An estrogen-sensitive fibroblast population drives abdominal muscle fibrosis in an inguinal hernia mouse model.

Greater than 25% of all men develop an inguinal hernia in their lifetime, and more than 20 million inguinal hernia repair surgeries are performed worldwide each year. The mechanisms causing abdominal muscle weakness, the formation of inguinal hernias, or their recurrence are largely unknown. We previously reported that excessively produced estrogen in the lower abdominal muscles (LAMs) triggers extensive LAM fibrosis, leading to hernia formation in a transgenic male mouse model expressing the human aromatase gene (Aromhum). To understand the cellular basis of estrogen-driven muscle fibrosis, we performed single-cell RNA sequencing on LAM tissue from Aromhum and wild-type littermates. We found a fibroblast-like cell group composed of 6 clusters, 2 of which were validated for their enrichment in Aromhum LAM tissue. One of the potentially novel hernia-associated fibroblast clusters in Aromhum was enriched for the estrogen receptor-α gene (Esr1hi). Esr1hi fibroblasts maximally expressed estrogen target genes and seemed to serve as the progenitors of another cluster expressing ECM-altering enzymes (Mmp3hi) and to upregulate expression of proinflammatory, profibrotic genes. The discovery of these 2 potentially novel and unique hernia-associated fibroblasts may lead to the development of novel treatments that can nonsurgically prevent or reverse inguinal hernias.

Erratum: Author Correction: Age-associated changes in the impact of sex steroids on influenza vaccine responses in males and females.

[This corrects the article DOI: 10.1038/s41541-019-0124-6.].

Age-associated changes in the impact of sex steroids on influenza vaccine responses in males and females.

Vaccine-induced immunity declines with age, which may differ between males and females. Using human sera collected before and 21 days after receipt of the monovalent A/Cal/09 H1N1 vaccine, we evaluated cytokine and antibody responses in adult (18-45 years) and aged (65+ years) individuals. After vaccination, adult females developed greater IL-6 and antibody responses than either adult males or aged females, with female antibody responses being positively associated with concentrations of estradiol. To test whether protection against influenza virus challenge was greater in females than males, we primed and boosted adult (8-10 weeks) and aged (68-70 weeks) male and female mice with an inactivated A/Cal/09 H1N1 vaccine or no vaccine and challenged with a drift variant A/Cal/09 virus. As compared with unvaccinated mice, vaccinated adult, but not aged, mice experienced less morbidity and better pulmonary viral clearance following challenge, regardless of sex. Vaccinated adult female mice developed antibody responses that were of greater quantity and quality and more protective than vaccinated adult males. Sex differences in vaccine efficacy diminished with age in mice. To determine the role of sex steroids in vaccine-induced immune responses, adult mice were gonadectomized and hormones (estradiol in females and testosterone in males) were replaced in subsets of animals before vaccination. Vaccine-induced antibody responses were increased in females by estradiol and decreased in males by testosterone. The benefit of elevated estradiol on antibody responses and protection against influenza in females is diminished with age in both mice and humans.

The Confluence of Sex Hormones and Aging on Immunity.

The immune systems of post-pubescent males and females differ significantly with profound consequences to health and disease. In many cases, sex-specific differences in the immune responses of young adults are also apparent in aged men and women. Moreover, as in young adults, aged women develop several late-adult onset autoimmune conditions more frequently than do men, while aged men continue to develop many cancers to a greater extent than aged women. However, sex differences in the immune systems of aged individuals have not been extensively investigated and data addressing the effectiveness of vaccinations and immunotherapies in aged men and women are scarce. In this review, we evaluate age- and sex hormone-related changes to innate and adaptive immunity, with consideration about how this impacts age- and sex-associated changes in the incidence and pathogenesis of autoimmunity and cancer as well as the efficacy of vaccination and cancer immunotherapy. We conclude that future preclinical and clinical studies should consider age and sex to better understand the ways in which these characteristics intersect with immune function and the resulting consequences for autoimmunity, cancer, and therapeutic interventions.

Sex Reporting in Preclinical Microbiological and Immunological Research.

Both sex (i.e., biological construct of male and female) and gender (i.e., social construct of masculine and feminine) impact the pathogenesis of diseases, including those caused by microbial infections. Following the 2015 NIH policy for consideration of sex as a biological variable in preclinical research, in 2018, authors of papers published in primary-research American Society for Microbiology (ASM) journals will be asked to report the sex of the research subjects and animals and of materials derived directly from them. To address the need for sex reporting in ASM journals, we systematically reviewed 2,928 primary-research articles published in six primary-research ASM journals (Antimicrobial Agents and Chemotherapy, Clinical and Vaccine Immunology, Infection and Immunity, Journal of Bacteriology, Journal of Virology, and mBio) in 2016. Approximately 37% of animal studies and 9% of primary cell culture papers published in 2016 would have been affected by the new sex-reporting policy. For animal studies (i.e., studies with any nonhuman vertebrate hosts), most published papers either did not report the sex of the animals or used only female animals, and a minority used only males or both sexes. For published studies using primary cells from diverse animal species (i.e., humans and nonhuman vertebrates), almost all studies failed to report the sex of donors from which the cells were isolated. We believe that reporting the sex of animals and even of the donors of derived cells could improve the rigor and reproducibility of research conducted in microbiology and immunology and published in ASM journals.

Rodent Gymnastics: Neurobehavioral Assays in Ischemic Stroke.

Despite years of research, most preclinical trials on ischemic stroke have remained unsuccessful owing to poor methodological and statistical standards leading to "translational roadblocks." Various behavioral tests have been established to evaluate traits such as sensorimotor function, cognitive and social interactions, and anxiety-like and depression-like behavior. A test's validity is of cardinal importance as it influences the chance of a successful translation of preclinical results to clinical settings. The mission of choosing a behavioral test for a particular project is, therefore, imperative and the present review aims to provide a structured way to evaluate rodent behavioral tests with implications in ischemic stroke.