Androgens Modulate the Immune Profile in a Mouse Model of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is associated with a low-grade inflammation, but it is unknown how hyperandrogenism, the hallmark of PCOS, affects the immune system. Using a PCOS-like mouse model, it is demonstrated that hyperandrogenism affects immune cell populations in reproductive, metabolic, and immunological tissues differently in a site-specific manner. Co-treatment with an androgen receptor antagonist prevents most of these alterations, demonstrating that these effects are mediated through androgen receptor activation. Dihydrotestosterone (DHT)-exposed mice displayed a drastically reduced eosinophil population in the uterus and visceral adipose tissue (VAT). A higher frequency of natural killer (NK) cells and elevated levels of IFN-γ and TNF-α are seen in uteri of androgen-exposed mice, while NK cells in VAT and spleen displayed a higher expression level of CD69, a marker of activation or tissue residency. Distinct alterations of macrophages in the uterus, ovaries, and VAT are also found in DHT-exposed mice and can potentially be linked to PCOS-like traits of the model. Indeed, androgen-exposed mice are insulin-resistant, albeit unaltered fat mass. Collectively, it is demonstrated that hyperandrogenism causes tissue-specific alterations of immune cells in reproductive organs and VAT, which can have considerable implications on tissue function and contribute to the reduced fertility and metabolic comorbidities associated with PCOS.

Creating Designer Engineered Extracellular Vesicles for Diverse Ligand Display, Target Recognition, and Controlled Protein Loading and Delivery.

Efficient and targeted delivery of therapeutic agents remains a bottleneck in modern medicine. Here, biochemical engineering approaches to advance the repurposing of extracellular vesicles (EVs) as drug delivery vehicles are explored. Targeting ligands such as the sugar GalNAc are displayed on the surface of EVs using a HaloTag-fused to a protein anchor that is enriched on engineered EVs. These EVs are successfully targeted to human primary hepatocytes. In addition, the authors are able to decorate EVs with an antibody that recognizes a GLP1 cell surface receptor by using an Fc and Fab region binding moiety fused to an anchor protein, and they show that this improves EV targeting to cells that overexpress the receptor. The authors also use two different protein-engineering approaches to improve the loading of Cre recombinase into the EV lumen and demonstrate that functional Cre protein is delivered into cells in the presence of chloroquine, an endosomal escape enhancer. Lastly, engineered EVs are well tolerated upon intravenous injection into mice without detectable signs of liver toxicity. Collectively, the data show that EVs can be engineered to improve cargo loading and specific cell targeting, which will aid their transformation into tailored drug delivery vehicles.

The role of B cells in immune cell activation in polycystic ovary syndrome.

Variations in B cell numbers are associated with polycystic ovary syndrome (PCOS) through unknown mechanisms. Here, we demonstrate that B cells are not central mediators of PCOS pathology and that their frequencies are altered as a direct effect of androgen receptor activation. Hyperandrogenic women with PCOS have increased frequencies of age-associated double-negative B memory cells and increased levels of circulating immunoglobulin M (IgM). However, the transfer of serum IgG from women into wild-type female mice induces only an increase in body weight. Furthermore, RAG1 knockout mice, which lack mature T- and B cells, fail to develop any PCOS-like phenotype. In wild-type mice, co-treatment with flutamide, an androgen receptor antagonist, prevents not only the development of a PCOS-like phenotype but also alterations of B cell frequencies induced by dihydrotestosterone (DHT). Finally, B cell-deficient mice, when exposed to DHT, are not protected from developing a PCOS-like phenotype. These results urge further studies on B cell functions and their effects on autoimmune comorbidities highly prevalent among women with PCOS.

Polycystic ovary syndrome is a lifelong condition associated with disrupted hormone levels, which affects around 15-20% of women. Characterised by increased levels of male sex hormones released by ovaries and adrenal glands, the condition affects menstrual cycles and can cause infertility and diabetes. Alongside the increase in male sex hormones, changes in the number of B cells have recently been observed in polycystic ovary syndrome. B cells produce antibodies that are important for fighting infection. However, it is thought that they might aggravate the condition by releasing antibodies and other inflammatory molecules which instead attack the body. It remained unclear whether changes in the B cell numbers were a result of excessive hormone levels or whether the B cells themselves were responsible for increasing the levels of male sex hormones. Ascani et al. showed that exposing female mice to excess male sex hormones leads to symptoms of polycystic ovary syndrome and causes the same changes to B cell frequencies as observed in women. This effect was prevented by simultaneously treating mice with a drug that blocks the action of male sex hormones. On the other hand, transferring antibodies from women with polycystic ovary syndrome to mice led to greater body weight and variation in B cell numbers. However, it did not result in clear symptoms of polycystic ovary syndrome. Furthermore, mice without B cells still developed symptoms when exposed to male sex hormones, showing that B cells alone are not solely responsible for the development of the condition. Taken together, the experiments show that B cells are not central mediators of polycystic ovary syndrome and the variation in their numbers is due to excess male sex hormones. This raises the question of whether B cells are an appropriate target for the treatment of this complex condition and paves the way for studies on how other immune cells are altered by hormones. Future work should also investigate how B cell function affects symptoms associated with polycystic ovary syndrome, given the association between antibody transfer and weight gain in mice.

Yoga Practice Reduces the Psychological Distress Levels of Prison Inmates.

Background: Psychiatric ill-health is prevalent among prison inmates and often hampers their rehabilitation. Rehabilitation is crucial for reducing recidivistic offending. A few studies have presented evidence of the positive effect of yoga on the well-being of prison inmates. The conclusion of those previous studies that yoga is an effective method in the rehabilitation process of inmates, and deserves and requires further attention. Aims: The current study aimed to evaluate the effect of 10 weeks of yoga practice on the mental health profile, operationalized in the form of psychological distress, of inmates. Methods: One hundred and fifty-two volunteer participants (133 men; 19 women) were randomly placed in either of two groups: to participate in weekly 90-min yoga class (yoga group) or a weekly 90-min free-choice physical exercise (control group). The study period lasted for 10 weeks. Prior to and at the end of the study period the participants completed a battery of self-reported inventories, including the Brief Symptom Inventory (BSI). Results: Physical activity (including yoga) significantly reduced the inmates' levels of psychological distress. Yoga practice improved all primary symptom dimensions and its positive effect on the obsessive-compulsive, paranoid ideation, and somatization symptom dimensions of the BSI stayed significant even when comparing with the control group. Conclusions: Yoga as a form of physical activity is effective for reducing psychological distress levels in prison inmates, with specific effect on symptoms such as suspicious and fearful thoughts about losing autonomy, memory problems, difficulty in making decisions, trouble concentrating, obsessive thought, and perception of bodily dysfunction.

Macrophages of distinct origins contribute to tumor development in the lung.

Tissue-resident macrophages can self-maintain without contribution of adult hematopoiesis. Herein we show that tissue-resident interstitial macrophages (Res-TAMs) in mouse lungs contribute to the pool of tumor-associated macrophages (TAMs) together with CCR2-dependent recruited macrophages (MoD-TAMs). Res-TAMs largely correlated with tumor cell growth in vivo, while MoD-TAMs accumulation was associated with enhanced tumor spreading. Both cell subsets were depleted after chemotherapy, but MoD-TAMs rapidly recovered and performed phagocytosis-mediated tumor clearance. Interestingly, anti-VEGF treatment combined with chemotherapy inhibited both Res and Mod-TAM reconstitution without affecting monocyte infiltration and improved its efficacy. Our results reveal that the developmental origin of TAMs dictates their relative distribution, function, and response to cancer therapies in lung tumors.