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

Oyebola O. Oyesola, Michael T. Shanahan, Matt Kanke, Bridget M. Mooney, Lauren M. Webb, Shuchi Smita, Macy K. Matheson, Pamela Campioli, Duc Pham, Simon P. Früh, John W. McGinty, Madeline J. Churchill, Jordan L. Cahoon, Pavithra Sundaravaradan, Becca A. Flitter, Karthik Mouli, Marija S. Nadjsombati, Elena Kamynina, Seth A. Peng, Rebecca L. CubittKarsten Gronert, James D. Lord, Isabella Rauch, Jakob von Moltke, Praveen Sethupathy, Elia D. Tait Wojno

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish (US)
Article numbere20202178
JournalJournal of Experimental Medicine
Volume218
Issue number9
DOIs
StatePublished - Jul 20 2021

ASJC Scopus subject areas

  • Medicine(all)

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