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

Mukhopadhyay, Subhankar and Heinz, Eva and Porreca, Immacolata and Alasoo, Kaur and Yeung, Amy and Yang, Huei Ting and Schwerd, Tobias and Forbester, Jessica L. and Hale, Christine and Agu, Chukwuma A. and Choi, Yoon Ha and Rodrigues, Julia and Capitani, Melania and Jostins-Dean, Luke and Thomas, David C. and Travis, Simon and Gaffney, Daniel and Skarnes, William C. and Thomson, Nicholas and Uhlig, Holm H. and Dougan, Gordon and Powrie, Fiona (2020) Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2. Journal of Experimental Medicine, 217 (2). e20180649. ISSN 0022-1007 (https://doi.org/10.1084/jem.20180649)

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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 IL-10RB-/-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.

ORCID iDs

Mukhopadhyay, Subhankar, Heinz, Eva ORCID logoORCID: https://orcid.org/0000-0003-4413-3756, Porreca, Immacolata, Alasoo, Kaur, Yeung, Amy, Yang, Huei Ting, Schwerd, Tobias, Forbester, Jessica L., Hale, Christine, Agu, Chukwuma A., Choi, Yoon Ha, Rodrigues, Julia, Capitani, Melania, Jostins-Dean, Luke, Thomas, David C., Travis, Simon, Gaffney, Daniel, Skarnes, William C., Thomson, Nicholas, Uhlig, Holm H., Dougan, Gordon and Powrie, Fiona;
CORE (COnnecting REpositories)