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PGD2 and CRTH2 counteract Type 2 cytokine-elicited intestinal epithelial responses during helminth infection.

ABSTRACT: Type 2 inflammation is associated with epithelial cell responses, including goblet cell hyperplasia, that promote worm expulsion during intestinal helminth infection. How these epithelial responses are regulated remains incompletely understood. Here, we show that mice deficient in the prostaglandin D2 (PGD2) receptor CRTH2 and mice with CRTH2 deficiency only in nonhematopoietic cells exhibited enhanced worm clearance and intestinal goblet cell hyperplasia following infection with the helminth Nippostrongylus brasiliensis. Small intestinal stem, goblet, and tuft cells expressed CRTH2. CRTH2-deficient small intestinal organoids showed enhanced budding and terminal differentiation to the goblet cell lineage. During helminth infection or in organoids, PGD2 and CRTH2 down-regulated intestinal epithelial Il13ra1 expression and reversed Type 2 cytokine-mediated suppression of epithelial cell proliferation and promotion of goblet cell accumulation. These data show that the PGD2-CRTH2 pathway negatively regulates the Type 2 cytokine-driven epithelial program, revealing a mechanism that can temper the highly inflammatory effects of the anti-helminth response.

SUBMITTER: Oyesola OO

PROVIDER: S-EPMC8294949 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundSoil-transmitted helminths (STHs) and humans share long co-evolutionary histories over which STHs have evolved strategies to permit their persistence by downregulating host immunity. Understanding the interactions between STHs and other pathogens can inform our understanding of human evolution and contemporary disease patterns.MethodologyWe worked with Tsimane forager-horticulturalists in the Bolivian Amazon, where STHs are prevalent. We tested whether STHs and eosinophil levels-likely indicative of infection in this population-are associated with dampened immune responses to in vitro stimulation with H1N1 and lipopolysaccharide (LPS) antigens. Whole blood samples (n = 179) were treated with H1N1 vaccine and LPS and assayed for 13 cytokines (INF-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, GM-CSF and TNF-ɑ). We evaluated how STHs and eosinophil levels affected cytokine responses and T helper (Th) 1 and Th2-cytokine suite responses to stimulation.ResultsInfection with Ascaris lumbricoides was significantly (P ≤ 0.05) associated with lower response of some cytokines to H1N1 and LPS in women. Eosinophils were significantly negatively associated with some cytokine responses to H1N1 and LPS, with the strongest effects in women, and associated with a reduced Th1- and Th2-cytokine response to H1N1 and LPS in women and men.Conclusions and implicationsConsistent with the 'old friends' and hygiene hypotheses, we find that STHs were associated with dampened cytokine responses to certain viral and bacterial antigens. This suggests that STH infections may play an essential role in immune response regulation and that the lack of STH immune priming in industrialized populations may increase the risk of over-reactive immunity. Lay Summary: Indicators of helminth infection were associated with dampened cytokine immune responses to in vitro stimulation with viral and bacterial antigens in Tsimane forager-horticulturalists in the Bolivian Amazon, consistent with the 'old friends' and hygiene hypotheses.

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PGD2 and CRTH2 counteract Type 2 cytokine-elicited intestinal epithelial responses during helminth infection.

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