Anti-TNF Therapy in IBD Exerts Its Therapeutic Effect Through Macrophage IL-10 Signalling

Overview

Journal Gut

Specialty Gastroenterology

Date 2019 Sep 12

PMID 31506328

Citations 73

Authors

Pim J Koelink

Felicia M Bloemendaal

Bofeng Li

Liset Westera

Esther W M Vogels

Manon van Roest

Anouk K Gloudemans

Angelique B van t Wout

Hannelie Korf

Severine Vermeire

Anje A Te Velde

Cyriel Y Ponsioen

Geert Ram dHaens

J Sjef Verbeek

Terrence L Geiger

Manon E Wildenberg

Gijs R van den Brink

Affiliations

Soon will be listed here.

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+CD45Rb 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+CD45Rb 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.

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