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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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Reduced granulomatous formation and improved survival in the ICOSLKO mice.(A). Liver samples from ICOSL knockout and C57BL/6J mice 7, 12, 16 and 20 weeks post-infection with Schistosoma japonicum were embedded in paraffin. Liver sections were examined under a microscope to determine the pathology of egg granuloma; individual egg granulomas were located and their maximal diameters across opposing axes (A and B) were measured under an optical microscope; the volume of granuloma was calculated based on formula V = πAB2/6 [26]. Open symbols represent ICOS KO mice and closed symbols represent WT mice. There were 5 mice at each time point and 10granulomas in each mouse were measured at each time point. Symbols denotes the mean of 10granulomas in each mouse 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). (B). Kaplan-Meier survival analysis of mice inoculated with S. japonicum(ICOSL KO vs WT, n = 20, Log rank test P = 0.017). The survival analysis data are representative of three independent experiments with similar results.
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pntd.0003434.g004: Reduced granulomatous formation and improved survival in the ICOSLKO mice.(A). Liver samples from ICOSL knockout and C57BL/6J mice 7, 12, 16 and 20 weeks post-infection with Schistosoma japonicum were embedded in paraffin. Liver sections were examined under a microscope to determine the pathology of egg granuloma; individual egg granulomas were located and their maximal diameters across opposing axes (A and B) were measured under an optical microscope; the volume of granuloma was calculated based on formula V = πAB2/6 [26]. Open symbols represent ICOS KO mice and closed symbols represent WT mice. There were 5 mice at each time point and 10granulomas in each mouse were measured at each time point. Symbols denotes the mean of 10granulomas in each mouse 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). (B). Kaplan-Meier survival analysis of mice inoculated with S. japonicum(ICOSL KO vs WT, n = 20, Log rank test P = 0.017). The survival analysis data are representative of three independent experiments with similar results.

Mentions: Histological examination of granulomas in mice infected with S. japonicum showed that granulomas were found in mouse livers 7 weeks post-infection (Fig. 4A). The volume of the granuloma was the largest at that time point (Fig. 4A). Twelve weeks after the infection, the formation of granuloma began to reduce (Fig. 4A). Comparing the volume of granulomas in the ICOSL KO and wild type mice at 7, 12, 16 and 20 weeks after the infection showed that the size of granulomas were significantly smaller in the ICOSL KO mice than those of the WT mice(P<0.05) (Fig. 4A). Furthermore, ICOSL KO mice showed improved survival compared to WT mice (P = 0.017) (Fig. 4B).


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)

Reduced granulomatous formation and improved survival in the ICOSLKO mice.(A). Liver samples from ICOSL knockout and C57BL/6J mice 7, 12, 16 and 20 weeks post-infection with Schistosoma japonicum were embedded in paraffin. Liver sections were examined under a microscope to determine the pathology of egg granuloma; individual egg granulomas were located and their maximal diameters across opposing axes (A and B) were measured under an optical microscope; the volume of granuloma was calculated based on formula V = πAB2/6 [26]. Open symbols represent ICOS KO mice and closed symbols represent WT mice. There were 5 mice at each time point and 10granulomas in each mouse were measured at each time point. Symbols denotes the mean of 10granulomas in each mouse 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). (B). Kaplan-Meier survival analysis of mice inoculated with S. japonicum(ICOSL KO vs WT, n = 20, Log rank test P = 0.017). The survival analysis data are representative of three independent experiments with similar results.
© Copyright Policy
Related In: Results  -  Collection

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

pntd.0003434.g004: Reduced granulomatous formation and improved survival in the ICOSLKO mice.(A). Liver samples from ICOSL knockout and C57BL/6J mice 7, 12, 16 and 20 weeks post-infection with Schistosoma japonicum were embedded in paraffin. Liver sections were examined under a microscope to determine the pathology of egg granuloma; individual egg granulomas were located and their maximal diameters across opposing axes (A and B) were measured under an optical microscope; the volume of granuloma was calculated based on formula V = πAB2/6 [26]. Open symbols represent ICOS KO mice and closed symbols represent WT mice. There were 5 mice at each time point and 10granulomas in each mouse were measured at each time point. Symbols denotes the mean of 10granulomas in each mouse 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). (B). Kaplan-Meier survival analysis of mice inoculated with S. japonicum(ICOSL KO vs WT, n = 20, Log rank test P = 0.017). The survival analysis data are representative of three independent experiments with similar results.
Mentions: Histological examination of granulomas in mice infected with S. japonicum showed that granulomas were found in mouse livers 7 weeks post-infection (Fig. 4A). The volume of the granuloma was the largest at that time point (Fig. 4A). Twelve weeks after the infection, the formation of granuloma began to reduce (Fig. 4A). Comparing the volume of granulomas in the ICOSL KO and wild type mice at 7, 12, 16 and 20 weeks after the infection showed that the size of granulomas were significantly smaller in the ICOSL KO mice than those of the WT mice(P<0.05) (Fig. 4A). Furthermore, ICOSL KO mice showed improved survival compared to WT mice (P = 0.017) (Fig. 4B).

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