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

Mucosal Immunol. 2019 Jan;12(1):64-76. doi: 10.1038/s41385-018-0096-2. Epub 2018 Oct 18.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bleomycin
  • CD11c Antigen / metabolism
  • Cell Communication
  • Cell Proliferation
  • Cells, Cultured
  • Humans
  • Lung / immunology*
  • Lung / pathology
  • Lung Injury / chemically induced
  • Lung Injury / immunology*
  • Lung Injury / parasitology
  • Macrophages / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nippostrongylus / immunology*
  • Respiratory Mucosa / physiology*
  • Strongylida Infections / immunology*
  • Trefoil Factor-2 / genetics
  • Trefoil Factor-2 / metabolism*
  • Wound Healing


  • CD11c Antigen
  • Trefoil Factor-2
  • Bleomycin