Testicular activin and follistatin levels are elevated during the course of experimental autoimmune epididymo–orchitis in mice

Abstract

Experimental autoimmune epididymo-orchitis (EAEO) is a model of chronic inflammation, induced by immunisation with testicular antigens, which reproduces the pathology of some types of human infertility. Activins A and B regulate spermatogenesis and steroidogenesis, but are also pro-inflammatory, pro-fibrotic cytokines. Expression of the activins and their endogenous antagonists, inhibin and follistatin, was examined in murine EAEO. Adult untreated and adjuvant-treated control mice showed no pathology. All mice immunised with testis antigens developed EAEO by 50 days, characterised by loss of germ cells, immune cell infiltration and fibrosis in the testis, similar to biopsies from human inflamed testis. An increase of total CD45+ leukocytes, comprising CD3+ T cells, CD4 + CD8− and CD4 + CD25+ T cells, and a novel population of CD4 + CD8+ double positive T cells was also detected in EAEO testes. This was accompanied by increased expression of TNF, MCP-1 and IL-10. Activin A and B and follistatin protein levels were elevated in EAEO testes, with peak activin expression during the active phase of the disease, whereas mRNA expression of the inhibin B subunits (Inha and Inhbb) and activin receptor subunits (Acvr1b and Acvr2b) were downregulated. These data suggest that activin–follistatin regulation may play a role during the development of EAEO.

Infectious, inflammatory and ‘autoimmune’ male factor infertility: how do rodent models inform clinical practice?

“…Interestingly, in our mouse model of EAO, highly elevated numbers of CD4+ T cells, while reduced numbers of CD8+ T cells were detected, confirmed by a higher ratio of CD4+/CD8+ T cells in the testis. Moreover, a new population of double positive CD4+CD8+ T cells was identified in mouse EAO testis, previously identified in different organs with autoimmune disorders ( Nicolas et al , 2017a ). Although, the increased accumulation of various immunoregulatory T cell subtypes, such as CD4+CD25+Foxp3+, CD4+Foxp3+ and CD8+Foxp3+ T cells, has been reported in chronically inflamed rat testes, these cells were not able to suppress inflammatory responses generated by the effector T cells during the onset of EAO ( Guazzone et al , 2009 ; Fijak et al , 2011 ).…”

“…Later stages of the disease are characterized by disruption of the BTB, extensive necrosis and fibrosis of seminiferous tubules ( Doncel et al , 1989 ; Lustig et al , 1993 ; Tung and Teuscher, 1995 ; Perez et al , 2012 ; Nicolas et al , 2017a ) (Fig. 3 E and F).…”

Cytokines in Male Fertility and Reproductive Pathologies: Immunoregulation and Beyond

“…Affected tubules show degeneration of the germinal epithelium sparing few spermatogonia and Sertoli cells; concomitant thickening of the lamina propria may result in complete fibrosis of the tubules accompanied by increased collagen production (“tubular shadows”) ( 123 ). Notably, these are typical morphological features of experimental autoimmune orchitis (EAO) ( 124 – 127 ). Consistent with relevant animal models, infiltrating lymphocytes are primarily effector memory T cells (CD45R0+; CD4+>CD8+), which are accompanied by increased numbers of non-resident CD68+ macrophages and mast cells ( 58 , 123 , 128 – 132 ).…”

“…Besides cytokines and chemokines, other pro-inflammatory molecules, such as high-mobility group box protein 1, are involved in the regulation of inflammatory reactions in rat and human testis and might serve as targets for therapeutic intervention ( 150 ). In addition, involvement of galectin-1, activins, and inhibin in the development of testicular immunopathology is documented ( 127 , 151 – 153 ).…”

“…Future developments may include application of anti-fibrotic treatments to prevent long-term testicular damage, emerging from investigations of agents that block TGFβ and activin signaling in the testis and epididymis during key stages of infection [e.g., Ref. ( 127 , 169 )].…”