@article {Koelinkgutjnl-2019-318264, author = {Pim J Koelink and Felicia M Bloemendaal and Bofeng Li and Liset Westera and Esther W M Vogels and Manon van Roest and Anouk K Gloudemans and Angelique B van {\textquoteright}t Wout and Hannelie Korf and S{\'e}verine Vermeire and Anje A te Velde and Cyriel Y Ponsioen and Geert RAM D{\textquoteright}Haens and J Sjef Verbeek and Terrence L Geiger and Manon E Wildenberg and Gijs R van den Brink}, title = {Anti-TNF therapy in IBD exerts its therapeutic effect through macrophage IL-10 signalling}, elocation-id = {gutjnl-2019-318264}, year = {2019}, doi = {10.1136/gutjnl-2019-318264}, publisher = {BMJ Publishing Group}, abstract = {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.}, issn = {0017-5749}, URL = {https://gut.bmj.com/content/early/2019/09/20/gutjnl-2019-318264}, eprint = {https://gut.bmj.com/content/early/2019/09/20/gutjnl-2019-318264.full.pdf}, journal = {Gut} }