of ADT-induced anemia should avoid unnecessary work-up in mild cases of normocytic normochromic anemia. However, assessment and treatment of more severe anemia may be required. This should be determined on an individual basis. In contrast to the well-described actions of ADT on erythropoiesis, its effect on other hemopoietic lineages has been less well elucidated. While preclinical studies have found roles for androgens in maturation and differentiated function of neutrophils, lymphocytes and platelets, the implications of these findings for men with prostate cancer receiving ADT require further studies.

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“…On the other hand, AR can be activated by other factors in addition to androgens, such as estrogens (62,63), antiandrogens (64,65), and kinases (66,67). Interestingly, our recent studies suggested that the androgen-independent activity of AR is important for promoting neutrophil differentiation (14). In line with this, our data also demonstrate that AR of bone marrow cells can suppress wound healing even when there is low testosterone in the host, supporting the notion that AR can function in an androgen-independent manner.…”

Section: Figurementioning

confidence: 98%

“…However, the in vivo role of androgens/AR signals in different cell types involved in the wound-healing process remains unclear. In addition, increasing evidence suggests that androgens do not necessarily act through AR (11), while AR also has some androgenindependent functions (12)(13)(14). However, the approaches using surgical or chemical castration to diminish androgen levels cannot separate the effects of AR from androgens.…”

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.

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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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Neutropenia with impaired host defense against microbial infection in mice lacking androgen receptor

Cited by 119 publications

References 73 publications

Sex disparity in colonic adenomagenesis involves promotion by male hormones, not protection by female hormones

Sex disparity in colonic adenomagenesis involves promotion by male hormones, not protection by female hormones

Hematological changes during androgen deprivation therapy

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

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