This pattern was corroborated by Reactome, Biocarta, and Gene Ontology Biological Process (GOBP) analyses, which indicated decreased proliferation and enhanced immune activity (Figure 4C+D, Supplementary Figure S4D+E, and Supplementary Tables T7–T9). (F) Heatmap indicates log2 expression (TPM+1) of Ar, Esr1 and Esr2 (upper panel). Low reads for CD3e, Adgre1 (F4/80) and Lrrc26 confirmed the purity of the NK cell isolates. Knowledge of group allocation was unavoidable during the experimental procedures and euthanasia, but following data collection, analyses were performed while the participants were blinded to group affiliation wherever possible to minimize bias. The data are presented as median with individual values or standard error. To investigate whether sexual hormones might have an influence on ALA development, gonadectomy was performed in groups of 8 weeks old male and female mice. The Mann Whitney U test was applied to compare the liver abscess sizes between male and female mice over the time period monitored and the Paired t-test was used to determine the difference between abscesses that were culture positive for E. In this communication, we report on the use of the C57BL/6 ALA mouse model to analyze the role of sexual hormones for ALA susceptibility and provide evidence that testosterone increases susceptibility for ALA by modulation the secretion of IFNγ by EhLPPG-activated NKT cells. In this mouse model, female mice are able to clear parasites injected into the liver within 3 days, whereas in male mice viable ameba can be isolated up to 14 days. One of the main producer of IFNγ in early response to microbial infections are natural killer T (NKT) cells, which are immune cells, bridging the early innate and the adaptive immune response. Effects of dopamine, epinephrine, and glucocorticoids on NK cell activities. Approximately 40 years ago, GCs were shown to have an inhibitory effect on NK cell functions.33,34,35 This finding has been confirmed by many labs, and more details about the effect of GCs on NK cell reactivity have been reported.34,36,37,38,39,40,41 Through binding to GC receptors, GCs typically alter gene transcription. During this response, the hypothalamus is activated, resulting in the release of corticotropin-releasing hormone (CRH). Glucocorticoids (GCs) are steroid hormones that are released during the so-called stress response by activation of the hypothalamic–pituitary–adrenal (HPA) axis (Fig. 2). As the regulation of helper ILCs by neurotransmitters and neuropeptides has been the subject of several recent reviews,31 we will focus here on the regulation of NK cell activities by the nervous system. Within this synapse, activating and inhibitory NK cell receptors can interact with their respective ligands on the target cell. Many examples have shown that the nervous system and the immune system interact and thereby influence each other’s activity. Using an AIRE deficient in vivo mouse model, a link between sex biased AIRE expression and increased susceptibility of males to experimental autoimmune thyroiditis (EAT) was established (90). The role of androgens was confirmed by orchiectomy, where the lack of male hormones phenocopied female AIRE expression levels. These data suggest that low testosterone levels could enhance immune response by increasing circulating (activated) CD16+ DCs (80). Moreover, in female ARKO mice, the average number of pups per litter is lower than in WT female mice, regardless of homo- or heterozygous genotype, pointing to possible defects in female ovulation and fertility (41). A phenotypic analysis performed in ARKO male mice showed that they have a female-like appearance and reduced body weight, compared to male wild-type (WT) mice. Partial androgen insensitivity syndrome (PAIS) is characterized by impaired male genitalia development, showing external genital feminization and secondary sexual characteristics like breast development. Since males carry one copy of X chromosome, AR mutations with functional consequences are definitely expressed in all cells of affected males. The effect of testosterone treatment on the bone of women with low serum levels of this hormone is not clear but probably small. It was found that male mice had higher numbers of aromatase-positive neurons in the areas of the brain responsible for modulating aggressive and sexual behavior. Androgens, mainly testosterone and DHT, are the male sex hormones required for development of the male reproductive system and secondary sexual characteristics. They play a crucial role in regulating type 2 inflammation in response to infections with parasites and can promote allergic processes. Passive immunotherapies comprise monoclonal antibodies that target tumor specific antigens. Many different types of cancer immunotherapies exist and are divided in two groups according to their passive or active nature. Castration resistant prostate cancer (CRPC) becomes evident after a median of 18–24 months of ADT. These results underline the necessity to develop new selective drugs to specifically target stromal AR in prostate tumors, at least at early stages (131). Based on the NK cell yields from each mouse, cell suspensions were prepared for use in killing assays. Positive isolation was performed to obtain a pure NK cell suspension. All procedures were performed under light anesthesia with 9% (v/v) desflurane (Baxter) in 30/10% (v/v) oxygen/air, and the mice were continuously warmed at 37 °C. The human SU.86.86 cell line (ATCC) was cultivated in RPMI supplemented with 10% FBS and 1% penicillin–streptomycin. The mouse KPC3595 cell line42 was kindly provided by Ivonne Regel, Institute of Tumor Immunology, Medical Faculty of the Martin Luther University Halle-Wittenberg. For co-culture experiments, the culture medium of the target cell line was used. This study supports a complex physiological role for T and/or its metabolites in immune regulation. Amer J, Salhab A, Snobar H and Alhabil Y (2023) The immune and metabolic treatment approach of using testosterone on mice models of liver injury. We assessed serum IL-6 levels, the activity of isolated liver tissue-resident NK (trNK) cells, and the expression of IL-6 receptors on trNK cells. A Mann-Whitney U test was performed to evaluate whether the mice metabolic panel elements (ALT, AST, Cholesterol, Triglyceride, and FBS levels) were altered following testosterone treatment in both the acute and chronic liver injury groups. In our current study, we aimed to assess the molecular and metabolic aspects of testosterone and their modulatory effects on liver tissue-resident NK cells’ phenotype activations in mice models of liver injury. However, Hsu et al used several mouse models and found that PD-1 was also expressed on NK cells, and PD-L1 expression on tumor cells led to impaired NK cell immune effect, thus the generation of more aggressive tumors . It was reported that PD-L1 expression in cancer cells could lead to reduced NK cell responses via altering the PD-1/PD-L1 inhibitory axis .
