Induction of experimental autoimmune orchitis in mice: responses to elevated circulating levels of the activin-binding protein, follistatin

Reproduction. 2017 Sep;154(3):293-305. doi: 10.1530/REP-17-0010. Epub 2017 Jun 30.

Abstract

Experimental autoimmune orchitis (EAO) is a rodent model of chronic testicular inflammation that mimics the pathology observed in some types of human infertility. In a previous study, testicular expression of the inflammatory/immunoregulatory cytokine, activin A, was elevated in adult mice during the onset of EAO, indicating a potential role in the regulation of the disease. Consequently, we examined the development of EAO in mice with elevated levels of follistatin, an endogenous activin antagonist, as a potential therapeutic approach to testicular inflammation. Prior to EAO induction, mice received a single intramuscular injection of a non-replicative recombinant adeno-associated viral vector carrying a gene cassette of the circulating form of follistatin, FST315 (FST group). Serum follistatin levels were increased 5-fold in the FST group compared with the control empty vector (EV) group at 30 and 50 days of EAO, but intra-testicular levels of follistatin or activin A were not significantly altered. Induction of EAO was reduced, but not prevented, with mild-to-severe damage in 75% of the EV group and 40% of the FST group, at 50 days following immunisation with testicular homogenate. However, the EAO damage score (based on disruption of the blood-testis barrier, apoptosis, testicular damage and fibrosis) and extent of intratesticular inflammation (expression of inflammatory mediators) were directly proportional to the levels of activin A measured in the testis at 50 days. These data implicate activin A in the progression of EAO, thereby providing a potential therapeutic target; however, elevating circulating follistatin levels were not sufficient to prevent EAO development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins / antagonists & inhibitors
  • Activins / metabolism
  • Animals
  • Apoptosis*
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / metabolism
  • Autoimmune Diseases / pathology
  • Autoimmune Diseases / physiopathology*
  • Biomarkers / blood
  • Biomarkers / metabolism
  • Blood-Testis Barrier / immunology
  • Blood-Testis Barrier / metabolism
  • Blood-Testis Barrier / pathology
  • Blood-Testis Barrier / physiopathology
  • Disease Models, Animal*
  • Disease Progression
  • Fibrosis
  • Follistatin / administration & dosage
  • Follistatin / blood*
  • Follistatin / genetics
  • Follistatin / metabolism
  • Gene Expression Regulation
  • Gene Transfer Techniques
  • Inflammation Mediators / metabolism
  • Male
  • Mice, Inbred C57BL
  • Orchitis / immunology
  • Orchitis / metabolism
  • Orchitis / pathology
  • Orchitis / physiopathology*
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / blood
  • Recombinant Proteins / metabolism
  • Testis / immunology
  • Testis / metabolism*
  • Testis / pathology
  • Up-Regulation*

Substances

  • Biomarkers
  • Follistatin
  • Inflammation Mediators
  • Recombinant Proteins
  • activin A
  • Activins