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Th17 down-regulation is involved in reduced progression of schistosomiasis fibrosis in ICOSL KO mice.

Wang B, Liang S, Wang Y, Zhu XQ, Gong W, Zhang HQ, Li Y, Xia CM - PLoS Negl Trop Dis (2015)

Bottom Line: The results showed that ICOSL KO mice exhibited improved survival, reduced liver granulomatous inflammation around parasite eggs, markedly inhibited hepatic fibrosis development, lower levels of Th17-related cytokines (IL-17/IL-21), Th2-related cytokines (IL-4/IL-6/IL-10), a pro-fibrotic cytokine (IL-13), and TGF-β1, but higher level of Th1-related cytokine (IFN-γ) compared to wild-type (WT) mice.The reduced progression of fibrogenesis was correlated with the down-regulation of Th17 and Th2 and the elimination of ICOSL/ICOS interactions.Our findings suggest that IL-17-producing cells contribute to the hepatic granulomatous inflammation and subsequent fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Parasitology, Medical College of Soochow University, Suzhou,Jiangsu Province, The Peoples Republic of China.

ABSTRACT

Background: Granulomatous and fibrosing inflammation in response to parasite eggs is the main pathology that occurs during infection with Schistosoma spp. CD4+ T cells play critical roles in both host immune responses against parasitic infection and immunopathology in schistosomiasis,and coordinate many types of immune cells that contribute to fibrosis. ICOSL plays an important role in controlling specific aspects of T cell activation, differentiation, and function. Previous work has suggested that ICOS is essential for Th17 cell development. However, the immunopathogenesis of this pathway in schistosomiasis fibrosisis still unclear.

Methodology/principal findings: Using models of schistosomiasis in ICOSL KO and the C57BL/6 WT mice, we studied the role of the ICOSL/ICOS interaction in the mediation of the Th17 response in host granulomatous inflammation, particularly in liver fibrosis during S. japonicum infection, and investigated the immune responses and pathology of ICOSL KO mice in these models. The results showed that ICOSL KO mice exhibited improved survival, reduced liver granulomatous inflammation around parasite eggs, markedly inhibited hepatic fibrosis development, lower levels of Th17-related cytokines (IL-17/IL-21), Th2-related cytokines (IL-4/IL-6/IL-10), a pro-fibrotic cytokine (IL-13), and TGF-β1, but higher level of Th1-related cytokine (IFN-γ) compared to wild-type (WT) mice. The reduced progression of fibrogenesis was correlated with the down-regulation of Th17 and Th2 and the elimination of ICOSL/ICOS interactions.

Conclusions/significance: Our findings suggest that IL-17-producing cells contribute to the hepatic granulomatous inflammation and subsequent fibrosis. Importantly, there was a clearly positive correlation between the presence of IL-17-producing cells and ICOS expression in ICOSL KO mice, and additional results indicated that Th17 was involved in the pathological tissue remodeling in liver fibrosis induced by schistosomiasis.

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Expression of fibrosis-related factors in ICOSL KO and WT mice.(A). The areas of egg granulomas or fibrosis were chosen, and a two-step immunohistochemical method (peroxidase-conjugated polymer) was used on paraffin section of liver as described in the Materials and Methods. The dark brown area represents positive particles and arrow shows eggs of S. japonicum (original magnification×400). (B). The percentage of positive staining cells in 15 granulomas was calculated to assess the expression of IL-13, TGF-β1, MMP-9 and TIMP-1 on inflammatory cells of the granulomas in ICOSL KO mice at 12 weeks (IL-13 and TGF-β1) or 16 weeks (MMP-9 and TIMP-1) post-infection. Each bar represents mean of % positively staining cells in 15 granulomas +/− SD of 5 mice per group from two independent experiments.*P<0.05 between ICOSL KO and WT mice groups, Student’s t-test.
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pntd.0003434.g005: Expression of fibrosis-related factors in ICOSL KO and WT mice.(A). The areas of egg granulomas or fibrosis were chosen, and a two-step immunohistochemical method (peroxidase-conjugated polymer) was used on paraffin section of liver as described in the Materials and Methods. The dark brown area represents positive particles and arrow shows eggs of S. japonicum (original magnification×400). (B). The percentage of positive staining cells in 15 granulomas was calculated to assess the expression of IL-13, TGF-β1, MMP-9 and TIMP-1 on inflammatory cells of the granulomas in ICOSL KO mice at 12 weeks (IL-13 and TGF-β1) or 16 weeks (MMP-9 and TIMP-1) post-infection. Each bar represents mean of % positively staining cells in 15 granulomas +/− SD of 5 mice per group from two independent experiments.*P<0.05 between ICOSL KO and WT mice groups, Student’s t-test.

Mentions: Along with more extensive size of granulomas in the liver, the expression of TGF-β1 and IL-13 was significantly increased in murine schistosomiasis(Fig. 5B). Many cells were stained dark yellow in the slides of liver tissue, mainly around granuloma inflammatory cellsand the portal area cells around areas of fibrosis (Fig. 5A). Liver cells around granulomas also showed strong expression of TGF-β1 and IL-13. The expression levels of TGF-β1 and IL-13 in S. japonicum infected ICOSL KO mice were lower than those in S. japonicum infected WT mice at 12 weeks post-infection (P<0.05) (Fig. 5B). These observations were consistent with analysis of cytokines in the supernatants of SEA-stimulated splenocytes (Fig. 1G, 1H). In addition, we observed lower levels of the fibrosis-associated immunopathologic elements MMP-9 and TIMP-1 in the ICOSL KO mice compared to the controls at the advanced stage of infection (16 weeks) (Fig. 5B).


Th17 down-regulation is involved in reduced progression of schistosomiasis fibrosis in ICOSL KO mice.

Wang B, Liang S, Wang Y, Zhu XQ, Gong W, Zhang HQ, Li Y, Xia CM - PLoS Negl Trop Dis (2015)

Expression of fibrosis-related factors in ICOSL KO and WT mice.(A). The areas of egg granulomas or fibrosis were chosen, and a two-step immunohistochemical method (peroxidase-conjugated polymer) was used on paraffin section of liver as described in the Materials and Methods. The dark brown area represents positive particles and arrow shows eggs of S. japonicum (original magnification×400). (B). The percentage of positive staining cells in 15 granulomas was calculated to assess the expression of IL-13, TGF-β1, MMP-9 and TIMP-1 on inflammatory cells of the granulomas in ICOSL KO mice at 12 weeks (IL-13 and TGF-β1) or 16 weeks (MMP-9 and TIMP-1) post-infection. Each bar represents mean of % positively staining cells in 15 granulomas +/− SD of 5 mice per group from two independent experiments.*P<0.05 between ICOSL KO and WT mice groups, Student’s t-test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4295877&req=5

pntd.0003434.g005: Expression of fibrosis-related factors in ICOSL KO and WT mice.(A). The areas of egg granulomas or fibrosis were chosen, and a two-step immunohistochemical method (peroxidase-conjugated polymer) was used on paraffin section of liver as described in the Materials and Methods. The dark brown area represents positive particles and arrow shows eggs of S. japonicum (original magnification×400). (B). The percentage of positive staining cells in 15 granulomas was calculated to assess the expression of IL-13, TGF-β1, MMP-9 and TIMP-1 on inflammatory cells of the granulomas in ICOSL KO mice at 12 weeks (IL-13 and TGF-β1) or 16 weeks (MMP-9 and TIMP-1) post-infection. Each bar represents mean of % positively staining cells in 15 granulomas +/− SD of 5 mice per group from two independent experiments.*P<0.05 between ICOSL KO and WT mice groups, Student’s t-test.
Mentions: Along with more extensive size of granulomas in the liver, the expression of TGF-β1 and IL-13 was significantly increased in murine schistosomiasis(Fig. 5B). Many cells were stained dark yellow in the slides of liver tissue, mainly around granuloma inflammatory cellsand the portal area cells around areas of fibrosis (Fig. 5A). Liver cells around granulomas also showed strong expression of TGF-β1 and IL-13. The expression levels of TGF-β1 and IL-13 in S. japonicum infected ICOSL KO mice were lower than those in S. japonicum infected WT mice at 12 weeks post-infection (P<0.05) (Fig. 5B). These observations were consistent with analysis of cytokines in the supernatants of SEA-stimulated splenocytes (Fig. 1G, 1H). In addition, we observed lower levels of the fibrosis-associated immunopathologic elements MMP-9 and TIMP-1 in the ICOSL KO mice compared to the controls at the advanced stage of infection (16 weeks) (Fig. 5B).

Bottom Line: The results showed that ICOSL KO mice exhibited improved survival, reduced liver granulomatous inflammation around parasite eggs, markedly inhibited hepatic fibrosis development, lower levels of Th17-related cytokines (IL-17/IL-21), Th2-related cytokines (IL-4/IL-6/IL-10), a pro-fibrotic cytokine (IL-13), and TGF-β1, but higher level of Th1-related cytokine (IFN-γ) compared to wild-type (WT) mice.The reduced progression of fibrogenesis was correlated with the down-regulation of Th17 and Th2 and the elimination of ICOSL/ICOS interactions.Our findings suggest that IL-17-producing cells contribute to the hepatic granulomatous inflammation and subsequent fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Parasitology, Medical College of Soochow University, Suzhou,Jiangsu Province, The Peoples Republic of China.

ABSTRACT

Background: Granulomatous and fibrosing inflammation in response to parasite eggs is the main pathology that occurs during infection with Schistosoma spp. CD4+ T cells play critical roles in both host immune responses against parasitic infection and immunopathology in schistosomiasis,and coordinate many types of immune cells that contribute to fibrosis. ICOSL plays an important role in controlling specific aspects of T cell activation, differentiation, and function. Previous work has suggested that ICOS is essential for Th17 cell development. However, the immunopathogenesis of this pathway in schistosomiasis fibrosisis still unclear.

Methodology/principal findings: Using models of schistosomiasis in ICOSL KO and the C57BL/6 WT mice, we studied the role of the ICOSL/ICOS interaction in the mediation of the Th17 response in host granulomatous inflammation, particularly in liver fibrosis during S. japonicum infection, and investigated the immune responses and pathology of ICOSL KO mice in these models. The results showed that ICOSL KO mice exhibited improved survival, reduced liver granulomatous inflammation around parasite eggs, markedly inhibited hepatic fibrosis development, lower levels of Th17-related cytokines (IL-17/IL-21), Th2-related cytokines (IL-4/IL-6/IL-10), a pro-fibrotic cytokine (IL-13), and TGF-β1, but higher level of Th1-related cytokine (IFN-γ) compared to wild-type (WT) mice. The reduced progression of fibrogenesis was correlated with the down-regulation of Th17 and Th2 and the elimination of ICOSL/ICOS interactions.

Conclusions/significance: Our findings suggest that IL-17-producing cells contribute to the hepatic granulomatous inflammation and subsequent fibrosis. Importantly, there was a clearly positive correlation between the presence of IL-17-producing cells and ICOS expression in ICOSL KO mice, and additional results indicated that Th17 was involved in the pathological tissue remodeling in liver fibrosis induced by schistosomiasis.

Show MeSH
Related in: MedlinePlus