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P066 CCR2-monocytes are essential for the resolution of inflammation and tissue repair in colitis.

M. Stakenborg, G. Goverse, G. Farro, P. J. Gomez-Pinilla, 
G. E. Boeckxstaens, G. Matteoli*

KU Leuven, P.O. Box 701, Department of Clinical and Experimental Medicine, Leuven, Belgium

Background

Monocyte recruitment in the gut wall via C-C chemokine receptor 2 (CCR2) is a major hallmark in the pathogenesis of inflammatory bowel disease (IBD). Classically, monocytes are considered as the main mediators of tissue damage during colitis. However, monocyte-derived macrophages may be essential for the resolution of inflammation. In the current study, we aim to define whether monocytes play a role in the induction of inflammation and/or are crucial for tissue repair.

Methods

Acute colitis was induced in wild-type (WT, C57BL/6) and CCR2-/- mice by 2.5% dextran sodium sulfate (DSS) in drinking water for 5 days. Disease progression was assessed via a standardised disease activity index (DAI) including body weight loss, stool consistency, and blood in the faeces. To study the role of monocytes during chronic colitis, mice were subjected to 3 cycles of 2% DSS. Monocyte and neutrophil recruitment and macrophage differentiation in the colon were assessed by flow cytometry and cell sorting.

Results

During acute DSS colitis (day 5), CCR2-/- mice displayed a reduced DAI and body weight loss as compared with WT mice indicating that inhibiting monocyte recruitment reduces tissue inflammation. On the contrary, during the recovery phase (day 10 to 14), CCR2-/- mice showed increased DAI and body weight loss compared with WT (24.5% vs 8.6%). Interestingly, the induction of chronic colitis confirmed that CCR2-monocytes are crucial for the resolution of inflammation. During the 1st cycle of DSS, body weight loss in WT mice (6.8%) was 10-fold higher than in CCR2-/- animals (0.67%). Interestingly, from day 10 onward, CCR2-/- mice continued to lose weight, showing altered stool consistency and blood in the faeces. During the 2nd and 3rd subsequent DSS cycles, CCR2-/- mice failed to recover body weight and presented increased disease severity compared with WT. This phenotype in CCR2-/- mice correlated with increased colonic tissue alterations such as epithelial erosion, cell infiltration, and fibrosis. Flow cytometry analysis showed increased accumulation of ROS+ neutrophils in CCR2-/- mice (WT:9,5x105; CCR2-/-:37,6x105; p < 0.05), whereas immune infiltrate in WT mice mainly consisted of differentiated MHCII+ macrophages expressing typical M2 markers such as Arg-1, IL-10, CD163, MRC1, Lyve1, and Stab1.

Conclusion

Our data demonstrate a dual role of monocytes during colitis, inducing the inflammatory response during the first phase and playing a crucial role in the resolution of inflammation and tissue repair at a later stage. Further understanding of the mechanisms leading to immune regulation and mucosal repair is vitally important to improve treatment for patients suffering from IBD.