Macrophage-Dependent Regeneration of Pulmonary Epithelia Requires Trefoil Factor 2 for Wnt Expression

Coordination between epithelial and myeloid cell lineages may facilitate tissue repair, but mechanistic evidence is lacking. Independently of Type 2 cytokines (interleukin-4/13), and T, B or ILC populations, lung macrophages promoted epithelial proliferation following injury caused by Nippostrongylus brasiliensis or bleomycin sulfate. Multiple myeloid populations up-regulated Trefoil factor 2 (TFF2) following lung injury and CD11c-driven Tff2 deletion impaired the proliferative expansion of pro-SpC + distal lung epithelial progenitors. Direct interactions between macrophages and damaged epithelia resulted Wnt production, which accelerated epithelial proliferation, trans-epithelial resistance, and barrier function in a TFF2-dependent manner. In summary, the current study demonstrates that TFF2 is a regenerative cytokine expressed by macrophages to facilitate repair of infectious or non-infectious lung damage.