Estrogen regulates sex-specific localization of regulatory T cells in adipose tissue of obese female mice

Ishikawa, Akari; Wada, Tsutomu; Nishimura, Sanshiro; Ito, Tetsuo; Okekawa, Akira; Onogi, Yasuhiro; Watanabe, Eri; Sameshima, Azusa; Tanaka, Tomoko; Tsuneki, Hiroshi; Saito, Shigeru; Sasaoka, Toshiyasu

doi:10.1371/journal.pone.0230885

Cited by 31 publications

(37 citation statements)

References 45 publications

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“… 35 , 36 Furthermore, adipose tissue in males contains more macrophages and immune cells with higher and longer-raised cytokine concentrations than in females. 37 , 38 , 39 This might become the source of more rapid and intense systemic inflammation in men contributing to the detrimental rise of cytokines (cytokine storm) observed in critical SARS-CoV-2 infections. It is conceivable that this rapid cytokine response, mediated by adipose tissue among other factors, could even be beneficial initially by providing an immediate immune response.…”

Section: Sex Differences In Covid-19mentioning

confidence: 99%

Sexual dimorphism in COVID-19: potential clinical and public health implications

Bechmann

Barthel

Schedl

et al. 2022

The Lancet Diabetes & Endocrinology

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Current evidence suggests that severity and mortality of COVID-19 is higher in men than in women, whereas women might be at increased risk of COVID-19 reinfection and development of long COVID. Differences between sexes have been observed in other infectious diseases and in the response to vaccines. Sex-specific expression patterns of proteins mediating virus binding and entry, and divergent reactions of the immune and endocrine system, in particular the hypothalamic-pituitary-adrenal axis, in response to acute stress might explain the higher severity of COVID-19 in men. In this Personal View, we discuss how sex hormones, comorbidities, and the sex chromosome complement influence these mechanisms in the context of COVID-19. Due to its role in the severity and progression of SARS-CoV-2 infections, we argue that sexual dimorphism has potential implications for disease treatment, public health measures, and follow-up of patients predisposed to the development of long COVID. We suggest that sex differences could be considered in future pandemic surveillance and treatment of patients with COVID-19 to help to achieve better disease stratification and improved outcomes.

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Section: Sex Differences In Covid-19mentioning

confidence: 99%

Sexual dimorphism in COVID-19: potential clinical and public health implications

Bechmann

Barthel

Schedl

et al. 2022

The Lancet Diabetes & Endocrinology

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“…MDSCs and Tregs are antipodally modulated by estrogen and androgen. The FOXP3 promoter region has an estrogen receptor α response element that controls expression [62,63], and estrogen suppresses Treg function and proliferation. In con-trast, estrogen aids MDSC function, potentiated by progesterone [64].…”

Section: Introductionmentioning

confidence: 99%

Hijacking Sexual Immuno-Privilege in GBM—An Immuno-Evasion Strategy

Sharpe

Baskin

Jenson

et al. 2021

IJMS

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Regulatory T-cells (Tregs) are immunosuppressive T-cells, which arrest immune responses to ‘Self’ tissues. Some immunosuppressive Tregs that recognize seminal epitopes suppress immune responses to the proteins in semen, in both men and women. We postulated that GBMs express reproductive-associated proteins to manipulate reproductive Tregs and to gain immune privilege. We analyzed four GBM transcriptome databases representing ≈900 tumors for hypoxia-responsive Tregs, steroidogenic pathways, and sperm/testicular and placenta-specific genes, stratifying tumors by expression. In silico analysis suggested that the presence of reproductive-associated Tregs in GBM tumors was associated with worse patient outcomes. These tumors have an androgenic signature, express male-specific antigens, and attract reproductive-associated Related Orphan Receptor C (RORC)-Treg immunosuppressive cells. GBM patient sera were interrogated for the presence of anti-sperm/testicular antibodies, along with age-matched controls, utilizing monkey testicle sections. GBM patient serum contained anti-sperm/testicular antibodies at levels > six-fold that of controls. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are associated with estrogenic tumors which appear to mimic placental tissue. We demonstrate that RORC-Tregs drive poor patient outcome, and Treg infiltration correlates strongly with androgen levels. Androgens support GBM expression of sperm/testicular proteins allowing Tregs from the patient’s reproductive system to infiltrate the tumor. In contrast, estrogen appears responsible for MDSC/TAM immunosuppression.

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“…Importantly, T reg accrual in WAT in male mice was reduced during obesogenic diet feeding 36 . In contrast, obesogenic diet feeding promoted WAT T reg expansion in T S housed young female mice 89 , which may explain the limited induction of metabolic diseases. While we did not directly examine WAT T reg cells in our model , expansion of T reg cell numbers in WAT at homeostasis has been demonstrated 20 .…”

Section: Discussionmentioning

confidence: 94%

Aging mitigates the severity of obesity-associated metabolic sequelae in a gender independent manner

et al. 2021

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Background Understanding gender-associated bias in aging and obesity-driven metabolic derangements has been hindered by the inability to model severe obesity in female mice. Methods Here, using chow- or high fat diet (HFD)-feeding regimens at standard (TS) and thermoneutral (TN) housing temperatures, the latter to model obesity in female mice, we examined the impact of gender and aging on obesity-associated metabolic derangements and immune responsiveness. Analysis included quantification of: (i) weight gain and adiposity; (ii) the development and severity of glucose dysmetabolism and non-alcoholic fatty liver disease (NAFLD); and (iii) induction of inflammatory pathways related to metabolic dysfunction. Results We show that under chow diet feeding regimen, aging was accompanied by increased body weight and white adipose tissue (WAT) expansion in a gender independent manner. HFD feeding regimen in aged, compared to young, male mice at TS, resulted in attenuated glucose dysmetabolism and hepatic steatosis. However, under TS housing conditions only aged, but not young, HFD fed female mice developed obesity. At TN however, both young and aged HFD fed female mice developed severe obesity. Independent of gender or housing conditions, aging attenuated the severity of metabolic derangements in HFD-fed obese mice. Tempered severity of metabolic derangements in aged mice was associated with increased splenic frequency of regulatory T (Treg) cells, Type I regulatory (Tr1)-like cells and circulating IL-10 levels and decreased vigor of HFD-driven induction of inflammatory pathways in adipose and liver tissues. Conclusion Our findings suggest that aging-associated altered immunological profile and inflammatory vigor may play a dominant role in the attenuation of obesogenic diet-driven metabolic dysfunction.

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Estrogen regulates sex-specific localization of regulatory T cells in adipose tissue of obese female mice

Cited by 31 publications

References 45 publications

Sexual dimorphism in COVID-19: potential clinical and public health implications

Sexual dimorphism in COVID-19: potential clinical and public health implications

Hijacking Sexual Immuno-Privilege in GBM—An Immuno-Evasion Strategy

Aging mitigates the severity of obesity-associated metabolic sequelae in a gender independent manner

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