Particles from the Echinococcus granulosus laminated layer inhibit IL-4 and growth factor-driven Akt phosphorylation and proliferative responses in macrophages

Abstract

Proliferation of macrophages is a hallmark of inflammation in many type 2 settings including helminth infections. The cellular expansion is driven by the type 2 cytokine interleukin-4 (IL-4), as well as by M-CSF, which also controls homeostatic levels of tissue resident macrophages. Cystic echinococcosis, caused by the tissue-dwelling larval stage of the cestode Echinococcus granulosus, is characterised by normally subdued local inflammation. Infiltrating host cells make contact only with the acellular protective coat of the parasite, called laminated layer, particles of which can be ingested by phagocytic cells. Here we report that a particulate preparation from this layer (pLL) strongly inhibits the proliferation of macrophages in response to IL-4 or M-CSF. In addition, pLL also inhibits IL-4-driven up-regulation of Relm-α, without similarly affecting Chitinase-like 3 (Chil3/Ym1). IL-4-driven cell proliferation and up-regulation of Relm-α are both known to depend on the phosphatidylinositol (PI3K)/Akt pathway, which is dispensable for induction of Chil3/Ym1. Exposure to pLL in vitro inhibited Akt activation in response to proliferative stimuli, providing a potential mechanism for its activities. Our results suggest that the E. granulosus laminated layer exerts some of its anti-inflammatory properties through inhibition of PI3K/Akt activation and consequent limitation of macrophage proliferation.

New insights of the local immune response against both fertile and infertile hydatid cysts

“…How these proteins enter the hydatid cyst is not clearly defined; the germinal layer consists of a distal cytoplasmic syncytium from which microtriches project into the laminated layer; these two parasite structures form a barrier that deny access to both host defense macromolecules and cells [44]. Particles of the laminated layer are described to inhibit macrophage proliferation [45] and induce the production of arginase (inhibiting nitric oxide (NO) activity) [46]. In fact, infertile hydatid cysts are correlated with higher levels of NO, and it has been proposed that NO-producing immune cells are unable to penetrate the physical barrier imposed by the laminated layer [47], however, as seen in Fig 5D, this is a possibility.…”

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

“…In line with these results and in the absence of growth factors, both parasitic antigens stimulated phosphorylation of mTOR (Ser2448) in BMDCs, being this effect higher with pLL compared to HF ( Figure 5). 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 .…”

“…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 . Furthermore, the upregulation of the co-stimulatory molecule CD40 was inhibited in DCs by interfering with Akt and GSK3 activation 38 .…”

Granulomatous responses in larval taeniid infections

“…infection of mice with a high dose of T. crassiceps , selective and massive apoptosis of eosinophils was observed . In terms of cell proliferation, the E. granulosus LL can inhibit proliferation of both resident and recruited macrophages in response to IL‐4 or the basal proliferative signal M‐CSF …”

“…54 In terms of cell proliferation, the E. granulosus LL can inhibit proliferation of both resident and recruited macrophages in response to IL-4 or the basal proliferative signal M-CSF. 140 With respect to mechanisms that operate on the overall control of immunity, much recent information in Echinococcus infections points to a strong participation of Foxp3 + regulatory T cells and the regulatory and profibrotic cytokine TGFβ. [141][142][143][144][145][146][147][148][149] Two studies in mice 143,144 show massive increase in local expression of TGFβ pathway proteins in E. multilocularis-infected livers during the course of chronic infection, relating it to the fibrosis process.…”