IL-33 Contributes to Schistosoma japonicum-induced Hepatic Pathology through Induction of M2 Macrophages

Abstract

Interleukin (IL)-33 is involved in T helper (Th)2-biased immune responses in mice infected with Schistosoma, but the precise mechanism remains to be elucidated. Herein, we investigated the role of IL-33 and its receptor ST2L in hepatic granuloma pathology induced by Schistosoma japonicum infection. We found that IL-33 induced the increased production of IL-5 and IL-13 from splenocytes and liver mononuclear cells (MNCs) of infected mice. The infected mice developed significantly higher number of ST2L-expressing cells in spleen and liver. Most of the ST2L-expressing cells in liver were F4/80+ macrophages, indicating the key role of macrophages in the response to IL-33. However, the liver MNCs in male-only worm infection had a poor response to IL-33, though elevated serum IL-33 was observed. ST2L+F4/80+ cells were lower in male-only worm infection than that of mixed infection. IL-33 and soluble egg antigen (SEA) upregulated ST2L expression on macrophages in vitro and ST2L-expressing macrophage displayed MHCII-CD11b+M2 phenotype. Macrophage deletion significantly attenuated IL-33-induced type 2 immunity and egg granuloma formation during S. japonicum infection. These data demonstrate that IL-33 contributes to hepatic granuloma pathology through induction of M2 macrophages during S. japonicum infection.

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

“…It is known that IL-33 induces M2 polarization of macrophages (26,(28)(29)(30) and that M2 are essential for the excretion of schistosome eggs across intestinal tissues (14). It has also been reported that due to the impairment of their expulsion across the intestinal wall, more schistosome eggs accumulate in intestinal tissues (31,32).…”

“…1e), indicating that IL-33 may be dispensable for the excretion of schistosome eggs. Because several studies reported a pathogenic role for IL-33 in egg-induced liver pathology by an increased number of liver tissue eggs (25,26), we sought to see whether IL-33 de ciency would be associated with a decreased number of eggs in liver tissues of IL-33 −/− compared to WT mice.…”

“…However, the role of ILC2-activating cytokines IL-25, IL-33 and TSLP in schistosomiasis remains less understood. Focusing on the liver pathogenesis during S. japonicum infection, two studies showed that IL-33 contributes to the pathology development via induction of type 2 immune responses in infected mice (25,26). Indeed, studies have shown that IL-33 plays a critical role in the development of liver pathology through ILC2-derived IL-13-induced activation of hepatic stellate cells (HSC) (27) and alternative activation of macrophages (M2) (26).…”

“…Focusing on the liver pathogenesis during S. japonicum infection, two studies showed that IL-33 contributes to the pathology development via induction of type 2 immune responses in infected mice (25,26). Indeed, studies have shown that IL-33 plays a critical role in the development of liver pathology through ILC2-derived IL-13-induced activation of hepatic stellate cells (HSC) (27) and alternative activation of macrophages (M2) (26). Moreover, Yu et al (25) found that injection of exogenous IL-33 into S. japonicum-infected mice led to increased worm burden at the sixth week of infection without affecting their fecundity, suggesting that IL-33 might play a role in the migration and maturation of schistosome worms.…”

“…Because IL-33 is known to induce and/or amplify M2 polarization of macrophages (26,(28)(29)(30), known to be essential for the excretion of schistosome eggs (14), we thought that in addition to contributing to the maturation of schistosome worms through induction of type 2 immunity during prepatent schistosome infection, IL-33 may also play a critical role in the excretion of S. mansoni eggs across the intestinal tissues. We hypothesized that IL-33 de ciency will impair the maturation and reproduction of S. mansoni worms, and the expulsion of their eggs across the intestinal wall, leading to accumulation of eggs in intestinal tissues of IL-33 −/− mice (31,32), and that type 2 immunity would be impaired in the absence of IL-33.…”