Endocrine Abstracts

JOINT2395

Background: The role of steroid hormones in the pathophysiology of neurological problems is well established, however, the mechanisms involved in their development are not well understood. More recently, there has been increasing evidence on the important involvement of brain immunity in health and disease. We aimed to study the role of steroid hormones in the regulation of neuro-immunity, using established zebrafish models of cortisol deficiency.

Methods: We analysed adult brains from two zebrafish lines with differentially impaired steroidogenesis: 21-hydroxylase deficiency (cyp21a2−/−), which are cortisol deficient and have normal sex hormones, and side-chain cleavage enzyme deficiency (cyp11a2−/−), which are deficient in both cortisol and sex hormones, developing as infertile males. We extracted brain RNA and conducted paired-end sequencing, followed by transcriptome study by Gene Set Enrichment Analysis (GSEA) to identify dysregulated biological processes.

Results: In the cyp21a2−/− zebrafish, we found that cortisol deficiency impacted on the regulation of immune processes within the brain in a sex-specific manner. When compared to wild-type (WT) siblings the brains of mutant males showed wide upregulation of the immune response, including biological processes involved in the immune cell chemotaxis, response to cytokines, response to other organisms. By contrast, these processes were downregulated in the cyp21a2−/− female brains and in the cyp11a2−/− brains. In addition, granulocyte activation and leukocyte differentiation were also upregulated in the cyp21a2−/− male brains, however, they were not found to be dysregulated in the other groups. We then compared male against female brain transcriptomes within the WT and cyp21a2−/− groups. Immune processes including the major histocompatibility (MHC) complex assembly, immune cell differentiation, activation, T-cell proliferation, response to biotic stimulus, macrophage migration, were downregulated in males compared to females only in WT fish, but not in cortisol deficient mutants. Moreover, leukocyte chemotaxis and migration were downregulated in WT males but upregulated in cyp12a2−/− males compared to females.

Conclusion: Our results indicate that cortisol deficiency has a different impact on the regulation of brain immunity in male zebrafish compared to females, or to androgen-deficient males. The differential dysregulation of the immune response in the brains of our mutant lines would indicate that androgens have a cortisol-dependent suppressive effect on brain immunity in zebrafish. Further research into the role of sex hormones and their relationship with glucocorticoids in regulating the immune response is warranted to better understand sex-specific patterns in the development of neurological conditions, and the relevance of replacement therapies in patients with steroid deficiencies.