Testicular inflammation is a cause of fertility disturbance in men with fibrosis being a common observation. Experimental autoimmune orchitis (EAO) in mice reflects this immunopathology (1). Yet the cells responsible for production of extracellular matrix components (ECMC) in testicular inflammation are unknown, but resident fibroblasts or peritubular cells (PTCs) are potential sources. Activins (Transforming growth factor-β superfamily members) regulate fibrosis in many tissues and control spermatogenesis and steroidogenesis in the normal testis. Activin A levels increase substantially during murine EAO, prompting the question of its involvment in the subsequent fibrosis.
Accordingly, we investigated the pro-fibrotic actions of activin A in isolated adult mouse PTCs and 3T3 fibroblasts. Activin A increased fibronectin mRNA levels, and production of collagen type I and fibronectin proteins in both PTC and 3T3 fibroblasts. Activin A also increased α-smooth muscle actin protein and mRNA expression in 3T3 fibroblasts, and collagen type IV mRNA levels in PTCs. Follistatin-288, an activin A antagonist, inhibited these effects. Furthermore, treatment with tumour necrosis factor (TNF) caused an increase of activin A production by isolated mouse Sertoli cells (SC) in vitro. Since TNF is elevated during the course of murine EAO (1), this indicates a role for activin production by SC in response to TNF in the outcome of testicular inflammation.
In line with our EAO model, where Inhba mRNA levels were correlated with collagen and fibronectin deposition, EAO damage score and severity of fibrosis (1), collagen and fibronectin, as well as activin A (Inhba) mRNA, were found to be increased in human testicular biopsies containing lymphocytic infiltrates and impaired spermatogenesis.
These data indicate that both resident fibroblasts and PTCs may contribute to testicular fibrosis under activin A control, subsequent to inflammation. Antagonists of activin action may be beneficial as therapeutics in limiting fertility impairment in patients with testicular inflammation.