Non-classical monocyte homing to the gut via α4β7 integrin mediates macrophage-dependent intestinal wound healing

Abstract

ObjectiveTo study the role of α4β7 integrin for gut homing of monocytes and to explore the biological consequences of therapeutic α4β7 inhibition with regard to intestinal wound healing.DesignWe studied the expression of homing markers on monocyte subsets in the peripheral blood and on macrophage subsets in the gut of patients with IBD and controls with flow cytometry and immunohistochemistry. Integrin function was addressed with dynamic adhesion assays and in vivo gut homing assays. In vivo wound healing was studied in mice deficient for or depleted of α4β7 integrin.ResultsClassical and non-classical monocytes were clearly dichotomous regarding homing marker expression including relevant expression of α4β7 integrin on human and mouse non-classical monocytes but not on classical monocytes. Monocyte-expressed α4β7 integrin was functionally important for dynamic adhesion to mucosal vascular addressin cell adhesion molecule 1 and in vivo gut homing. Impaired α4β7-dependent gut homing was associated with reduced (effect size about 20%) and delayed wound healing and suppressed perilesional presence of wound healing macrophages. Non-classical monocytes in the peripheral blood were increased in patients with IBD under clinical treatment with vedolizumab.ConclusionIn addition to reported effects on lymphocytes, anti-α4β7 therapy in IBD also targets non-classical monocytes. Impaired gut homing of such monocytes might lead to a reduction of wound healing macrophages and could potentially explain increased rates of postoperative complications in vedolizumab-treated patients, which have been observed in some studies.

β6 integrinosis: a new lethal autosomal recessive ITGB6 disorder leading to impaired conformational transitions of the αVβ6 integrin receptor

“…We read with interest the recent work by Schleier et al 1 demonstrating consequences of impaired α4β7 integrin-dependent gut homing of intestinal macrophages on wound healing, which fits well with own observations we have made in a case of congenital infantile intractable diarrhoea linked to impaired integrin receptors in intestinal epithelia (α V β6). Specifically, a male dizygotic twin was delivered dystrophic (1715 g) at 36 weeks of gestational age and developed intractable diarrhoea within the following 2 months, contrary to his twin brother.…”

Ulcerative colitis: understanding its cellular pathology could provide insights into novel therapies

“…It prevents lymphocyte infiltration from the blood into the inflamed gut tissue, reducing local inflammation [51]. In addition to this effect, vedolizumab also reduces α4β7-dependent gut homing of non-classical monocytes, resulting in a decrease in alternatively activated M2-like macrophages in the gut [52]. In contrast to other anti-adhesion drugs, the use of vedolizumab in UC patients did not increase the rates of opportunistic or enteric infections and there were no reported cases of progressive multifocal leukoencephalopathy [53].…”

“…Following encouraging results in randomized, double-blind, placebo-controlled trials in the pivotal phase III GEMINI studies, vedolizumab has been approved by US FDA for the treatment of adult patients with active UC who had a poor response to standard therapies [54]. Nevertheless, mononuclear phagocyte enrichment was detected in non-responder UC patients before vedolizumab treatment, which further increased post treatment [52], partly explaining why some UC patients do not respond as well to this drug.…”

Baseline levels of dynamic CD4+ T cell adhesion to MAdCAM-1 correlate with clinical response to vedolizumab treatment in ulcerative colitis: a cohort study

“…The anti-α4β7 antibody vedolizumab is successfully used for the treatment of IBD since 2014 [3,8] and has been shown to inhibit immune cell homing to the inflamed gut [9,10] indicating that cell trafficking is a central event in the pathogenesis of IBD [11]. Randomized controlled trials [3,8], as well as several real-world cohorts [12][13][14], demonstrated the efficacy and safety of vedolizumab in ulcerative colitis (UC) and Crohn's disease (CD).…”