IL-33/ST2 macrophage crosstalk promotes lung epithelial repair

Increasing evidence points to a central role for macrophages in tissue regeneration, however, the molecular mechanisms underlying this function remain unknown. Here, using depletion and adoptive transfer approaches, we demonstrate a major role of alveolar macrophages in facilitating bronchial re-epithelialization. In addition, we identify a novel, and paradoxical, protective role for the IL-33/ST2 axis in epithelial repair following naphthalene (NA)-induced lung injury. We defined two subsets of ST2 expressing myeloid cells, namely recruited monocyte-derived cells and resident alternatively activated macrophages (AAMs), which infiltrate the airways during the regeneration of the bronchial epithelium. Further, ST2-deficient mice exhibited an incomplete epithelial repair which was associated with a dysfunctional AAM phenotype and a reduction in the proliferation of a self-renewing subset of Clara progenitor stem cells. Notably, reconstitution of ST2 + AAMs, post NA, completely restored the epithelium in ST2-deficient animals. In contrast, the monocyte/macrophage-dependent CCL2/CCR2 axis was redundant for repair, however, anti ST2-antibody treatment to CCR2 −/− mice resulted in ineffective epithelial regeneration and confirmed the observations seen with ST2-deficiency after NA-induced injury. Thus, the IL-33/ST2 pathway regulates effective Clara cell regeneration and bronchial re-epithelialization via AAM polarization and may lead to new therapeutic insights in acute respiratory diseases.