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

View Article: PubMed Central - PubMed

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.

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Distribution of α-smooth muscle actin (αSMA) in paraffin sections from untreated (a,e,i,m), adjuvant control (b,f,j,n), low grade (c,g,k,o) and severe EAEO (d,h,l,p) testis at 30 (a–d), 50 (e–h) and 80 (i–l) days after the first immunisation. Panels m–p represent a higher magnification of images i–l. In the testis from untreated and adjuvant controls, αSMA is localised in the peritubular cells as a thin layer, but in low grade and severe EAEO testis, the αSMA is diffusely distributed within the cell. αSMA is also seen in the blood vessels (asterisks) within the testis. Scale bars represent 100 μm.
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f6: Distribution of α-smooth muscle actin (αSMA) in paraffin sections from untreated (a,e,i,m), adjuvant control (b,f,j,n), low grade (c,g,k,o) and severe EAEO (d,h,l,p) testis at 30 (a–d), 50 (e–h) and 80 (i–l) days after the first immunisation. Panels m–p represent a higher magnification of images i–l. In the testis from untreated and adjuvant controls, αSMA is localised in the peritubular cells as a thin layer, but in low grade and severe EAEO testis, the αSMA is diffusely distributed within the cell. αSMA is also seen in the blood vessels (asterisks) within the testis. Scale bars represent 100 μm.

Mentions: In order to investigate the peritubular fibrotic response observed in EAEO testis, an analysis of α-smooth muscle actin (αSMA) localisation and distribution by immunofluorescence staining was performed (Fig. 6). The staining revealed a change in the distribution of the αSMA layer in low grade EAEO at 30, 50 and 80 days (Fig. 6c,g,k,o) in areas where the seminiferous tubules were smaller and spermatogenesis was disrupted. The altered distribution and thickening of the αSMA layer was more pronounced in severe EAEO at 30, 50 and 80 days (Fig. 6d,h,l,p). The layer of αSMA was diffusely distributed within the peritubular cells in EAEO testes compared to a thin and compact layer in untreated and adjuvant control testes. The same altered distribution of the layer of αSMA was also observed in human testis samples with focal inflammatory lesions and impaired spermatogenesis (Supplementary Fig. S1).


Testicular activin and follistatin levels are elevated during the course of experimental autoimmune epididymo – orchitis in mice
Distribution of α-smooth muscle actin (αSMA) in paraffin sections from untreated (a,e,i,m), adjuvant control (b,f,j,n), low grade (c,g,k,o) and severe EAEO (d,h,l,p) testis at 30 (a–d), 50 (e–h) and 80 (i–l) days after the first immunisation. Panels m–p represent a higher magnification of images i–l. In the testis from untreated and adjuvant controls, αSMA is localised in the peritubular cells as a thin layer, but in low grade and severe EAEO testis, the αSMA is diffusely distributed within the cell. αSMA is also seen in the blood vessels (asterisks) within the testis. Scale bars represent 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5304336&req=5

f6: Distribution of α-smooth muscle actin (αSMA) in paraffin sections from untreated (a,e,i,m), adjuvant control (b,f,j,n), low grade (c,g,k,o) and severe EAEO (d,h,l,p) testis at 30 (a–d), 50 (e–h) and 80 (i–l) days after the first immunisation. Panels m–p represent a higher magnification of images i–l. In the testis from untreated and adjuvant controls, αSMA is localised in the peritubular cells as a thin layer, but in low grade and severe EAEO testis, the αSMA is diffusely distributed within the cell. αSMA is also seen in the blood vessels (asterisks) within the testis. Scale bars represent 100 μm.
Mentions: In order to investigate the peritubular fibrotic response observed in EAEO testis, an analysis of α-smooth muscle actin (αSMA) localisation and distribution by immunofluorescence staining was performed (Fig. 6). The staining revealed a change in the distribution of the αSMA layer in low grade EAEO at 30, 50 and 80 days (Fig. 6c,g,k,o) in areas where the seminiferous tubules were smaller and spermatogenesis was disrupted. The altered distribution and thickening of the αSMA layer was more pronounced in severe EAEO at 30, 50 and 80 days (Fig. 6d,h,l,p). The layer of αSMA was diffusely distributed within the peritubular cells in EAEO testes compared to a thin and compact layer in untreated and adjuvant control testes. The same altered distribution of the layer of αSMA was also observed in human testis samples with focal inflammatory lesions and impaired spermatogenesis (Supplementary Fig. S1).

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus