Testosterone is an endogenous regulator of BAFF and splenic B cell number Nature Communications

Testosterone reduced the number of splenic B cells only in the controls (Fig. 1c). Male G-ARKO mice had 1.8-fold more B cells in the spleen than littermate controls (with the Pgk1-Cre construct only) (Fig. 1a, b). Indeed, a variant in the BAFF gene has been coupled to soluble BAFF levels, blood B cell levels, and increased risk of multiple sclerosis and SLE15. BAFF deficiency in mice results in an arrest at the transitional B cell stage in the spleen13 and thus a lack of mature B cells. Notably, while O-ARKO mice mimic the bone marrow B cell pattern of G-ARKO, they display unaltered numbers of mature B cells in the spleen11. testosterone order deficiency induced by castration also increases disease activity in mouse models of autoimmune disease such as experimental autoimmune glomerulonephritis and lupus4,5, and androgen treatment improves survival in male lupus NZB/NZW F1 mice6. Here we show that testosterone regulates the cytokine BAFF, an essential survival factor for B cells.
In three initial Sertoli cell specific AR knock out mice (SCARKO) models 44, 45, 48, the number of Sertoli cells was normal and the cells underwent appropriate maturation with the correct timing during puberty. In agreement with this idea, AR was not eliminated in all Leydig cells and AR was lost in some Sertoli cells of the LC-ARKO mice. Circulating testosterone concentrations in PTM-ARKO mice are within the normal range, but only because of increased LH input. PTM-ARKO mice have normal numbers of adult Leydig cells but, there are also significant numbers of precursor Leydig cells present in adult mice 77, 78.
Exposure of the enriched cells to the α- adrenergic agonist phenylephrine for 48 h reduced the number of stromal cells in a dose-dependent manner (Fig. 6c). D–g Proportion of annexin V+ cells (d), carboxyfluorescein succinimidyl ester (CFSE) content in the cells (e), and number of FRCs (f, g) after exposure to phenylephrine (10−4 M) with or without phentolamine (10−5 M) for 48 h. C Primary splenic stromal cell number after exposure to the α-adrenergic agonist phenylephrine (10−6–10−4 M) and/or the α-adrenergic antagonist phentolamine (10−7–10−5 M) for 48 h. Other α- and β-adrenergic and dopaminergic receptors were found at lower levels and therefore were not likely expressed (Fig. 6a). Robust expression of classical FRC genes such as Ccl19, Ccl21a, Cxcl13 and Tnfsf13b (Baff) suggested these were bona fide splenic FRC (Supplementary Fig. 6d). To determine whether splenic FRCs express adrenergic receptors, we sorted splenic FRCs by FACS (Supplementary Fig. 6a, b).
Inhibitors that target alternative functional domains (N-terminal domain, DNA-binding domain) of the protein are still under development. Aberrant androgen receptor coregulator activity may contribute to the progression of prostate cancer. In humans, the androgen receptor is encoded by the AR gene located on the X chromosome at Xq11–12.
However, in C57BL/6 mice harboring the Sle1 lupus susceptibility allele, ERα signaling increases in females, favoring the activation of B cells through an increase in B220+CD86+ and B220+CD22+ cells (144). In MRL and MRL/Faslpr/lpr mice, elevated levels of PRL decrease the absolute numbers of pro-B and immature cells in both strains and increase the expression of the antiapoptotic molecule BIRC5 (mRNA) in pro-B (MRL/Faslpr/lpr) and immature cells (MRL and MRL/Faslpr/lpr) (42). Similarly, PRL also increases the expression of Bcl-2 in the splenic B cells of R4A-γ2b mice (138). Furthermore, in splenic B cells from BALB/c mice, the expression of AID mRNA was reduced in vitro in the presence of P4 (73); therefore, it could induce a decrease in isotype switching. It is probable that testosterone interferes during the early stages of B-cell development, since in castrated C57BL/6 mice, the number of newly migrated B cells from the BM (B220lowCD24high) increases, as does the number of early-stage pro-B cells in the BM (101). Furthermore, understanding the role of B cells in autoimmune diseases and the subsequent production of pathogenic autoantibodies enables us to understand how hormonal regulation of B cell-intrinsic signals (ontogeny and function) may contribute to autoimmunity pathogenesis.
Rhox5, is an example of a highly induced gene by testosterone (up to 50-fold) that supports cellular metabolism and insulin signaling plus produces factors required by germ cells including Ins2 . PCI encodes a serine protease inhibitor and PCI knockout mice have spermatogenesis defects including detached germ cells, disruption of the BTB and damage to Sertoli cells. Until recently, all survey studies employing mouse models in which AR is absent or inactive specifically in Sertoli cells assayed mRNA levels in extracts from total testis, which may have limited the detection of differences in cell specific gene expression. Although specific knock out of AR has been studied in every cell in the testis, nearly all testosterone-mediated gene expression information related to spermatogenesis has been limited to Sertoli cells. Mice in which testosterone levels were depleted or enhanced in all cells were the first models used to assay gene expression in the testis. Germ cell development from the meiotic pachytene spermatocyte stage onward was accelerated in the TgSCAR in agreement with the idea that the meiosis is regulated by testosterone order signaling in Sertoli cells.
Studies have shown small or inconsistent correlations between testosterone levels and male orgasm experience, as well as sexual assertiveness in both sexes. 2020 guidelines from the American College of Physicians support the discussion of testosterone treatment in adult men with age-related low levels of testosterone who have sexual dysfunction. Decline of testosterone production with age has led to interest in androgen replacement therapy. The brain is also affected by this sexual differentiation; the enzyme aromatase converts testosterone into estradiol that is responsible for masculinization of the brain in male mice.
Like in SLE, it is suggested that PRL favors the maturation of autoreactive clones of B cells that evade central tolerance mechanisms and induce the maturation of autoantibody-producing cells. Therefore, B cells from patients with MS and hyperprolactinemia are less susceptible to apoptosis. It is important to emphasize the importance of the protective effect of estrogens through the mechanisms of regulatory cells. Furthermore, estrogens can also contribute to CNS neuroprotection by promoting the anti-inflammatory M2 phenotype of microglia, which favors an increase in the percentage of CD19+CD9+IL-10+ regulatory B cells (175). Thus, estrogens have a protective effect against EAE and its clinical manifestations, such as dysbiosis, output.jsbin.com through increasing the percentage of regulatory B cells and enriching a favorable microbiome (179).
In free-ranging baboons, where success in male-male physical conflict determines males’ reproductive access to females, high status males – who have higher testosterone than subordinate males (Gesquiere et al. 2011) – heal faster than subordinates (Archie et al. 2012), perhaps because of positive phenotypic correlation. The ability to mount a rapid response to local infection or tissue injury is of particular utility, as high testosterone males more frequently engage in aggressive physical competition with other males (Archer 2006). If only the energetically costlier forms of immunity are downregulated in higher testosterone males, then energetic availability may underlie some of the associations reported in the literature. Numerous cytokines, for example, play critical roles in immune cell signaling and lymphocyte differentiation and have varying impacts on physiology and varying energetic costs (Table 1). While meta-analyses suggest that testosterone is overall immunosuppressive (Foo et al. 2016), there is still ambiguity depending on which aspects of immune function are studied, and whether the impacts of testosterone on immune function are direct or indirect. These findings are bolstered by experimental work in a reptile model showing that immune function is enhanced when exogenous testosterone is paired with food supplementation, but without food supplementation exogenous testosterone results in decreased innate immune function (Ruiz et al. 2010). However, recent studies and meta-analyses find mixed evidence that endogenous testosterone is an active immunosuppressant in free-living mammals (Foo et al. 2016; Nunn et al. 2009; Roberts et al. 2004).