The Role of KLF4 and KLF2 Crosstalk in Endothelial to Mesenchymal Transition and Pulmonary Fibrosis

Transcription factors KLF4 and KLF2 are both known to be highly expressed in the vasculature and described to play a role in pulmonary physiology. However, the mechanism by which KLF4 and KLF2 might regulate each other has not been investigated. To address this gap, the relationship of Klf4 with Klf2 was examined using the in vitro and in vivo loss-of-function approaches as they relate to overall lung architecture and lung physiology. Key findings include the upregulation and autoregulation of KLF2 in the absence of KLF4, as well as loss of endothelial cell (EC) identity and transition of these cells into mesenchymal cell state, accompanied by fibrosis, alveolar enlargement, and alterations in lung physiology. Importantly, intravenous administration of alpha-1-antitrypsin (A1AT) ameliorated this pathological phenotype in the mouse model. Together, these results suggest a novel mechanism by which KLF4 depletion causes pathological EndoMT, dysregulation leading to fibrotic state, as well as a potential therapeutic approach.