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

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.

• Authors: Nour Nicolas, Julie A Muir, Susan Hayward, Justin L Chen, Peter G Stanton, Paul Gregorevic, David M de Kretser, Kate L Loveland, Sudhanshu Bhushan, Andreas Meinhardt, Monika Fijak, Mark P Hedger
• Journal: Reproduction (Cambridge, England) (Reproduction) Vol. 154 Issue 3 Pg. 293-305 (09 2017) ISSN: 1741-7899 [Electronic] England
• PMID: 28667125 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 Society for Reproduction and Fertility.

Chemical References

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

Topics

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