Background: Schistosomiasis is an immunopathogenic disease in which Th17 cells play vital roles. Hepatic granuloma formation and subsequent fibrosis are its main pathologic manifestations and the leading causes of hepatic cirrhosis, and effective therapeutic interventions are lacking. In this study, we explored the effects of fasudil, a selective RhoA–Rho-associated kinase (ROCK) inhibitor, on Th17 cells and the pathogenesis of schistosomiasis. Methods: Mice were infected with Schistosoma japonicum and treated with fasudil. The worm burden, hepatic granuloma formation, and fibrosis were evaluated. The roles of fasudil on Th17, Treg, and hepatic stellate cells were analyzed. Results: Fasudil therapy markedly reduced the granuloma size and collagen deposit in livers from mice infected with S. japonicum. However, fasudil therapy did not affect the worm burden in infected mice. The underlying cellular and molecular mechanisms were investigated. Fasudil suppressed the activation and induced the apoptosis of CD4+ T cells. Fasudil inhibited the differentiation and effector cytokine secretion of Th17 cells, whereas it upregulated Treg cells in vitro. It also restrained the in vivo interleukin (IL)-4 and IL-17 levels in infected mice. Fasudil directly induced the apoptosis of hepatic stellate cells and downregulated the expressions of hepatic fibrogenic genes, such as collagen type I (Col-I), Col-III, and transforming growth factor-1 (TGF-β1). These effects may contribute to its anti-pathogenic roles in schistosomiasis. Conclusions: Fasudil inhibits hepatic granuloma formation and fibrosis with downregulation of Th17 cells. Fasudil might serve as a novel therapeutic agent for hepatic fibrosis due to schistosome infections and perhaps other disorders.

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However, in liver fibrosis caused by CCl 4 , Th1 cells occupied the dominant position, while proportions of Th2, Th17, and Treg cells decreased gradually. In conclusion, liver fibrosis was a complex pathological process that was regulated by a series of cytokines and immune cells. The pathological progressions and immune responses to S. japonicum or CCl 4 induced liver fibrosis were different, possibly because of their different injury mechanisms. The appropriate animal model should be selected according to the needs of different experiments and the pathogenic factors of liver fibrosis in the study.

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Schistosomiasis is an immunopathogenic disease characterized by egg granuloma and fibrosis. The hepatic fibrosis of schistosomiasis is caused by the coordinated action of local immune cells, liver-resident cells and related cytokines around the eggs of the liver. B-cell-activating factor (BAFF), expressed in many cells, is an essential factor for promoting the survival, differentiation, and maturation of cells. The overexpression of BAFF is closely related to many autoimmune diseases and fibrosis, but has not been reported to play a role in liver fibrosis caused by schistosomiasis. In the study, we found that, during Schistosoma japonicum (S. japonicum) infection in mice, the level of BAFF and its receptor BAFF-R progressively increased, then decreased with the extension of infection time, which was consistent with the progression of hepatic granuloma and fibrosis. Anti-BAFF treatment attenuated the histopathological damage in the liver of infected mice. The average areas of individual granulomas and liver fibrosis in anti-BAFF treatment mice were significantly lower than those in control mice, respectively. Anti-BAFF treatment increased the IL-10, decreased IL-4, IL-6, IL-17A, TGF-β, and downregulated the antibody level against S. japonicum antigens. These results suggested that BAFF acts a strong player in the immunopathology of schistosomiasis. Anti-BAFF treatment may influence Th2 and Th17 responses, and reduce the inflammatory reaction and fibrosis of schistosomiasis liver egg granuloma. It is suggested that BAFF might be a prospective target for the development of new methods to treat schistosomiasis liver fibrosis.

Background The activation of immune response driven by the eggs of Schistosoma japonicum and the subsequent secretions is the culprit behind granulomatous inflammation and liver fibrosis. Evidence suggests that PKCλ/ι participates in a variety of physiological and pathological processes, including the regulation of metabolism, growth, proliferation and differentiation of cells. However, the role of PKCλ/ι in liver disease caused by Schistosoma japonicum remains unclear. Methods In the present study, we observe the pathological changes of egg-induced granulomatous inflammation and fibrosis in the liver of mice infected by Schistosoma japonicum by using conditional PKCλ/ι-knockout mice and wild-type control. Immune cytokines and fibrogenic factors were analyzed by performing flow cytometry and real-time fluorescence quantitative PCR. Results The results of H&E and Masson staining show that the degree of granulomatous lesions and fibrosis in the liver of the infected PKCλ/ι-knockout mice was significantly reduced compared with those of the infected wild-type mice. The mean area of single granuloma and hepatic fibrosis in the PKCλ/ι-knockout mice was significantly lower than that of the wild-type mice (85,295.10 ± 5399.30 μm2 vs. 1,433,702.04 ± 16,294.01 μm2, P < 0.001; 93,778.20 ± 8949.05 μm2 vs. 163,103.01 ± 11,103.20 μm2, P < 0.001), respectively. Serological analysis showed that the ALT content was significantly reduced in the infected knockout mice compared with infected wild-type mice. RT-PCR analysis showed that IL-4 content in knockout mice was significantly increased after Schistosoma japonicum infection, yet the increase was less than that in infected wild-type mice (P < 0.05). PKCλ/ι deficiency led to reduced expression of fibrosis-related factors, including TGF-β1, Col-1, Col-3, α-SMA and liver DAMP factor HMGB1. Flow cytometry analysis showed that the increasing percentage of Th2 cells, which mainly secrete IL-4 cytokines in spleen cells, was significantly lower in PKCλ/ι-deficient mice compared with wild-type mice after infection (P < 0.05). Conclusions Our data demonstrate that PKCλ/ι deficiency alleviating granulomatous inflammation and fibrosis in the liver of mice with S. japonicum infection by downregulating Th2 immune response is the potential molecular mechanism behind the role of PKCλ/ι in schistosomiasis. Graphical Abstract

Schistosomiasis is a widespread zoonosis. It seriously threats human health. Schistosomiasis is caused by schistosomes, which belong to Schistosoma genus, a kind of blood-dwelling fluke worms, mainly living in the venus portal-mesenteric system of human by digenetic intravascular parasite. People who infected by schistosomes may appear the symptoms with abdominal pain, diarrhea, anemia, and splenomegaly, progressing from egg-granulomas eventually to hepatic fibrosis. This review describes hepatic fibrosis caused by schistosomes, Clonorchis sinensis and Toxoplasma gondii, Capillaria hepatica and hydatid, mainly focused on the hepatic fibrosis caused by S. mansoni and S. japonicum. T helper (Th) cells (Th1, Th2, Th17 and Treg cells) play an important role in the process of anti-schistosomiasis infection and immune regulation. Especially, the balance of Th1/Th2, Th17/Treg is closely related to the development of hepatic fibrosis. Th2 and Th17 cells can promote the granuloma formation by the secretion of IL-4 and IL-17 respectively; while Th1 and Treg cells can suppress the granuloma formation. These CD4 + T cell subsets are in complicated cross-talk in schistosomiasis immunity. Hepatic fibrosis caused by these parasites are also the key and difficult points of prevention and treatment of parasitic diseases, with further study about their molecular mechanism will provide us more thinking about parasitic effective prevention and treatment.

Asthma is a chronic airway inflammatory disease affecting millions of people in the world. CD4+ T helper cells play central roles in its pathogenesis. We have reported that atypical protein kinase PKCλ/ι regulates Th2 differentiation and function. Recently, we found that PKCλ/ι was involved in the regulation of Th17 differentiation and function. PKCλ/ι-deficient CD4+ T cells showed impaired ability to differentiate into Th17 cells in vitro under Th17-polarizing culture conditions. The secretion of IL-17, IL-17F, IL21 and IL-22, were inhibited from PKCλ/ι-deficient T cells under non-polarizing and Th17-polarizing culture conditions. Moreover, the impaired Th17 differentiation and function by the PKCλ/ι-deficiency was associated with the downregulation of Stat3 and Rorgt, key Th17 transcription factors. On the other hand, PKCλ/ι did not affect the development and induction of regulatory T (Treg) cells. In order to study the in vivo roles of PKCλ/ι-Th17 axis, we applied a murine model of house dust mites (HDM)-induced allergic airway inflammation, in which Th17 cells and neutrophils are dominant responder among others. The infiltrating cells in the lungs and bronchoalveolar lavage fluids were significantly reduced in conditional PKCλ/ι-deficient mice. Th17 and Th2 effector cytokines, such as IL-17, IL-4, IL-5 and IL-13 were inhibited in the bronchoalveolar lavage fluids. Their mRNA levels in the lungs were also significantly downregulated. Thus, PKCλ/ι emerges as an important regulator of Th17 differentiation and allergic airway inflammation. Further investigations are underway to explore the underlying molecular mechanisms.