TNFα promotes mucosal wound repair through enhanced platelet activating factor receptor signaling in the epithelium

• Published in: Mucosal immunology Vol. 12; no. 4; pp. 909 - 918
• Main Authors: Birkl, Dorothee, Quiros, Miguel, García-Hernández, Vicky, Zhou, Dennis W., Brazil, Jennifer C., Hilgarth, Roland, Keeney, Justin, Yulis, Mark, Bruewer, Matthias, García, Andrés J., O´Leary, Monique N., Parkos, Charles A., Nusrat, Asma
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2019; Elsevier Limited
• Subjects: ADAM10 Protein - metabolism; Allergology; Animals; Antibodies; Biomarkers; Biomedical and Life Sciences; Biomedicine; Colon; Crohn's disease; Epidermal growth factor; Epithelium; Epithelium - metabolism; Epithelium - pathology; G protein-coupled receptors; Gastroenterology; Humans; Immunology; Inflammatory bowel diseases; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Intestine; Mice; Morbidity; Mucosa; Mucous Membrane - metabolism; Mucous Membrane - pathology; NF-kappa B - metabolism; Platelet Membrane Glycoproteins - genetics; Platelet Membrane Glycoproteins - metabolism; Platelet-activating factor; Platelets; rac1 GTP-Binding Protein - metabolism; Rac1 protein; Reactive Oxygen Species - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Signal Transduction; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α; Ulcerative colitis; Wound Healing
• ISSN: 1933-0219; 1935-3456
• DOI: 10.1038/s41385-019-0150-8

Pathobiology of several chronic inflammatory disorders, including ulcerative colitis and Crohn’s disease is related to intermittent, spontaneous injury/ulceration of mucosal surfaces. Disease morbidity has been associated with pathologic release of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα). In this report, we show that TNFα promotes intestinal mucosal repair through upregulation of the GPCR platelet activating factor receptor (PAFR) in the intestinal epithelium. Platelet activating factor (PAF) was increased in healing mucosal wounds and its engagement with epithelial PAFR leads to activation of epidermal growth factor receptor, Src and Rac1 signaling to promote wound closure. Consistent with these findings, delayed colonic mucosal repair was observed after administration of a neutralizing TNFα antibody and in mice lacking PAFR. These findings suggest that in the injured mucosa, the pro-inflammatory milieu containing TNFα and PAF sets the stage for reparative events mediated by PAFR signaling.