%0 Journal Article %A Pim J Koelink %A Felicia M Bloemendaal %A Bofeng Li %A Liset Westera %A Esther W M Vogels %A Manon van Roest %A Anouk K Gloudemans %A Angelique B van 't Wout %A Hannelie Korf %A Séverine Vermeire %A Anje A te Velde %A Cyriel Y Ponsioen %A Geert RAM D'Haens %A J Sjef Verbeek %A Terrence L Geiger %A Manon E Wildenberg %A Gijs R van den Brink %T Anti-TNF therapy in IBD exerts its therapeutic effect through macrophage IL-10 signalling %D 2019 %R 10.1136/gutjnl-2019-318264 %J Gut %P gutjnl-2019-318264 %X 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. %U https://gut.bmj.com/content/gutjnl/early/2019/09/09/gutjnl-2019-318264.full.pdf