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Mucosal Immunol. 2018 Oct 18. doi: 10.1038/s41385-018-0096-2. [Epub ahead of print]

Macrophages promote epithelial proliferation following infectious and non-infectious lung injury through a Trefoil factor 2-dependent mechanism.

Author information

1
Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, 19104, USA.
2
Department of Pathology, University of California, San Francisco, CA, 94143, USA.
3
Pulmonary, Allergy, and Critical Care Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
4
Departments of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania Perelman School of Medicine, Monell Chemical Senses Center, and Philadelphia VA Medical Center Surgical Service, Philadelphia, USA.
5
Department of Biological Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, 19104, USA.
6
PENN Center for Pulmonary Biology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
7
Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, 19104, USA. debroski@vet.upenn.edu.

Abstract

Coordinated efforts between macrophages and epithelia are considered essential for wound healing, but the macrophage-derived molecules responsible for repair are poorly defined. This work demonstrates that lung macrophages rely upon Trefoil factor 2 to promote epithelial proliferation following damage caused by sterile wounding, Nippostrongylus brasiliensis or Bleomycin sulfate. Unexpectedly, the presence of T, B, or ILC populations was not essential for macrophage-driven repair. Instead, conditional deletion of TFF2 in myeloid-restricted CD11cCre TFF2 flox mice exacerbated lung pathology and reduced the proliferative expansion of CD45- EpCAM+ pro-SPC+ alveolar type 2 cells. TFF2 deficient macrophages had reduced expression of the Wnt genes Wnt4 and Wnt16 and reconstitution of hookworm-infected CD11cCre TFF2flox mice with rWnt4 and rWnt16 restored the proliferative defect in lung epithelia post-injury. These data reveal a previously unrecognized mechanism wherein lung myeloid phagocytes utilize a TFF2/Wnt axis as a mechanism that drives epithelial proliferation following lung injury.

PMID:
30337651
DOI:
10.1038/s41385-018-0096-2

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