Dataset Information

FOXP3+ Regulatory T Cells in Hepatic Fibrosis and Splenomegaly Caused by Schistosoma japonicum: The Spleen May Be a Major Source of Tregs in Subjects with Splenomegaly.

ABSTRACT: Schistosoma eggs cause chronic liver inflammation and a complex disease characterized by hepatic fibrosis (HF) and splenomegaly (SplM). FOXP3+ Tregs could regulate inflammation, but it is unclear where these cells are produced and what roles they play in human schistosomiasis. We investigated blood and spleen FOXP3+ Tregs in Chinese fishermen with lifelong exposure to Schistosoma japonicum and various degrees of liver and spleen disease. FOXP3+ Tregs accounted for 4.3% of CD4+ T cells and 41.2% of FOXP3+CD4+ T cells; they could be divided into CD45RA-FOXP3hi effector (eTregs) and CD45RA+FOXP3low naive Tregs. Blood Treg levels were high in severe HF (+1.3; p = 0.004) and in SplM (+1.03, p = 0.03). Multivariate regression showed that severe HF (+0.85, p = 0.01) and SplM (+0.97; p = 0.05) were independently associated with the higher proportion of Tregs in the blood. This effect was mostly due to an increase in the proportion of eTregs in the blood of HF+++ (+0.9%; p = 0.04) and SplM (+0.9%; p = 0.04) patients. The proportion of eTregs expressing CXCR3 in the blood was lower in the HF+++ patients (37.4 +/- 5.9%) than in those with milder fibrosis (51.7 ± 2%; p = 0.009), whereas proportion were similar for cells expressing CD25hi, CCR7, and CTLA-4. Splenectomy improves symptoms and was associated with decreases in blood FOXP3+ Treg (-2.5; p<0.001) and eTreg (-1.3; p = 0.03) levels. SplM spleens contained a high proportion of eTregs with CXCR3, CCR5 and CTLA4 upregulation and CCR7 downregulation. This, and the strong expression of ligands of CXCR3 and CCR5 in the liver (n = 8) but not in the spleen suggested that spleen eTregs migrated to Th1-infiltrated liver tissues. Such migration may be attenuated in hepatosplenic patients due to lower levels of CXCR3 expression on Tregs (p = 0.009). Thus, higher blood Treg levels are associated with severe liver disease and splenomegaly. Our data are consistent with the hypothesis that the spleen is a major source of Tregs in subjects with splenomegaly. In most cases, Tregs migrate to the Th1-infiltrated liver and the lower levels of CXCR3+ Tregs in the blood of patients with severe schistosomiasis suggest that decreases in Treg migration sites of inflammation may aggravate the disease.

SUBMITTER: Romano A

PROVIDER: S-EPMC4701139 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

FOXP3+ Regulatory T Cells in Hepatic Fibrosis and Splenomegaly Caused by Schistosoma japonicum: The Spleen May Be a Major Source of Tregs in Subjects with Splenomegaly.

Romano Audrey A Hou Xunya X Sertorio Mathieu M Dessein Hélia H Cabantous Sandrine S Oliveira Pablo P Li Jun J Oyegue Sandrine S Arnaud Violaine V Luo Xinsong X Daujat-Chavanieu Martine M Mariani Odette O Sastre Xavier X Dombey Anne-Marie AM He Hongbin H Li Yuesheng Y Dessein Alain A

PLoS neglected tropical diseases 20160105 1

Schistosoma eggs cause chronic liver inflammation and a complex disease characterized by hepatic fibrosis (HF) and splenomegaly (SplM). FOXP3+ Tregs could regulate inflammation, but it is unclear where these cells are produced and what roles they play in human schistosomiasis. We investigated blood and spleen FOXP3+ Tregs in Chinese fishermen with lifelong exposure to Schistosoma japonicum and various degrees of liver and spleen disease. FOXP3+ Tregs accounted for 4.3% of CD4+ T cells and 41.2% ...[more]

PMID: 26731721

Similar Datasets

Project description:Determining the molecular events induced in the spleen during schistosome infection is an essential step in better understanding the immunopathogenesis of schistosomiasis and the mechanisms by which schistosomes modulate the host immune response. The present study defines the transcriptional and cellular events occurring in the murine spleen during the progression of Schistosoma japonicum infection. Additionally, we compared and contrasted these results with those we have previously reported for the liver. Microarray analysis combined with flow cytometry and histochemistry demonstrated that transcriptional changes occurring in the spleen were closely related to changes in cellular composition. Additionally, the presence of alternatively activated macrophages, as indicated by up-regulation of Chi3l3 and Chi3l4 and expansion of F4/80+ macrophages, together with enhanced expression of the immunoregulatory genes ANXA1 and CAMP suggests the spleen may be an important site for the control of S. japonicum-induced immune responses. The most striking difference between the transcriptional profiles of the infected liver and spleen was the contrasting expression of chemokines and cell adhesion molecules. Lymphocyte chemokines including the homeostatic chemokines, CXCL13, CCL19 and CCL21, were significantly down-regulated in the spleen but up-regulated in the liver. Eosinophil (CCL11, CCL24), neutrophil (CXCL1) and monocyte (CXCL14, CCL12) chemokines and the cell adhesion molecules VCAM1, NCAM1, PECAM1 were up-regulated in the liver but unchanged in the spleen. Chemokines up-regulated in both organs were expressed at significantly higher levels in the liver. Co-ordinated expression of these genes probably contributes to the development of a chemotactic signalling gradient that promotes recruitment of effector cells to the liver, thereby facilitating the development of hepatic granulomas and fibrosis. Together these data provide, for the first time, a comprehensive overview of the molecular events occurring in the spleen during schistosomiasis and will substantially further our understanding of the local and systemic mechanisms driving the immunopathogenesis of this disease.

Project description:Determining the molecular events induced in the spleen during schistosome infection is an essential step in better understanding the immunopathogenesis of schistosomiasis and the mechanisms by which schistosomes modulate the host immune response. The present study defines the transcriptional and cellular events occurring in the murine spleen during the progression of Schistosoma japonicum infection. Additionally, we compared and contrasted these results with those we have previously reported for the liver. Microarray analysis combined with flow cytometry and histochemistry demonstrated that transcriptional changes occurring in the spleen were closely related to changes in cellular composition. Additionally, the presence of alternatively activated macrophages, as indicated by up-regulation of Chi3l3 and Chi3l4 and expansion of F4/80(+) macrophages, together with enhanced expression of the immunoregulatory genes ANXA1 and CAMP suggests the spleen may be an important site for the control of S. japonicum-induced immune responses. The most striking difference between the transcriptional profiles of the infected liver and spleen was the contrasting expression of chemokines and cell adhesion molecules. Lymphocyte chemokines, including the homeostatic chemokines CXCL13, CCL19 and CCL21, were significantly down-regulated in the spleen but up-regulated in the liver. Eosinophil (CCL11, CCL24), neutrophil (CXCL1) and monocyte (CXCL14, CCL12) chemokines and the cell adhesion molecules VCAM1, NCAM1, PECAM1 were up-regulated in the liver but unchanged in the spleen. Chemokines up-regulated in both organs were expressed at significantly higher levels in the liver. Co-ordinated expression of these genes probably contributes to the development of a chemotactic signalling gradient that promotes recruitment of effector cells to the liver, thereby facilitating the development of hepatic granulomas and fibrosis. Together these data provide, for the first time, a comprehensive overview of the molecular events occurring in the spleen during schistosomiasis and will substantially further our understanding of the local and systemic mechanisms driving the immunopathogenesis of this disease.

Project description:BackgroundHepatic macrophages regulate liver granuloma formation and fibrosis caused by infection with Schistosoma japonicum, with the manner of regulation dependent on macrophage activation state. Interleukin (IL)-37 may have immunomodulatory effects on macrophages. However, whether IL-37 can affect liver granuloma formation and fibrosis by affecting the polarization of macrophages in S. japonicum infection remains unclear. The aim of this study was to investigate IL-37-affected macrophage polarization in liver granuloma formation and fibrosis in S. japonicum infection.MethodsAn enzyme-linked immunosorbent assay (ELISA) was used to detect the expression of IL-37 in the serum of patients with acute S. japonicum infection and in the serum of healthy people. Recombinant IL-37 (rIL-37), CPP-IgG2Fc-IL-37 and no CPP-IgG2Fc-IL-37 proteins were injected into S. japonicum-infected mice every 3 days for a total of 6 times from day 24 post infection onwards. Subsequently, ELISA, quantitative reverse transcription-PCR, fluorescence-activated cell sorting and western blot were used to analyze whether IL-37 inhibits the formation of liver granulomas and the development of liver fibrosis by regulating the phenotypic transition of macrophages. Finally, the three IL-37 proteins and SIS3, a Smad3 inhibitor, were co-cultured in mouse peritoneal macrophages to explore the mechanism underlying the promotion of the polarization of M0 macrophages to the M2 phenotype by IL-37.ResultsSerum IL-37 levels were upregulated in schistosomiasis patients, and this increased level of IL-37 protein apparently alleviated the liver granuloma of mice in infection models. It also could induce liver and peritoneal macrophages to polarize to the M2 phenotype in S. japonicum-infected mice. The S. japonicum-infected mice injected with CPP-IgG2Fc-IL-37 group exhibited the most obvious improvement in inflammatory reaction against the liver granuloma. The number and ratio of M2 macrophages in the liver and peritoneal cavity were significantly higher in the three IL-37 protein groups, especially in the CPP-IgG2Fc-IL-37 group, compared to the controls. Similar results were also found regarding liver function damage. IL-37 induced macrophage M2 polarization by promoting AMP-activated protein kinase (AMPK) phosphorylation in vitro. Among all groups, the activation of AMPK was most significant in the CPP-IgG2Fc-IL-37 group, and it was found that SMAD3 could enhance the anti-inflammatory function of IL-37.ConclusionsThe results show that IL-37 was able to promote the polarization of macrophages to the M2 phenotype, thereby inhibiting the development of schistosomiasis. In comparison to the rIL-37 protein, the CPP-IgG2Fc-IL-37 protein has the advantages of being effective in small doses and having fewer side effects and a better efficacy.

Dataset Information

FOXP3+ Regulatory T Cells in Hepatic Fibrosis and Splenomegaly Caused by Schistosoma japonicum: The Spleen May Be a Major Source of Tregs in Subjects with Splenomegaly.

Publications

FOXP3+ Regulatory T Cells in Hepatic Fibrosis and Splenomegaly Caused by Schistosoma japonicum: The Spleen May Be a Major Source of Tregs in Subjects with Splenomegaly.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets