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

Abstract

ObjectiveMacrophage 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.DesignWe 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.ResultsAnti-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.ConclusionThe therapeutic efficacy of anti-TNF in resolving intestinal inflammation is critically dependent on IL-10 signalling in macrophages.

E prostanoid receptor 4 expressing macrophages promote the regeneration of the intestinal epithelial barrier upon inflammation

“…The presence of CD206 + regulatory macrophages has been proposed as a favorable prognostic factor in determining the response rate to anti-TNFα therapy in patients with CD (15,16). In addition, recent studies even suggest that induction of CD206 + macrophages vai the Fc 5 portion of ipilimumab mediating the activation of the Fcγ receptor maybe an essential component of the anti-TNFα therapy (40). The correlation between the expression of EP4 and CD206 observed in our study indicates a new mechanistic role of PGE2 in inducing wound healing macrophages.…”

Ameliorative Effect of Heat-Killed Lactobacillus plantarum L.137 and/or Aloe vera against Colitis in Mice

“…Accordingly, anti-TNF agents are effective in moderate and severe IBD in both children and adolescents, and their application resulted in limiting the use of corticosteroids [54]. A recent study has demonstrated that the therapeutic role of anti-TNF agents is critically dependent on IL-10 to resolve intestinal inflammation [55]. Hence, it is noteworthy assuming that IL-10 plays a role in the ameliorative effect of Aloe and/or HK L.137 on colitis.…”

Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140

“…Notably, anti-TNF therapy response rests on TNF neutralisation, but specifically in CD also on its potency to bind membrane bound TNF on CD-tissue infiltrated macrophages 38 , which causes differentiation of 11 macrophages to a more regulatory CD206 + M2-like phenotype 31,39 . This is for example evidenced by the clinical observation using etanercept (does not bind membrane bound TNF), which is not effective in CD, whilst infliximab is 39 .…”

“…Previous studies have demonstrated that successful anti-TNF therapy is associated with an increase in CD206 + regulatory macrophages 31 and a decrease in pro-inflammatory cytokines 10 and SP140 expression 10 in CD mucosa. Thus, our data suggests that SP140 inhibition could be also beneficial in supporting the anti-TNF therapy.…”