Particles from the Echinococcus granulosus Laminated Layer Inhibit CD40 Upregulation in Dendritic Cells by Interfering with Akt Activation

Abstract

The larval stage of the cestode Echinococcus granulosus causes cystic echinococcosis in humans and livestock. This larva is protected by the millimeter-thick, mucin-based laminated layer (LL), from which materials have to be shed to allow parasite growth. We previously reported that dendritic cells (DCs) respond to microscopic pieces of the mucin gel of the LL (pLL) with unconventional maturation phenotypes, in the absence or presence of Toll-like receptor (TLR) agonists, including lipopolysaccharide (LPS).

Activation of the NLRP3 Inflammasome by Particles from the Echinococcus granulosus Laminated Layer

“…In mouse bone marrow-derived dendritic cells (BMDC), in particular, pLL induce the expression of CD86 and enhance lipopolysaccharide (LPS)-elicited CD86 and interleukin 10 (IL-10) expression while blunting the responses of CD40 and IL-12p70 (as well as its subunit IL-12/23p40) to LPS (35). These changes elicited by pLL require actin dynamics, phosphatidylinositol 3-kinase (PI3K) class I, and probably the kinase Syk, but not particle phagocytosis, and appear to be receptor independent (36). These features match a mechanism termed "membrane affinity-triggered signaling" (MATS), proposed by Yan Shi to explain DC and macrophage responses to solid, mostly crystalline materials (38).…”

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.…”

“…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 .…”

“…In contrast, in presence of HF, only a decrease in CD40 was observed, which was also enhanced by this immunosuppressive drug ( Figure 2B). This slight phenotypic maturation in DCs could be explained by the absence of activation in the NFB and MAP kinases pathways 38 . 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 .…”

“…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 . In the present manuscript, we address how the recognition of purified laminar layer (pLL) or HF from E. granulosus by DCs, induces phenotypical and functional changes in a mTORC1-dependent manner, with a subsequent in vitro splenocyte proliferation required to trigger an anthelminthic response.…”