Distinct roles of KLF4 in mesenchymal cell subtypes during lung fibrogenesis
Rachana R. Chandran, Yi Xie, Eunate Gallardo‐Vara, Taylor Adams, Rolando García-Milian, Inamul Kabir, Abdul Q. Sheikh, Naftali Kaminski, Kathleen A. Martin, Erica L. Herzog, Daniel M. Greif
Abstract
Abstract During lung fibrosis, the epithelium induces signaling to underlying mesenchyme to generate excess myofibroblasts and extracellular matrix; herein, we focus on signaling in the mesenchyme. Our studies indicate that platelet-derived growth factor receptor (PDGFR)-β + cells are the predominant source of myofibroblasts and Kruppel-like factor (KLF) 4 is upregulated in PDGFR-β + cells, inducing TGFβ pathway signaling and fibrosis. In fibrotic lung patches, KLF4 is down-regulated, suggesting KLF4 levels decrease as PDGFR-β + cells transition into myofibroblasts. In contrast to PDGFR-β + cells, KLF4 reduction in α-smooth muscle actin (SMA) + cells non-cell autonomously exacerbates lung fibrosis by inducing macrophage accumulation and pro-fibrotic effects of PDGFR-β + cells via a Forkhead box M1 to C-C chemokine ligand 2—receptor 2 pathway. Taken together, in the context of lung fibrosis, our results indicate that KLF4 plays opposing roles in PDGFR-β + cells and SMA + cells and highlight the importance of further studies of interactions between distinct mesenchymal cell types.