RT Journal Article
SR Electronic
T1 Anti-TNF therapy in IBD exerts its therapeutic effect through macrophage IL-10 signalling
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP gutjnl-2019-318264
DO 10.1136/gutjnl-2019-318264
A1 Pim J Koelink
A1 Felicia M Bloemendaal
A1 Bofeng Li
A1 Liset Westera
A1 Esther W M Vogels
A1 Manon van Roest
A1 Anouk K Gloudemans
A1 Angelique B van 't Wout
A1 Hannelie Korf
A1 Séverine Vermeire
A1 Anje A te Velde
A1 Cyriel Y Ponsioen
A1 Geert RAM D'Haens
A1 J Sjef Verbeek
A1 Terrence L Geiger
A1 Manon E Wildenberg
A1 Gijs R van den Brink
YR 2019
UL http://gut.bmj.com/content/early/2019/09/20/gutjnl-2019-318264.abstract
AB Objective Macrophage interleukin (IL)-10 signalling plays a critical role in the maintenance of a regulatory phenotype that prevents the development of IBD. We have previously found that anti-tumour necrosis factor (TNF) monoclonal antibodies act through Fcγ-receptor (FcγR) signalling to promote repolarisation of proinflammatory intestinal macrophages to a CD206+ regulatory phenotype. The role of IL-10 in anti-TNF-induced macrophage repolarisation has not been examined.Design We used human peripheral blood monocytes and mouse bone marrow-derived macrophages to study IL-10 production and CD206+ regulatory macrophage differentiation. To determine whether the efficacy of anti-TNF was dependent on IL-10 signalling in vivo and in which cell type, we used the CD4+CD45Rbhigh T-cell transfer model in combination with several genetic mouse models.Results Anti-TNF therapy increased macrophage IL-10 production in an FcγR-dependent manner, which caused differentiation of macrophages to a more regulatory CD206+ phenotype in vitro. Pharmacological blockade of IL-10 signalling prevented the induction of these CD206+ regulatory macrophages and diminished the therapeutic efficacy of anti-TNF therapy in the CD4+CD45Rbhigh T-cell transfer model of IBD. Using cell type-specific IL-10 receptor mutant mice, we found that IL-10 signalling in macrophages but not T cells was critical for the induction of CD206+ regulatory macrophages and therapeutic response to anti-TNF.Conclusion The therapeutic efficacy of anti-TNF in resolving intestinal inflammation is critically dependent on IL-10 signalling in macrophages.