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Anti-TNF therapy in IBD exerts its therapeutic effect through macrophage IL-10 signalling.

Tijdschriftbijdrage - Tijdschriftartikel

Objective Macrophage interleukin (IL)-10 signallingplays a critical role in the maintenance of a regulatoryphenotype that prevents the development of IBD.We have previously found that anti-tumour necrosisfactor (TNF) monoclonal antibodies act through Fcγreceptor (FcγR) signalling to promote repolarisation ofproinflammatory intestinal macrophages to a CD206+regulatory phenotype. The role of IL-10 in anti-TNFinduced macrophage repolarisation has not beenexamined.Design We used human peripheral blood monocytesand mouse bone marrow-derived macrophages to studyIL-10 production and CD206+ regulatory macrophagedifferentiation. To determine whether the efficacy ofanti-TNF was dependent on IL-10 signalling in vivo andin which cell type, we used the CD4+CD45Rbhigh T-celltransfer model in combination with several geneticmouse models.Results Anti-TNF therapy increased macrophage IL-10production in an FcγR-dependent manner, which causeddifferentiation of macrophages to a more regulatoryCD206+ phenotype in vitro. Pharmacological blockadeof IL-10 signalling prevented the induction of theseCD206+ regulatory macrophages and diminishedthe therapeutic efficacy of anti-TNF therapy in theCD4+CD45Rbhigh T-cell transfer model of IBD. Usingcell type-specific IL-10 receptor mutant mice, we foundthat IL-10 signalling in macrophages but not T cellswas critical for the induction of CD206+ regulatorymacrophages and therapeutic response to anti-TNF.Conclusion The therapeutic efficacy of anti-TNF inresolving intestinal inflammation is critically dependenton IL-10 signalling in macrophages.
Tijdschrift: Gut
ISSN: 0017-5749
Issue: 6
Volume: 69
Pagina's: 1 - 11
Aantal pagina's: 11
Jaar van publicatie:2020