MAPK phosphatase 1 inhibition of p38α within lung myofibroblasts is essential for spontaneous fibrosis resolution
Sean M. Fortier, … , Anton M. Bennett, Marc Peters-Golden
Sean M. Fortier, … , Anton M. Bennett, Marc Peters-Golden
Published March 21, 2024
Citation Information: J Clin Invest. 2024;134(10):e172826. https://doi.org/10.1172/JCI172826.
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Research Article Cell biology Pulmonology

MAPK phosphatase 1 inhibition of p38α within lung myofibroblasts is essential for spontaneous fibrosis resolution

Abstract

Fibrosis following tissue injury is distinguished from normal repair by the accumulation of pathogenic and apoptosis-resistant myofibroblasts (MFs), which arise primarily by differentiation from resident fibroblasts. Endogenous molecular brakes that promote MF dedifferentiation and clearance during spontaneous resolution of experimental lung fibrosis may provide insights that could inform and improve the treatment of progressive pulmonary fibrosis in patients. MAPK phosphatase 1 (MKP1) influences the cellular phenotype and fate through precise and timely regulation of MAPK activity within various cell types and tissues, yet its role in lung fibroblasts and pulmonary fibrosis has not been explored. Using gain- and loss-of-function studies, we found that MKP1 promoted lung MF dedifferentiation and restored the sensitivity of these cells to apoptosis — effects determined to be mainly dependent on MKP1’s dephosphorylation of p38α MAPK (p38α). Fibroblast-specific deletion of MKP1 following peak bleomycin-induced lung fibrosis largely abrogated its subsequent spontaneous resolution. Such resolution was restored by treating these transgenic mice with the p38α inhibitor VX-702. We conclude that MKP1 is a critical antifibrotic brake whose inhibition of pathogenic p38α in lung fibroblasts is necessary for fibrosis resolution following lung injury.

Authors

Sean M. Fortier, Natalie M. Walker, Loka R. Penke, Jared D. Baas, Qinxue Shen, Jennifer M. Speth, Steven K. Huang, Rachel L. Zemans, Anton M. Bennett, Marc Peters-Golden

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Figure 1

MKP1 (DUSP1) is the chief DUSP isoform expressed in normal lung fibroblasts, is reduced in IPF fibroblasts, and is downregulated by TGF-β.

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MKP1 (DUSP1) is the chief DUSP isoform expressed in normal lung fibrobla...
(A) Single-cell RNA-Seq of annotated human and mouse lung fibroblast populations (generated from the Chan-Zuckerberg CELL by GENE Discover online database) depicting the relative expression of each catalytically active DUSP/MKP gene. Circle color denotes the mean gene expression within each fibroblast subtype, and the circle size represents the proportion of each cell population expressing the indicated gene. (B) MKP1 protein expression measured by Western blotting in normal and IPF patient–derived human lung fibroblasts (left: representative blot of individual patient-derived cells; right: densitometric analysis of all such cells). (C) MKP1 and collagen I protein expression by Western blotting (left and middle) and MKP1 transcript by qPCR (right) in normal HLFs treated with TGF-β (2 ng/mL) for 3 hours or 48 hours, as indicated in C. Data points represent separate experiments. Significance for densitometric data in B (n = 7) and C (n = 4) and qPCR in C (n = 5) was determined by 2-tailed t test. **P < 0.01 and ****P < 0.0001.