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 - 2020/2/1
Y1 - 2020/2/1
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 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.
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 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.
KW - cell differentiation
KW - gene knockout techniques
KW - interleukin-10
U2 - 10.1084/jem.20180649
DO - 10.1084/jem.20180649
M3 - Article
C2 - 31819956
AN - SCOPUS:85076278448
SN - 0022-1007
VL - 217
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 2
M1 - e20180649
ER -