Interleukin (IL)-33 is dispensable for Schistosoma mansoni worm maturation and the maintenance of egg-induced pathology in intestines of infected mice

Abstract

Background Schistosomes are trematode worms that dwell in their definitive host’s blood vessels, where females lay eggs that need to be discharged into the environment with host excreta to maintain their life-cycle. Both worms and eggs require type 2 immunity for their maturation and excretion, respectively. However, the immune molecules that orchestrate such immunity remain unclear. Interleukin (IL)-33 is one of the epithelium-derived cytokines that induce type 2 immunity in tissues. The aim of this study was to determine the role of IL-33 in the maturation, reproduction and excretion of Schistosoma mansoni eggs, and in the maintenance of egg-induced pathology in the intestines of mice. Methods The morphology of S. mansoni worms and the number of eggs in intestinal tissues were studied at different time points post-infection in S. mansoni-infected IL-33-deficient (IL-33−/−) and wild-type (WT) mice. IL-5 and IL-13 production in the spleens and mesenteric lymph nodes were measured. Tissue histology was performed on the terminal ilea of both infected and non-infected mice. Results Worms from IL-33−/− and WT mice did not differ morphologically at 4 and 6 weeks post-infection (wpi). The number of eggs in intestinal tissues of IL-33−/− and WT mice differed only slightly. At 6 wpi, IL-33−/− mice presented impaired type 2 immunity in the intestines, characterized by a decreased production of IL-5 and IL-13 in mesenteric lymph nodes and fewer inflammatory infiltrates with fewer eosinophils in the ilea. There was no difference between IL-33−/− and WT mice in the levels of IL-25 and thymic stromal lymphopoietin (TSLP) in intestinal tissues. Conclusions Despite its ability to initiate type 2 immunity in tissues, IL-33 alone seems dispensable for S. mansoni maturation and its absence may not affect much the accumulation of eggs in intestinal tissues. The transient impairment of type 2 immunity observed in the intestines, but not spleens, highlights the importance of IL-33 over IL-25 and TSLP in initiating, but not maintaining, locally-induced type 2 immunity in intestinal tissues during schistosome infection. Further studies are needed to decipher the role of each of these molecules in schistosomiasis and clarify the possible interactions that might exist between them.

IL-33/ST2 Axis Deficiency Exacerbates Hepatic Pathology by Regulating Treg and Th17 Cells in Murine Schistosomiasis Japonica

“…21,23,24 Although IL-33 promotes type 2 immune responses in infected mice with S. japonicum while not in infected mice with S. mansoni, it has been associated with liver pathology in both experimental models. [20][21][22] The previously reported kinetics of IL-33 levels and the proportions of Treg and Th17 peak at the 8th week post infection are consistent with the period of immunopathological damage of schistosomiasis japonica. 20,25 However, a link between IL-33, an endogenous mediator of tissue damage and its immunomodulatory armamentarium of Th cells, especially Treg and Th17, has not been further elucidated.…”

“…45 However, the role of IL-33 remains controversial in different schistosomiasis settings. [20][21][22] Therefore, more comprehensive exploration and deeper understanding of the IL-33/ST2 pathway especially in the peak of immunopathology during Schistosoma infection are required. In this work, we compiled evidence that the absence of the IL-33/ST2 axis aggravates the liver immunopathology and fibrosis at the 8th week post S. japonicum infection and the lack of this pathway decreases the percentage and function of Treg, along with upregulating the percentage and function of Th17.…”

“…57 Reports from different groups have suggested that variable functions of IL-33 in Schistosoma infected mice, which might duo to different species involved, different infection stages and assessment time points. 21,22,56 Given the diverse function of IL-33 during inflammation disorders, further investigation of detailed molecular mechanisms by which the IL-33/ST2 axis protects hepatic pathology associated with schistosomiasis may be favorable for defining novel targets to prevent its onset.…”

“…Both S. japonicum and S. mansoni infection resulted in upregulated IL-33 in experimental mice. [20][21][22] Moreover, serum IL-33 levels are increased in patients with schistosomiasis japonica, mansoni and haematobium. 21,23,24 Although IL-33 promotes type 2 immune responses in infected mice with S. japonicum while not in infected mice with S. mansoni, it has been associated with liver pathology in both experimental models.…”

Schistosoma mansoni egg-derived extracellular vesicles: A promising vaccine candidate against murine schistosomiasis

“…It was observed that the egg count was significantly reduced in group III in comparison to group IV, although the adult counting showed higher reduction rate in group IV in both couple and total count. This could be explained by the fact that Th2 environment in the prepatent period of schistosomiasis is important for female worm maturation and reproduction [ 43 , 44 ]. In the current work IFN γ level was higher in group III indicating more skewing of the immune response toward Th1 environment, compromising the female worm maturation, fecundity and reproduction.…”