Testosterone Influence on Gene Expression in Lacrimal Glands of Mouse Models of Sjögren Syndrome

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Of interest to patients experiencing or aware of the dry eye presentation in PFS.

One leading cause of aqueous-deficient dry eye disease (ADDE) in humans is Sj¨ogren syndrome (SS).1 This autoimmune disease occurs almost exclusively in women and is associated with an extensive inflammation in the lacrimal gland, immune-mediated destruction and/or dysfunction of glandular epithelial cells, and significant decrease in aqueous tear output.

Of particular interest, androgen deficiency appears to have an important role in the development of lacrimal gland inflammation and ADDE in SS. androgen levels in women with SS are significantly decreased.8–10 We hypothesized that this reduction predisposes to lacrimal gland dysfunction, attenuated tear secretion, and ADDE. In support of our hypothesis, we discovered that testosterone administration to female mouse models of SS (e.g., MRL/MpJ-Tnfrsf6lpr [MRL/lpr] and NZB/NZW F1) suppresses inflammation in, and increases the functional activity of, lacrimal tissue.7,11–15 Similarly, topical and/or systemic androgen treatment appears to completely resolve lacrimal gland inflammation in dry eye dogs,16,17 and to alleviate dry eye signs and symptoms and promote tear flow in SS patients.5

To begin to test this hypothesis, we examined the nature and magnitude of testosterone’s influence on immune-related gene expression in the autoimmune lacrimal tissues of female MRL/lpr mice after onset of disease. We chose the MRL/lpr strain because, like in humans, the extent of lacrimal and salivary gland inflammation in MRL/lpr mice is far greater in females compared to males,18 and is dramatically reduced in response to androgen treatment.7,11–14

For comparative purposes, we also analyzed and compared the androgen impact on immune gene expression in lacrimal glands of female nonobese diabetic/LtJ (NOD) mice after onset of disease. These mice, which are an established model for type-1 insulin-dependent diabetes mellitus,19 have been used as a model for Sj¨ogren syndrome20–22 and, like in humans, have far greater inflammation in the salivary glands of females compared to males.18 However, unlike humans, the lacrimal glands of male NOD mice have significantly higher inflammation than those of females.18,23–25 Indeed, orchiectomy of NOD mice attenuates, whereas androgen treatment of castrated NOD males induces, lymphocyte accumulation in their lacrimal glands.23 This anomalous hormone effect is mediated through the lacrimal microenvironment24 and contrasts with the androgen-induced decrease in inflammation in salivary and pancreatic tissues in these mice.26,27 Given this background, we hypothesized that androgen exposure will significantly increase the expression and/or activity of immune-related genes in the lacrimal glands of female NOD mice. We also hypothesized that these opposing actions of androgens in female MRL/lpr and NOD lacrimal tissues involve regulation of similar immune-related genes, ontologies, and pathways.

Our study was prompted by our earlier discovery that androgens, but not estrogens, dramatically suppress the inflammation in lacrimal tissues of the female MRL/lpr and NZB/NZW FI mouse models of SS.11–14 We hypothesized that this androgen effect involves an alteration in the expression and/or activity of immune-related genes, because such genes are critically important in innate and adaptive immune responses.42 These genes might also have a major role in promoting the multiple immunosuppressive actions of androgens, including those directly on T cells, monocytes, macrophages, neutrophils, and B cell precursors, and indirectly on peripheral B cells.43,44 These androgen actions lead to regulation of the maturation, proliferation, migration, and/or function of immune cells; synthesis and secretion of antibodies, cytokines, adhesion molecules, and proto-oncogenes; and expression of autoantigens.2,43,44 A result is that androgens are protective in SS, as well as in other autoimmune diseases, such as systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis.2,5,6,43

androgen decreased the expression of multiple immune-related genes in lacrimal tissues of female MRL/lpr mice, and T increased the expression of these immune genes, which are typically expressed in NOD males,30 in female NOD lacrimal tissues. We also discovered that many of these regulated genes are the same as those typically highly expressed in inflamed compared to noninflamed lacrimal glands.

Our evidence indicates that this hormone action is a unique, tissue-specific effect, which is initiated through androgen binding to specific receptors in lacrimal gland epithelial cells.7 In addition, we hypothesize that this androgen interaction then elicits the altered expression and/or activity of immune-related genes in lacrimal tissue, leading to a decrease in immunopathologic lesions and an improvement in glandular function.

What, then, is that possible on/off switch? We hypothesized that this switch, which may comprise a single or multiple genes, is triggered by an androgen–androgen receptor interaction within lacrimal gland epithelial cell nuclei.

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