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. Cubitt; Karsten Gronert; James D. Lord; Isabella Rauch; Jakob von Moltke; Praveen Sethupathy; Elia D. Tait Wojno

doi:10.1084/jem.20202178

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

Molecular Microbiology and Immunology

Research output: Contribution to journal › Article › peer-review

30 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 language	English (US)
Article number	e20202178
Journal	Journal of Experimental Medicine
Volume	218
Issue number	9
DOIs	https://doi.org/10.1084/jem.20202178
State	Published - Jul 20 2021

ASJC Scopus subject areas

Immunology and Allergy
Immunology

Access to Document

10.1084/jem.20202178

Cite this

Oyesola, O. O., Shanahan, M. T., Kanke, M., Mooney, B. M., Webb, L. M., Smita, S., Matheson, M. K., Campioli, P., Pham, D., Früh, S. P., McGinty, J. W., Churchill, M. J., Cahoon, J. L., Sundaravaradan, P., Flitter, B. A., Mouli, K., Nadjsombati, M. S., Kamynina, E., Peng, S. A., ... Tait Wojno, E. D. (2021). PGD₂ and CRTH2 counteract Type 2 cytokine–elicited intestinal epithelial responses during helminth infection. Journal of Experimental Medicine, 218(9), Article e20202178. https://doi.org/10.1084/jem.20202178

Oyesola, OO, Shanahan, MT, Kanke, M, Mooney, BM, Webb, LM, Smita, S, Matheson, MK, Campioli, P, Pham, D, Früh, SP, McGinty, JW, Churchill, MJ, Cahoon, JL, Sundaravaradan, P, Flitter, BA, Mouli, K, Nadjsombati, MS, Kamynina, E, Peng, SA, Cubitt, RL, Gronert, K, Lord, JD, Rauch, I, von Moltke, J, Sethupathy, P & Tait Wojno, ED 2021, 'PGD₂ and CRTH2 counteract Type 2 cytokine–elicited intestinal epithelial responses during helminth infection', Journal of Experimental Medicine, vol. 218, no. 9, e20202178. https://doi.org/10.1084/jem.20202178

@article{a75a9edaedcf4bafa9014a3abf2015de,

title = "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.",

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

note = "Publisher Copyright: {\textcopyright} 2021 Oyesola et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).",

year = "2021",

month = jul,

day = "20",

doi = "10.1084/jem.20202178",

language = "English (US)",

volume = "218",

journal = "Journal of Experimental Medicine",

issn = "0022-1007",

publisher = "Rockefeller University Press",

number = "9",

}

TY - JOUR

T1 - PGD2 and CRTH2 counteract Type 2 cytokine–elicited intestinal epithelial responses during helminth infection

AU - Oyesola, Oyebola O.

AU - Shanahan, Michael T.

AU - Kanke, Matt

AU - Mooney, Bridget M.

AU - Webb, Lauren M.

AU - Smita, Shuchi

AU - Matheson, Macy K.

AU - Campioli, Pamela

AU - Pham, Duc

AU - Früh, Simon P.

AU - McGinty, John W.

AU - Churchill, Madeline J.

AU - Cahoon, Jordan L.

AU - Sundaravaradan, Pavithra

AU - Flitter, Becca A.

AU - Mouli, Karthik

AU - Nadjsombati, Marija S.

AU - Kamynina, Elena

AU - Peng, Seth A.

AU - Cubitt, Rebecca L.

AU - Gronert, Karsten

AU - Lord, James D.

AU - Rauch, Isabella

AU - von Moltke, Jakob

AU - Sethupathy, Praveen

AU - Tait Wojno, Elia D.

N1 - Publisher Copyright: © 2021 Oyesola et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

PY - 2021/7/20

Y1 - 2021/7/20

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85111541042&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85111541042&partnerID=8YFLogxK

U2 - 10.1084/jem.20202178

DO - 10.1084/jem.20202178

M3 - Article

C2 - 34283207

AN - SCOPUS:85111541042

SN - 0022-1007

VL - 218

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 9

M1 - e20202178

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this