Abstract
ES-62, a glycoprotein secreted by the parasitic filarial nematode Acanthocheilonema viteae, subverts host immune responses towards anti-inflammatory phenotypes by virtue of covalently attached phosphorylcholine (PC). The PC dictates that ES-62 exhibits protection in murine models of inflammatory disease and hence a library of drug-like PC-based small molecule analogues (SMAs) was synthesised. Four sulfone-containing SMAs termed 11a, 11e, 11i and 12b were found to reduce mouse bone marrow-derived dendritic cell (DC) pathogen-associated molecular pattern (PAMP)-induced pro-inflammatory cytokine production, inhibit NF-κB p65 activation, and suppress LPS-induced up-regulation of CD40 and CD86. Active SMAs also resulted in a DC phenotype that exhibited reduced capacity to prime antigen (Ag)-specific IFN-γ production during co-culture with naïve transgenic TCR DO.11.10 T cells in vitro and reduced their ability, following adoptive transfer, to prime the expansion of Ag-specific T lymphocytes, specifically TH17 cells, in vivo. Consistent with this, mice receiving DCs treated with SMAs exhibited significantly reduced severity of collagen-induced arthritis and this was accompanied by a significant reduction in IL-17+ cells in the draining lymph nodes. Collectively, these studies indicate that drug-like compounds that target DCs can be designed from parasitic worm products and demonstrate the potential for ES-62 SMA-based DC therapy in inflammatory disease.
Highlights
Dendritic cells (DCs) are professional antigen (Ag)-presenting cells that provide a critical link between the innate and adaptive immune systems
Given the pivotal role of DCs in the protection afforded by ES-62 in suppressing IL-17 responses in CIA12, we wished to determine whether DCs were a therapeutic target for the small molecule analogues (SMAs): we show that SMAs 11a and 12b, along with two other sulfones - 11e and 11i, modulate DC responses in vitro such that the cells are refractory to subsequent activation by Toll-like receptors (TLRs)-pathogen-associated molecular pattern (PAMP) and are characterised by their reduced expression of co-stimulatory molecules CD40 and CD86, inhibited production of IL-12, IL-6 and TNF-α, and abrogated priming of Ag-specific T helper cell 1 (TH1) responses
Sulfone-type SMAs 11a, 11e, 11i and 12b each reduced the LPS-stimulated production of IL-6, TNF-α and IL-12(p70) (Fig. 1E–G, left hand panels)
Summary
Dendritic cells (DCs) are professional antigen (Ag)-presenting cells that provide a critical link between the innate and adaptive immune systems. ES-62, a glycoprotein secreted by the rodent filarial nematode Acanthocheilonema viteae, was the first parasitic helminth molecule found to modulate the ability of DCs to prime polarised TH responses when it was shown that DCs matured with ES-62 promote Ag-specific IL-4 production by T cells whilst inhibiting their capacity to produce IFN-γ in vitro[6] This reflects that DCs exposed to ES-62 in vitro or in vivo, exhibit decreased capacity to generate pro-inflammatory responses to TLR2, 4 and 9 ligands (BLP, LPS and CpG), as evidenced by their reduced www.nature.com/scientificreports/. As such DCs mimic the previously reported effects in CIA observed when these SMAs were administered directly, these findings support the therapeutic potential of SMA-DC therapy in inflammatory diseases such as RA
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