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Schistosoma mansoni eggs retained in host tissues induce innate cytokine release, contributing to the induction of Type-2 immune responses and granuloma formation, important to restrain cytotoxic antigens, but leading to fibrosis. Interleukin(IL)-33 participates in experimental models of inflammation and chemically induced fibrosis, but its role in S. mansoni-induced fibrosis is still unknown. To explore the role of the IL-33/suppressor of the tumorigenicity 2 (ST2) pathway, serum and liver cytokine levels, liver histopathology, and collagen deposition were comparatively evaluated in S. mansoni-infected wild-type (WT) and IL-33-receptor knockout (ST2−/−) BALB/c mice. Our data show similar egg counts and hydroxyproline in the livers of infected WT and ST2−/− mice; however, the extracellular matrix in ST2−/− granulomas was loose and disorganised. Pro-fibrotic cytokines, such as IL-13 and IL-17, and the tissue-repairing IL-22 were significantly lower in ST2−/− mice, especially in chronic schistosomiasis. ST2−/− mice also showed decreased α-smooth muscle actin (α-SMA) expression in granuloma cells, in addition to reduced Col III and Col VI mRNA levels and reticular fibres. Therefore, IL-33/ST2 signalling is essential for tissue repairing and myofibroblast activation during S. mansoni infection. Its disruption results in inappropriate granuloma organisation, partly due to the reduced type III and VI collagen and reticular fibre formation. [ABSTRACT FROM AUTHOR]

Proposed model of eosinophil participation in Schistosoma mansoni induced granuloma formation/modulation and disease severity. The absence of eosinophils during S. mansoni infection resulted in significant lower concentration of cytokines from the Th2 profile, such as IL-13, IL-5, IL33 in liver of ∆dblGATA infected mice. There was also reduction in liver concentration of IL-17, and in the regulatory cytokines, IL-10 and TGF- β. In contrast, the liver concentration of TNF- α and INF- γ increased. The changes in liver immune response observed in ∆dblGATA infected mice was accompanied by stronger activation of M1 macrophages, lower expression of COLI and COLII genes and liver content of hydroxyproline, no evident signs of granuloma modulation at chronic schistosomiasis and increase in liver damage, which would contribute to higher mortality rate of ∆dblGATA infected mice. [Display omitted] • Ablation of eosinophils did not alter the S. mansoni load in infected mice. • Infected ΔdblGATA mice displayed reduced liver Th2 and regulatory responses. • S. mansoni infection led to increased liver Th1 response in ΔdblGATA mice. • Infected ΔdblGATA mice displayed larger granulomas and more intense tissue damage. • S. mansoni infection resulted in higher mortality rate in ΔdblGATA mice. The severity of chronic schistosomiasis has been mainly associated with the intensity and extension of the inflammatory response induced by egg-secreted antigens in the host tissue, especially in the liver and intestine. During acute schistosomiasis, eosinophils account for approximately 50% of the cells that compose the liver granulomas; however, the role of this cell-type in the pathology of schistosomiasis remains controversial. In the current study, we compared the parasite burden and liver immunopathological changes during experimental schistosomiasis in wild-type (WT) BALB/c mice and BALB/c mice selectively deficient for the differentiation of eosinophils (ΔdblGATA). Our data demonstrated that the absence of eosinophil differentiation did not alter the S. mansoni load or the liver retention of parasite eggs; however, there were significant changes in the liver immune response profile and tissue damage. S. mansoni infection in ΔdblGATA mice resulted in significantly lower liver concentrations of IL-5, IL-13, IL-33, IL-17, IL-10, and TGF-β and higher concentrations of IFN-γ and TNF-α, as compared to WT mice. The changes in liver immune response observed in infected ΔdblGATA mice were accompanied by lower collagen deposition, but higher liver damage and larger granulomas. Moreover, the absence of eosinophils resulted in a higher mortality rate in mice infected with a high parasite load. Therefore, the data indicated that eosinophils participate in the establishment and/or amplification of liver Th-2 and regulatory response induced by S. mansoni , which is necessary for the balance between liver damage and fibrosis, which in turn is essential for modulating disease severity. [ABSTRACT FROM AUTHOR]