Helminth-derived metabolites induce tolerogenic functional, metabolic, and transcriptional signatures in dendritic cells that attenuate experimental colitis.

Abstract

Inflammatory bowel diseases (IBD) are chronic inflammatory diseases in which abdominal pain, bloody diarrhea, weight loss, and fatigue collectively result in diminished quality of patient life. The disappearance of intestinal helminth infections in Western societies is associated with an increased prevalence of IBD and other immune-mediated inflammatory diseases. Evidence indicates that helminths induce tolerogenic dendritic cells (tolDCs), which promote intestinal tolerance and attenuate intestinal inflammation characteristic of IBD, but the exact mechanism is unclear. Helminth-derived excretory-secretory (HES) products including macromolecules, proteins, and polysaccharides have been shown to modulate the antigen presenting function of DCs with down-stream effects on effector CD4 + T cells. Previous studies indicate that DCs in helminth-infected animals induce tolerance to unrelated antigens and DCs exposed to HES display phenotypic and functional features of tolDCs. Here, we identify that nonpolar metabolites (HnpM) produced by a helminth, the murine gastrointestinal nematode Heligmosomoides polygyrus bakeri (Hpb), induce tolDCs as evidenced by decreased LPS-induced TNF and increased IL-10 secretion and reduced expression of MHC-II, CD86, and CD40. Furthermore, these DCs inhibited OVA-specific CD4 + T cell proliferation and induced CD4 + Foxp3 + regulatory T cells. Adoptive transfer of HnpM-induced tolDCs attenuated DSS-induced intestinal inflammation characteristic of IBD. Mechanistically, HnpM induced metabolic and transcriptional signatures in BMDCs consistent with tolDCs. Collectively, our findings provide groundwork for further investigation into novel mechanisms regulating DC tolerance and the role of helminth secreted metabolites in attenuating intestinal inflammation associated with IBD. Summary Sentence: Metabolites produced by Heligmosomoides polygyrus induce metabolic and transcriptional changes in DCs consistent with tolDCs, and adoptive transfer of these DCs attenuated DSS-induced intestinal inflammation.