Differential effects of activin A on macrophage responses: Implications for testis immunology

Abstract

The immune privilege of the testis facilitates the protection of the germ cells from autoimmune reactions and inflammatory damage in case of an infection. The macrophages, which comprise the majority of immune cells present in the testis, help facilitate immune privilege with their immunosuppressive phenotype. How exactly this phenotype is obtained, however, remains to be elucidated. The immunoregulatory Sertoli cells potentially express a factor driving the macrophage polarisation towards an anti-inflammatory phenotype. One factor secreted by the Sertoli cells, which could possibly be involved in the immunoregulatory phenotype of testicular macrophages is activin A. Activin A has previously been shown to be involved in many biological processes including immunoregulatory functions and can elicit pro- as well as anti-inflammatory responses. To assess the influence of activin A on macrophage phenotype, several different macrophage models were investigated in vitro. The phenotype and the possible influence on the immune responses was assessed in activin A-treated macrophages in a resting, as well as lipopolysaccharide-activated state with several different markers at the gene expression and protein level, as well as regarding possible metabolic implications. This study revealed, that activin A elicits differential effects on commonly used murine macrophage models, depending on their origin or maturity, the context and time points of the treatments, as well as the factors which were investigated. Generally, activin A appeared to induce a more pro-inflammatory phenotype in macrophage colony-stimulating factor-differentiated primary bone marrow-derived macrophages, while it could reduce pro-inflammatory responses in two murine cell lines tested. Additionally, it was demonstrated that activin A can alleviate the pro-inflammatory metabolic switch in activated macrophages in an immortalised bone marrow-derived macrophage cell line. Given the opposing findings of the effects of activin A in different macrophage in vitro cultures, results obtained with these commonly utilised models need to be assessed and evaluated with caution. This study demonstrates the complex actions of activin A in immune responses and suggests that activin A may also influence the microenvironment in the testis facilitating the immunoregulatory phenotype of testicular macrophages, supporting homeostasis and protection from inflammatory damage.