[en] Monocyte-derived macrophages (Mφs) are crucial regulators during muscularis inflammation. However, it is unclear which micro-environmental factors are responsible for monocyte recruitment and anti-inflammatory Mφ differentiation in this paradigm. Here, we investigate Mφ heterogeneity at different stages of muscularis inflammation and determine how environmental cues can attract and activate tissue-protective Mφs. Results showed that muscularis inflammation induced marked alterations in mononuclear phagocyte populations associated with a rapid infiltration of Ly6c+ monocytes that locally acquired unique transcriptional states. Trajectory inference analysis revealed two main pro-resolving Mφ subpopulations during the resolution of muscularis inflammation, i.e. Cd206+ MhcIIhi and Timp2+ MhcIIlo Mφs. Interestingly, we found that damage to the micro-environment upon muscularis inflammation resulted in EGC activation, which in turn stimulated monocyte infiltration and the consequent differentiation in anti-inflammatory CD206+ Mφs via CCL2 and CSF1, respectively. In addition, CSF1-CSF1R signaling was shown to be essential for the differentiation of monocytes into CD206+ Mφs and EGC proliferation during muscularis inflammation. Our study provides a comprehensive insight into pro-resolving Mφ differentiation and their regulators during muscularis inflammation. We deepened our understanding in the interaction between EGCs and Mφs, thereby highlighting pro-resolving Mφ differentiation as a potential novel therapeutic strategy for the treatment of intestinal inflammation.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Stakenborg, Michelle; Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
Abdurahiman, Saeed; Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
De Simone, Veronica; Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
Goverse, Gera; Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
Stakenborg, Nathalie; Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
van Baarle, Lies; Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
Wu, Qin; Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
Pirottin, Dimitri ; Université de Liège - ULiège > Département des sciences fonctionnelles (DSF)
Kim, Jung-Seok; Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
Chappell-Maor, Louise; Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
Pintelon, Isabel; Laboratory of Cell Biology & Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium
Thys, Sofie; Laboratory of Cell Biology & Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium
Pollenus, Emilie; Laboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical research, KU Leuven, Leuven, Belgium
Boon, Louis; Polpharma Biologics, Utrecht, the Netherlands
Van den Steen, Philippe; Laboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical research, KU Leuven, Leuven, Belgium
Hao, Marlene; Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
Van Ginderachter, Jo A; Cellular and Molecular Immunology Lab, Department of Bio-engineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium ; Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium
Boeckxstaens, Guy E; Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
Timmermans, Jean-Pierre; Laboratory of Cell Biology & Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium
Jung, Steffen; Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
Marichal, Thomas ; Université de Liège - ULiège > GIGA > GIGA I3 - Immunophysiology
Ibiza, Sales; Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium. sales.IbizaMartinez@uantwerpen.be ; Laboratory of Cell Biology & Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium. sales.IbizaMartinez@uantwerpen.be
Matteoli, Gianluca ; Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium. gianluca.matteoli@kuleuven.be
The authors would like to thank Iris Appeltans, Naomi Fabre, Tine Gommers and Karlien Vranken (TARGID, KU Leuven) for their technical assistance, and Pier Andrée Penttila and Reena Chinnaraj (FACS Core, KU Leuven) for their assistance with flow cytometry and sorting, the GIGA-Genomics platform (University of Liège) for their assistance in our scRNA-seq experiments. Images were recorded at the Cell and Tissue Imaging Cluster (KU Leuven) using a Zeiss LSM 880 – Airyscan (supported by Hercules AKUL/15/37_GOH1816N and FWO G.0929.15 to Pieter Vanden Berghe) and a Zeiss LSM 780 – SP Mai Tai HP DS (supported by Hercules AKUL/11/37 and FWO G.0929.15 to Pieter Vanden Berghe). BioRender was used for making graphical images.M.S. was supported by a PhD fellowship from the FWO-Research Foundation – Flanders (1186317 N). V.D.S. was supported by a postdoctoral fellowship in Fundamental Research by the Stichting tegen Kanker. G.G. was supported by a postdoctoral research fellowship of FWO. S.I. was supported by a MSCA-IF (79756–GLIAMAC) and a fellowship from the European Crohn’s and Colitis Organization (ECCO). G.M.’s lab was supported by FWO grants G0D8317N, G0A7919N, G086721N and S008419N, a grant from the KU Leuven Internal Funds (C12/15/016 and C14/17/097 and from the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) as well as a research grant from ECCO.
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