FPR2 regulates monocyte recruitment to promote mucosal wound repair
- Monique N. O'Leary 1
- Dorothee Birkl 1
- Miguel Quiros 1
- Michelle Reed 1
-
Veronica Azcutia
1
- Matthew Schaller 1
- Hikaru Nishio 2
- Justin Keeney 1
- Nicholas W. Lukacs 1
- Andrew S. Neish 2
- Charles A. Parkos 1
- Asma Nusrat 1
- 1 Pathology, University of Michigan, Ann Arbor, MI
- 2 Pathology, Emory University, Atlanta, GA
ISSN: 0892-6638, 1530-6860
Año de publicación: 2019
Volumen: 33
Número: S1
Páginas: 375.4
Tipo: Artículo
Otras publicaciones en: The FASEB Journal
Resumen
Mucosal wound repair is coordinated by a dynamic spatiotemporal cross talk of mediators with receptors on epithelial cells and infiltrating immune cells. After initial recruitment of neutrophils, monocytes infiltrate mucosal wounds in close proximity to repairing epithelium. Key regulators of mucosal repair include pro-inflammatory and pro-resolving mediators that help orchestrate temporal recruitment of immune cells, resolve acute inflammatory responses and regulate epithelial cell migration and proliferation. Immune cell derived mediators have been shown to activate G-protein coupled receptors (GPCR) that significantly impact the inflammatory response and repair. In this report, our studies were focused on how a GPCR, formyl peptide receptor 2 (FPR2), orchestrates mucosal repair. Fpr2/3−/− mice were utilized to investigate the role of formyl-peptide receptor 2/3 (FPR2/3), an orthologue of human FPR2/ALX, in regulating intestinal mucosal repair. Compared to wild type mice, Fpr2/3−/− mice exhibited delayed recovery from acute colitis and impaired repair after biopsy induced injury. Time course analyses of immune cell populations in the wound bed of wild type and Fpr2/3−/− mice by flow cytometry revealed mice lacking FPR2 have a reduced influx of inflammatory monocytes (defined as CD45+ CD11b+ Ly6G− Siglec F− F4/80lo Ly6Chi) on day 1 and 2 post wounding compared to wild type mice. To further supporting these data, we assessed expression of CCR2, a chemokine receptor and marker of conventional Ly6Chi inflammatory monocytes, in wounded tissue. We found reduced expression of CCR2 mRNA in tissue isolated from Fpr2/3−/− mice. Bone marrow transplant experiments revealed that monocytes from wild type mice had a competitive advantage over Fpr2/3−/− cells in migrating into healing mucosal wounds. Moreover, Fpr2/3−/− monocytes were defective in chemotaxis responses to the chemokine CCL20, a chemoattractant for monocytes that is upregulated during the early phase of inflammation. Analysis of Fpr2/3−/− monocytes revealed altered expression of the CCL20 receptor, CCR6, suggesting a role of Fpr2/3 and CCL20-CCR6 signaling in regulating monocyte recruitment to sites of mucosal injury. In summary, these findings identify the contribution of monocyte expressed FPR2/3 in facilitating their recruitment to sites of mucosal injury to promote wound repair.