Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2

Subhankar Mukhopadhyay; Eva Heinz; Immacolata Porreca; Kaur Alasoo; Amy Yeung; Huei Ting Yang; Tobias Schwerd; Jessica L. Forbester; Christine Hale; Chukwuma A. Agu; Yoon Ha Choi; Julia Rodrigues; Melania Capitani; Luke Jostins-Dean; David C. Thomas; Simon Travis; Daniel Gaffney; William C. Skarnes; Nicholas Thomson; Holm H. Uhlig; Gordon Dougan; Fiona Powrie

doi:10.1084/jem.20180649

Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2

Subhankar Mukhopadhyay
, Eva Heinz
, Immacolata Porreca
, Kaur Alasoo
, Amy Yeung
, Huei Ting Yang
, Tobias Schwerd
, Jessica L. Forbester
, Christine Hale
, Chukwuma A. Agu
, Yoon Ha Choi
, Julia Rodrigues
, Melania Capitani
, Luke Jostins-Dean
, David C. Thomas
, Simon Travis
, Daniel Gaffney
, William C. Skarnes
, Nicholas Thomson
, Holm H. Uhlig

Gordon Dougan, Fiona Powrie

Vector Biology

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

47 Citations (Scopus)

Abstract

Loss of IL-10 signaling in macrophages (Mφs) leads to inflammatory bowel disease (IBD). Induced pluripotent stem cells

(iPSCs) were generated from an infantile-onset IBD patient lacking a functional IL10RB gene. Mφs differentiated from IL10RB−/− iPSCs lacked IL-10RB mRNA expression, were unable to phosphorylate STAT3, and failed to reduce LPS induced

inflammatory cytokines in the presence of exogenous IL-10. IL-10RB−/− Mφs exhibited a striking defect in their ability to kill

Salmonella enterica serovar Typhimurium, which was rescuable after experimentally introducing functional copies of the IL10RB

gene. Genes involved in synthesis and receptor pathways for eicosanoid prostaglandin E2 (PGE2) were more highly induced in

IL-10RB−/− Mφs, and these Mφs produced higher amounts of PGE2 after LPS stimulation compared with controls.

Furthermore, pharmacological inhibition of PGE2 synthesis and PGE2 receptor blockade enhanced bacterial killing in Mφs.

These results identify a regulatory interaction between IL-10 and PGE2, dysregulation of which may drive aberrant Mφ

activation and impaired host defense contributing to IBD pathogenesis.

Original language	English
Article number	e20180649
Pages (from-to)	e20180649
Journal	Journal of Experimental Medicine
Volume	217
Issue number	2
DOIs	https://doi.org/10.1084/jem.20180649
Publication status	Published - 5 Dec 2019

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10.1084/jem.20180649Licence: CC BY

Jem 20180649Final published version, 2.86 MBLicence: CC BY

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Mukhopadhyay, S., Heinz, E., Porreca, I., Alasoo, K., Yeung, A., Yang, H. T., Schwerd, T., Forbester, J. L., Hale, C., Agu, C. A., Choi, Y. H., Rodrigues, J., Capitani, M., Jostins-Dean, L., Thomas, D. C., Travis, S., Gaffney, D., Skarnes, W. C., Thomson, N., ... Powrie, F. (2019). Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2. Journal of Experimental Medicine, 217(2), e20180649. Article e20180649. https://doi.org/10.1084/jem.20180649

@article{4e473876d0b24f86936097a033a1f96d,

title = "Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2",

abstract = "Loss of IL-10 signaling in macrophages (Mφs) leads to inflammatory bowel disease (IBD). Induced pluripotent stem cells(iPSCs) were generated from an infantile-onset IBD patient lacking a functional IL10RB gene. Mφs differentiated from IL10RB−/− iPSCs lacked IL-10RB mRNA expression, were unable to phosphorylate STAT3, and failed to reduce LPS inducedinflammatory cytokines in the presence of exogenous IL-10. IL-10RB−/− Mφs exhibited a striking defect in their ability to killSalmonella enterica serovar Typhimurium, which was rescuable after experimentally introducing functional copies of the IL10RBgene. Genes involved in synthesis and receptor pathways for eicosanoid prostaglandin E2 (PGE2) were more highly induced inIL-10RB−/− Mφs, and these Mφs produced higher amounts of PGE2 after LPS stimulation compared with controls.Furthermore, pharmacological inhibition of PGE2 synthesis and PGE2 receptor blockade enhanced bacterial killing in Mφs.These results identify a regulatory interaction between IL-10 and PGE2, dysregulation of which may drive aberrant Mφactivation and impaired host defense contributing to IBD pathogenesis.",

author = "Subhankar Mukhopadhyay and Eva Heinz and Immacolata Porreca and Kaur Alasoo and Amy Yeung and Yang, \{Huei Ting\} and Tobias Schwerd and Forbester, \{Jessica L.\} and Christine Hale and Agu, \{Chukwuma A.\} and Choi, \{Yoon Ha\} and Julia Rodrigues and Melania Capitani and Luke Jostins-Dean and Thomas, \{David C.\} and Simon Travis and Daniel Gaffney and Skarnes, \{William C.\} and Nicholas Thomson and Uhlig, \{Holm H.\} and Gordon Dougan and Fiona Powrie",

year = "2019",

month = dec,

day = "5",

doi = "10.1084/jem.20180649",

language = "English",

volume = "217",

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Mukhopadhyay, S, Heinz, E, Porreca, I, Alasoo, K, Yeung, A, Yang, HT, Schwerd, T, Forbester, JL, Hale, C, Agu, CA, Choi, YH, Rodrigues, J, Capitani, M, Jostins-Dean, L, Thomas, DC, Travis, S, Gaffney, D, Skarnes, WC, Thomson, N, Uhlig, HH, Dougan, G & Powrie, F 2019, 'Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2', Journal of Experimental Medicine, vol. 217, no. 2, e20180649, pp. e20180649. https://doi.org/10.1084/jem.20180649

TY - JOUR

T1 - Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2

AU - Mukhopadhyay, Subhankar

AU - Heinz, Eva

AU - Porreca, Immacolata

AU - Alasoo, Kaur

AU - Yeung, Amy

AU - Yang, Huei Ting

AU - Schwerd, Tobias

AU - Forbester, Jessica L.

AU - Hale, Christine

AU - Agu, Chukwuma A.

AU - Choi, Yoon Ha

AU - Rodrigues, Julia

AU - Capitani, Melania

AU - Jostins-Dean, Luke

AU - Thomas, David C.

AU - Travis, Simon

AU - Gaffney, Daniel

AU - Skarnes, William C.

AU - Thomson, Nicholas

AU - Uhlig, Holm H.

AU - Dougan, Gordon

AU - Powrie, Fiona

PY - 2019/12/5

Y1 - 2019/12/5

N2 - Loss of IL-10 signaling in macrophages (Mφs) leads to inflammatory bowel disease (IBD). Induced pluripotent stem cells(iPSCs) were generated from an infantile-onset IBD patient lacking a functional IL10RB gene. Mφs differentiated from IL10RB−/− iPSCs lacked IL-10RB mRNA expression, were unable to phosphorylate STAT3, and failed to reduce LPS inducedinflammatory cytokines in the presence of exogenous IL-10. IL-10RB−/− Mφs exhibited a striking defect in their ability to killSalmonella enterica serovar Typhimurium, which was rescuable after experimentally introducing functional copies of the IL10RBgene. Genes involved in synthesis and receptor pathways for eicosanoid prostaglandin E2 (PGE2) were more highly induced inIL-10RB−/− Mφs, and these Mφs produced higher amounts of PGE2 after LPS stimulation compared with controls.Furthermore, pharmacological inhibition of PGE2 synthesis and PGE2 receptor blockade enhanced bacterial killing in Mφs.These results identify a regulatory interaction between IL-10 and PGE2, dysregulation of which may drive aberrant Mφactivation and impaired host defense contributing to IBD pathogenesis.

AB - Loss of IL-10 signaling in macrophages (Mφs) leads to inflammatory bowel disease (IBD). Induced pluripotent stem cells(iPSCs) were generated from an infantile-onset IBD patient lacking a functional IL10RB gene. Mφs differentiated from IL10RB−/− iPSCs lacked IL-10RB mRNA expression, were unable to phosphorylate STAT3, and failed to reduce LPS inducedinflammatory cytokines in the presence of exogenous IL-10. IL-10RB−/− Mφs exhibited a striking defect in their ability to killSalmonella enterica serovar Typhimurium, which was rescuable after experimentally introducing functional copies of the IL10RBgene. Genes involved in synthesis and receptor pathways for eicosanoid prostaglandin E2 (PGE2) were more highly induced inIL-10RB−/− Mφs, and these Mφs produced higher amounts of PGE2 after LPS stimulation compared with controls.Furthermore, pharmacological inhibition of PGE2 synthesis and PGE2 receptor blockade enhanced bacterial killing in Mφs.These results identify a regulatory interaction between IL-10 and PGE2, dysregulation of which may drive aberrant Mφactivation and impaired host defense contributing to IBD pathogenesis.

U2 - 10.1084/jem.20180649

DO - 10.1084/jem.20180649

M3 - Article

SN - 0022-1007

VL - 217

SP - e20180649

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 2

M1 - e20180649

ER -

Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2

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