Thioredoxin peroxidase secreted by Echinococcus granulosus (sensu stricto) promotes the alternative activation of macrophages via PI3K/AKT/mTOR pathway

Abstract

BackgroundLarvae of Echinococcus granulosus (sensu lato) dwell in host organs for a long time but elicit only a mild inflammatory response, which indicates that the resolution of host inflammation is necessary for parasite survival. The recruitment of alternatively activated macrophages (AAMs) has been observed in a variety of helminth infections, and emerging evidence indicates that AAMs are critical for the resolution of inflammation. However, whether AAMs can be induced by E. granulosus (s.l.) infection or thioredoxin peroxidase (TPx), one of the important molecules secreted by the parasite, remains unclear.MethodsThe activation status of peritoneal macrophages (PMs) derived from mice infected with E. granulosus (sensu stricto) was analyzed by evaluating the expression of phenotypic markers. PMs were then treated in vivo and in vitro with recombinant EgTPx (rEgTPx) and its variant (rvEgTPx) in combination with parasite excretory-secretory (ES) products, and the resulting activation of the PMs was evaluated by flow cytometry and real-time PCR. The phosphorylation levels of various molecules in the PI3K/AKT/mTOR pathway after parasite infection and antigen stimulation were also detected.ResultsThe expression of AAM-related genes in PMs was preferentially induced after E. granulosus (s.s.) infection, and phenotypic differences in cell morphology were detected between PMs isolated from E. granulosus (s.s.)-infected mice and control mice. The administration of parasite ES products or rEgTPx induced the recruitment of AAMs to the peritoneum and a notable skewing of the ratio of PM subsets, and these effects are consistent with those obtained after E. granulosus (s.s.) infection. ES products or rEgTPx also induced PMs toward an AAM phenotype in vitro. Interestingly, this immunomodulatory property of rEgTPx was dependent on its antioxidant activity. In addition, the PI3K/AKT/mTOR pathway was activated after parasite infection and antigen stimulation, and the activation of this pathway was suppressed by pre-treatment with an AKT/mTOR inhibitor.ConclusionsThis study demonstrates that E. granulosus (s.s.) infection and ES products, including EgTPx, can induce PM recruitment and alternative activation, at least in part, via the PI3K/AKT/mTOR pathway. These results suggest that EgTPx-induced AAMs might play a key role in the resolution of inflammation and thereby favour the establishment of hydatid cysts in the host.

Modulation of the mTOR pathway plays a central role in dendritic cell functions after Echinococcus granulosus antigen recognition

“…We have previously reported that exosome-like vesicles induce maturation of BMDCs with an increase of CD86 and a slight downregulation in the expression of MHC II molecule 56 . Likewise, previous reports have shown a weak maturation phenotype in mouse and human DCs upon stimulation with Eg antigens in combination with potent immunogens 36,38,57,[57][58][59][60][61] . Uptake and processing of antigens by immature DCs are critical steps in producing an immune response.…”

“…Previous studies in E. granulosus have shown in GM-CSF derived DCs or M-CSF derived macrophages that exposure to pLL strongly inhibited PI3K, Akt and GSK3 phosphorylation induced by LPS, and that stimulation of DCs with pLL alone inhibited basal phosphorylation of these proteins 37,38 . On the other hand, Eg excretory/secretory products induced alternative activated macrophages phenotype (M2), through the activation of the PI3K/AKT/mTOR pathway 36 . Our data are in line with those reported by Wang et al 36 , but are not contrary to those described by Pittini et al 37 , given that the presence of pLL did not inhibit Akt or GSK3 phosphorylation in Flt3L-BMDCs.…”

“…On the other hand, Eg excretory/secretory products induced alternative activated macrophages phenotype (M2), through the activation of the PI3K/AKT/mTOR pathway 36 . Our data are in line with those reported by Wang et al 36 , but are not contrary to those described by Pittini et al 37 , given that the presence of pLL did not inhibit Akt or GSK3 phosphorylation in Flt3L-BMDCs.…”

“…Recently, the modulation of these metabolic pathways by the parasite E. granulosus has been reported. Eg excretory/secretory products activate the PI3K/AKT/mTOR pathway and the recruitment of alternatively activated macrophages 36 . Also, Eg LL inhibits macrophage and CD11c + antigen presenting-cells (APCs) proliferation in response to IL-4 and M-CSF in vivo and in vitro 37 .…”

The Functional Parasitic Worm Secretome: Mapping the Place of Onchocerca volvulus Excretory Secretory Products

“…This action is mediated through sheep hydatid fluid (SHF) and antigen B (AgB), which suppress monocyte differentiation and DC maturation, as assessed by the dysregulation of costimulatory molecules and inflammatory cytokines [ 83 ]. The secreted thioredoxin peroxidase of Echinococcus granulosus ( C ) was recently shown to alternatively activate macrophages through the PI3K/AKT/mTOR pathway [ 84 ]. An experimental administration of ESPs from the nematode Nippostrongylus brasiliensis induced a Th2 response strong enough to counteract the Th1-polarizing Freund’s adjuvant [ 85 ].…”