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Original article
Non-classical monocyte homing to the gut via α4β7 integrin mediates macrophage-dependent intestinal wound healing
  1. Lena Schleier1,
  2. Maximilian Wiendl1,
  3. Karin Heidbreder1,
  4. Marie-Theres Binder1,
  5. Raja Atreya1,
  6. Timo Rath1,
  7. Emily Becker1,
  8. Anja Schulz-Kuhnt1,
  9. Annette Stahl1,
  10. Lisa Lou Schulze1,
  11. Karen Ullrich1,
  12. Simon F Merz2,
  13. Lea Bornemann2,
  14. Matthias Gunzer2,
  15. Alastair J M Watson3,
  16. Clemens Neufert1,
  17. Imke Atreya1,
  18. Markus F Neurath1,
  19. Sebastian Zundler1
  1. 1 Department of Medicine 1, Kussmaul Campus for Medical Research & Translational Research Center, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2 Institute of Experimental Immunology and Imaging, University Duisburg-Essen and University Hospital Essen, Essen, Germany
  3. 3 Norwich Medical School, Norwich Research Park, University of East Anglia, Norwich, UK
  1. Correspondence to Dr Sebastian Zundler, Department of Medicine 1, University Hospital Erlangen, Ulmenweg 18, 91054 Erlangen, Germany; sebastian.zundler{at}uk-erlangen.de

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.

  • gut immunology
  • ulcerative colitis
  • surgery for IBD
  • inflammatory bowel disease
  • Crohn’s disease

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Footnotes

  • LS and MW contributed equally.

  • MFN and SZ contributed equally.

  • Contributors LS, MW, KH, MTB, EB, ASK, AS, LLS and SZ performed the experiments. RA, TR, EB, SFM, KU, LB, MG, AJMW, CN, IA, MFN and SZ provided clinical samples, protocols, reagents or designed experiments. LS, MW, KH, MTB, EB, AS, LLS, CN, IA, MFN and SZ analysed and interpreted the data. LS, MW and SZ drafted the manuscript. All authors critically revised the manuscript for important intellectual content.

  • Funding Fritz-Bender-Stiftung, Research Grant of the German Research Foundation (ZU 377/3-1), Takeda, scholarship of the Interdisciplinary Center for Clinical Research (IZKF) to LS.

  • Competing interests MFN has served as an advisor for Pentax, Giuliani, MSD, AbbVie, Janssen, Takeda and Boehringer. MFN and SZ received research support from Takeda, Roche and Shire.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it published Online First. The affiliations have been amended.

  • Patient consent for publication Not required.

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