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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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ICOSL KO mice infected with Schistosoma japonicum produced lower levels of ICOSL and IL-17R on CD19+ B cells than those of infected WT mice.CD19+B cells isolated from the spleens were stained for CD19 and were then stained for ICOSL (A) and IL-17R(B) as described in the Materials and Methods. All density plot charts were based on 104 cells, satisfying a gate set on the forward versus side light scatter that defined spleen lymphocytes. Open symbols represent ICOS KO mice and closed symbols represent WT mice. Data shown are pooled from two independent experiments, symbols denotes individual mice and lines denote mean values. §Significant genotype effect and * significant time effect (P< 0.05, Tukey HSD, ANOVA performed using combined data from two separate experiments).
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pntd.0003434.g003: ICOSL KO mice infected with Schistosoma japonicum produced lower levels of ICOSL and IL-17R on CD19+ B cells than those of infected WT mice.CD19+B cells isolated from the spleens were stained for CD19 and were then stained for ICOSL (A) and IL-17R(B) as described in the Materials and Methods. All density plot charts were based on 104 cells, satisfying a gate set on the forward versus side light scatter that defined spleen lymphocytes. Open symbols represent ICOS KO mice and closed symbols represent WT mice. Data shown are pooled from two independent experiments, symbols denotes individual mice and lines denote mean values. §Significant genotype effect and * significant time effect (P< 0.05, Tukey HSD, ANOVA performed using combined data from two separate experiments).

Mentions: The expression levels of ICOS and ICOSL in splenocytes of the WT mice were elevated at 4 weeks post-infection and peaked at 12 weeks before decreasing gradually (Figs. 2A, 3A). Relatively small changes in ICOS expression were observed in CD4+ T cells of ICOSL KO mice infected with S. japonicum. In contrast, the WT mice showed a comparatively considerable increase in ICOS expression after infection. The data also showed that the expression of ICOS was significantly down-regulated in ICOSL KO mice compared to WT controls at 4, 7, 12, and 16 weeks post-infection (Fig. 2A). As expected, the expression of ICOSL was extremely low in ICOSL KO mice at all time points after S. japonicum infection (P<0.05) (Fig. 3A). ICOSL KO mice also exhibited decreased levels of RORγtand IL-17Rafter 4 weeks post-infection (Figs. 2B and 3B).


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)

ICOSL KO mice infected with Schistosoma japonicum produced lower levels of ICOSL and IL-17R on CD19+ B cells than those of infected WT mice.CD19+B cells isolated from the spleens were stained for CD19 and were then stained for ICOSL (A) and IL-17R(B) as described in the Materials and Methods. All density plot charts were based on 104 cells, satisfying a gate set on the forward versus side light scatter that defined spleen lymphocytes. Open symbols represent ICOS KO mice and closed symbols represent WT mice. Data shown are pooled from two independent experiments, symbols denotes individual mice and lines denote mean values. §Significant genotype effect and * significant time effect (P< 0.05, Tukey HSD, ANOVA performed using combined data from two separate experiments).
© Copyright Policy
Related In: Results  -  Collection

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

pntd.0003434.g003: ICOSL KO mice infected with Schistosoma japonicum produced lower levels of ICOSL and IL-17R on CD19+ B cells than those of infected WT mice.CD19+B cells isolated from the spleens were stained for CD19 and were then stained for ICOSL (A) and IL-17R(B) as described in the Materials and Methods. All density plot charts were based on 104 cells, satisfying a gate set on the forward versus side light scatter that defined spleen lymphocytes. Open symbols represent ICOS KO mice and closed symbols represent WT mice. Data shown are pooled from two independent experiments, symbols denotes individual mice and lines denote mean values. §Significant genotype effect and * significant time effect (P< 0.05, Tukey HSD, ANOVA performed using combined data from two separate experiments).
Mentions: The expression levels of ICOS and ICOSL in splenocytes of the WT mice were elevated at 4 weeks post-infection and peaked at 12 weeks before decreasing gradually (Figs. 2A, 3A). Relatively small changes in ICOS expression were observed in CD4+ T cells of ICOSL KO mice infected with S. japonicum. In contrast, the WT mice showed a comparatively considerable increase in ICOS expression after infection. The data also showed that the expression of ICOS was significantly down-regulated in ICOSL KO mice compared to WT controls at 4, 7, 12, and 16 weeks post-infection (Fig. 2A). As expected, the expression of ICOSL was extremely low in ICOSL KO mice at all time points after S. japonicum infection (P<0.05) (Fig. 3A). ICOSL KO mice also exhibited decreased levels of RORγtand IL-17Rafter 4 weeks post-infection (Figs. 2B and 3B).

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