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

Mucosal Immunology (2019) | Download Citation

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Abstract

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.

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Acknowledgements

The authors thank Professor Takao Shimizu (University of Tokyo) for providing the Ptafr−/ mice and Nicolas Castro (Georgia Institute of Technology) for help with focal adhesion experiments. We thank Chithra K. Muraleedharan and Meenal Mhaskar for their technical support. This work was supported by NIH grants (HL127236 to A.J.G.; DK055679, DK089763, and DK059888, to A.N.; and DK61739, DK72564, and DK79392, to C.A.P.); a German Research Foundation (DFG) Research Fellowship (SI 2282/1-1, to DB); and a Crohn’s and Colitis Foundation Carreer Development Award (544599, to M.Q.).

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Author notes

  1. These authors contributed equally: Dorothee Birkl, Miguel Quiros

Affiliations

  1. Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA

    • Dorothee Birkl
    • , Miguel Quiros
    • , Vicky García-Hernández
    • , Jennifer C. Brazil
    • , Roland Hilgarth
    • , Justin Keeney
    • , Mark Yulis
    • , Monique N. O´Leary
    • , Charles A. Parkos
    •  & Asma Nusrat
  2. George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USA

    • Dennis W. Zhou
    •  & Andrés J. García
  3. Department of Surgery, St. Franziskus-Hospital Münster, 48145, Münster, Germany

    • Matthias Bruewer
  4. Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, 30332, USA

    • Andrés J. García

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Contributions

Conceptualization and methodology: D.B., M.Q., M.N.O., A.N. and C.A.P.; formal analysis: D.B., M.Q., M.N.O., D.Z., A.J.G., A.N. and C.A.P.; investigation: D.B., M.Q., M.N.O., A.N., C.A.P. V.G.H., D.Z. and J.K.; resources, A.N., C.A.P., M.B., J.C.B., R.H. and M.Y.; writing—original draft, review and editing: D.B., M.N.O., M.Q., C.A.P. and A.N.; supervision, A.N., M.Q., C.A.P. and M.N.O.; funding acquisition: A.N. and C.A.P.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Monique N. O´Leary or Asma Nusrat.

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DOI

https://doi.org/10.1038/s41385-019-0150-8