KLF4 is a therapeutically tractable brake on fibroblast activation that promotes resolution of pulmonary fibrosis
Loka R. Penke, … , Jared Baas, Marc Peters-Golden
Loka R. Penke, … , Jared Baas, Marc Peters-Golden
Published July 19, 2022
Citation Information: JCI Insight. 2022;7(16):e160688. https://doi.org/10.1172/jci.insight.160688.
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Research Article Pulmonology

KLF4 is a therapeutically tractable brake on fibroblast activation that promotes resolution of pulmonary fibrosis

Abstract

There is a paucity of information about potential molecular brakes on the activation of fibroblasts that drive tissue fibrosis. The transcription factor Krüppel-like factor 4 (KLF4) is best known as a determinant of cell stemness and a tumor suppressor. We found that its expression was diminished in fibroblasts from fibrotic lung. Gain- and loss-of-function studies showed that KLF4 inhibited fibroblast proliferation, collagen synthesis, and differentiation to myofibroblasts, while restoring their sensitivity to apoptosis. Conditional deletion of KLF4 from fibroblasts potentiated the peak degree of pulmonary fibrosis and abrogated the subsequent spontaneous resolution in a model of transient fibrosis. A small molecule inducer of KLF4 was able to restore its expression in fibrotic fibroblasts and elicit resolution in an experimental model characterized by more clinically relevant persistent pulmonary fibrosis. These data identify KLF4 as a pivotal brake on fibroblast activation whose induction represents a therapeutic approach in fibrosis of the lung and perhaps other organs.

Authors

Loka R. Penke, Jennifer M. Speth, Steven K. Huang, Sean M. Fortier, Jared Baas, Marc Peters-Golden

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Figure 1

KLF4 expression is diminished in fibrotic fibroblasts.

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KLF4 expression is diminished in fibrotic fibroblasts. Baseline KLF4 exp...
Baseline KLF4 expression in fibroblasts outgrown from lungs of patients with IPF and control nonfibrotic (normal) lungs by real-time quantitative PCR (qPCR) analysis (A) and protein densitometry of Western blots (B). (C) Correlation analysis between the baseline KLF4 and FOXM1 mRNA expression in normal (blue dots) and IPF (red dots) fibroblasts; the cell lines displayed in C are an unselected subset of those displayed in A. Baseline KLF4 expression in fibroblasts outgrown from mouse lungs on day 21 after bleomycin and saline by qPCR analysis (D) and protein densitometry of Western blots (E). KLF4 expression in CCL210 cells after 48 hours of TGF-β (2 ng/mL) stimulation analyzed by qPCR (F) and Western blot (G). Expression of KLF4 protein in CCL210 cells after 3 hours of PGE2 (0.5 M) treatment analyzed by Western blot (results depicted from 1 experiment representative of 3 experiments (H). In A–C, each symbol represents a single patient lung-derived fibroblast line, and in D and E, each symbol represents an individual murine lung-derived fibroblast line. In A, B, and D–F, mRNA and protein values are normalized to GAPDH and expressed relative to the control (normal human or saline-treated mouse). Data in A–F are shown as mean ± SEM. *P < 0.05, 2-way ANOVA.