Journal
MUCOSAL IMMUNOLOGY
Volume 15, Issue 6, Pages 1296-1308Publisher
SPRINGERNATURE
DOI: 10.1038/s41385-022-00563-2
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Funding
- FWO-Research Foundation Flanders [1186317 N]
- postdoctoral fellowship in Fundamental Research by the Stichting tegen Kanker
- MSCA-IF [79756-GLIAMAC]
- European Crohn's and Colitis Organization (ECCO)
- FWO [G0D8317N, G0A7919N, G086721N, S008419N]
- KU Leuven Internal Funds [C12/15/016, C14/17/097]
- International Organization for the Study of Inflammatory Bowel Diseases (IOIBD)
- ECCO
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Monocyte-derived macrophages (M phi s) play crucial roles in regulating muscularis inflammation. This study investigates the heterogeneity of M phi s at different stages of muscularis inflammation and identifies environmental cues that attract and activate tissue-protective M phi s. Results reveal the presence of two main pro-resolving M phi subpopulations during the resolution of muscularis inflammation, and the activation of EGCs in response to micro-environmental damage is shown to stimulate monocyte infiltration and the subsequent differentiation into anti-inflammatory M phi s. Additionally, CSF1-CSF1R signaling is essential for monocyte differentiation and EGC proliferation during muscularis inflammation.
Monocyte-derived macrophages (M phi s) are crucial regulators during muscularis inflammation. However, it is unclear which micro-environmental factors are responsible for monocyte recruitment and anti-inflammatory M phi differentiation in this paradigm. Here, we investigate M phi heterogeneity at different stages of muscularis inflammation and determine how environmental cues can attract and activate tissue-protective M phi s. 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 M phi subpopulations during the resolution of muscularis inflammation, i.e. Cd206(+) MhcII(hi) and Timp2(+) MhcII(lo) M phi s. 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(+) M phi s via CCL2 and CSF1, respectively. In addition, CSF1-CSF1R signaling was shown to be essential for the differentiation of monocytes into CD206(+) M phi s and EGC proliferation during muscularis inflammation. Our study provides a comprehensive insight into pro-resolving M phi differentiation and their regulators during muscularis inflammation. We deepened our understanding in the interaction between EGCs and M phi s, thereby highlighting pro-resolving M phi differentiation as a potential novel therapeutic strategy for the treatment of intestinal inflammation.
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