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

Schleier L, Wiendl M, Heidbreder K, Binder MT, Atreya R, Rath T, Becker E, Schulz-Kuhnt A, Stahl A, Schulze L, Ullrich K, Merz SF, Bornemann L, Gunzer M, Watson AJ, Neufert C, Atreya I, Neurath M, Zundler S (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Gut BMJ Publishing Group

DOI: 10.1136/gutjnl-2018-316772

Abstract

Objective: To 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. Design: We 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. Results: Classical 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. Conclusion: In 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.

Authors with CRIS profile

Maximilian Wiendl Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Raja Atreya Professur für Translationale Immunforschung bei chronisch entzündlichen Darmerkrankungen (Heisenberg-Professur) Timo Rath Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Elisabeth Becker Medizinische Fakultät Anja Schulz-Kuhnt Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Lisa Schulze Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Karen Ullrich Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Clemens Neufert Medizinische Fakultät Markus Neurath Lehrstuhl für Innere Medizin I Sebastian Zundler Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

IZKF-J63 (M1): The role of Interleukin-3 in experimental colitis and human inflammatory bowel disease Dec. 1, 2017 - Nov. 30, 2020

Involved external institutions

Universitätsklinikum Essen DE Germany (DE) University of East Anglia GB United Kingdom (GB)

How to cite

APA:

Schleier, L., Wiendl, M., Heidbreder, K., Binder, M.T., Atreya, R., Rath, T.,... Zundler, S. (2019). Non-classical monocyte homing to the gut via α4β7 integrin mediates macrophage-dependent intestinal wound healing. Gut. https://dx.doi.org/10.1136/gutjnl-2018-316772

MLA:

Schleier, Lena, et al. "Non-classical monocyte homing to the gut via α4β7 integrin mediates macrophage-dependent intestinal wound healing." Gut (2019).

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