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IL-7 suppresses macrophage autophagy and promotes liver pathology in Schistosoma japonicum-infected mice.

ABSTRACT: In schistosomiasis japonica and mansoni, parasite eggs trapped in host liver elicit severe liver granulomatous inflammation that subsequently leads to periportal fibrosis, portal hypertension, haemorrhage or even death. Macrophages are critical for granuloma formation and the development of liver fibrosis during schistosomiasis. However, whether the aberrant regulation of macrophage autophagy has an effect on the development of liver immunopathology in schistosomiasis remains to be elucidated. In this study, we showed that Schistosoma japonicum (S. japonicum) egg antigen (SEA)-triggered macrophage autophagy limited the development of pathology in host liver. However, engagement of IL-7 receptor (IL-7R/CD127) on macrophages by S. japonicum infection-induced IL-7 significantly suppressed SEA-triggered macrophage autophagy, which led to an enhanced liver pathology. In addition, anti-IL-7 neutralizing antibody or anti-CD127 blocking antibody treatment increased macrophage autophagy and suppressed liver pathology. Finally, we demonstrated that IL-7 protects macrophage against SEA-induced autophagy through activation of AMP-activated protein kinase (AMPK). Our study reveals a novel role for IL-7 in macrophage autophagy and identifies AMPK as a novel downstream mediator of IL-7-IL-7R signalling and suggests that manipulation of macrophage autophagy by targeting IL-7-IL-7R signalling may have the potential to lead to improved treatment options for liver pathogenesis in schistosomiasis.

SUBMITTER: Zhu J

PROVIDER: S-EPMC6010884 | biostudies-other | 2018 Jul

REPOSITORIES: biostudies-other

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IL-7 suppresses macrophage autophagy and promotes liver pathology in Schistosoma japonicum-infected mice.

Zhu Jifeng J Zhang Weiwei W Zhang Lina L Xu Lei L Chen Xiaojun X Zhou Sha S Xu Zhipeng Z Xiao Ming M Bai Hui H Liu Feng F Su Chuan C

Journal of cellular and molecular medicine 20180322 7

In schistosomiasis japonica and mansoni, parasite eggs trapped in host liver elicit severe liver granulomatous inflammation that subsequently leads to periportal fibrosis, portal hypertension, haemorrhage or even death. Macrophages are critical for granuloma formation and the development of liver fibrosis during schistosomiasis. However, whether the aberrant regulation of macrophage autophagy has an effect on the development of liver immunopathology in schistosomiasis remains to be elucidated. I ...[more]

PMID: 29566311

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Project description:BackgroundSchistosomiasis is a chronic infection, where the host immune response to the parasite changes from a predominantly Th1 to Th2 phenotype, when parasite enters the egg stage, restraining the host inflammatory immune responses to achieve a longer survival in the host. On the other hand, the development of Th2 responses causes immunopathological changes such as liver fibrosis. Therefore identification of schistosome-derived Th2 inducing molecules is important in the understanding of pathogenesis of schistosomiasis. A cyclophilin A homologue of Schistosoma japonicum was reported to be an egg-stage specific antigen, but its immunogenicity and immunoregulatory activities remain unknown.MethodsWe cloned and expressed the gene of cyclophilin A from Schistosoma japonicum (AY814078), named as SjCyP18 based on its molecular weight. The expression profiles in different stages of S. japonicum were examined by RT-PCR and immunofluorescence assay. The immunogenicity of SjCyP18 was measured by the presence of IgG in the sera from S. japonicum infected patients and animals, and the Th2-promting activities were examined by the subclass of immunoglobulins against SjCyP18 and by the IL-4 induction in T cells following footpad injection of SjCyP18.ResultsThe cloned SjCyP18 has 65% homology with human or mouse cyclophilin A at the amino acid level. In contrast to reports as an egg-stage specific antigen, the gene was found to be expressed in all stages of S. japonicum. IgG responses against SjCyP18 were found in some S. japonicum infected patients and were significantly induced when infection become patent and produce eggs in infected mice. Furthermore, the Th2-promoting subclass of IgG1 was the predominant isotype in S. japonicum infected mice. More importantly, footpad injection of SjCyP18 induced a greater production of IL-4 than that of IFN-γ by lymphocytes compared to responses from PBS injection controls.ConclusionThe cyclophilin A homologue found in S. japonicum is immunogenic and promotes Th2 responses in vivo which may contribute to the establishment of chronic infection by schistosomes.

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.

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IL-7 suppresses macrophage autophagy and promotes liver pathology in Schistosoma japonicum-infected mice.

Publications

IL-7 suppresses macrophage autophagy and promotes liver pathology in Schistosoma japonicum-infected mice.

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