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Increased flux through the mevalonate pathway mediates fibrotic repair without injury
Jennifer L. Larson-Casey, … , Veena B. Antony, A. Brent Carter
Jennifer L. Larson-Casey, … , Veena B. Antony, A. Brent Carter
Published October 14, 2019
Citation Information: J Clin Invest. 2019;129(11):4962-4978. https://doi.org/10.1172/JCI127959.
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Research Article Immunology Pulmonology

Increased flux through the mevalonate pathway mediates fibrotic repair without injury

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Abstract

Macrophages are important in mounting an innate immune response to injury as well as in repair of injury. Gene expression of Rho proteins is known to be increased in fibrotic models; however, the role of these proteins in idiopathic pulmonary fibrosis (IPF) is not known. Here, we show that BAL cells from patients with IPF have a profibrotic phenotype secondary to increased activation of the small GTPase Rac1. Rac1 activation requires a posttranslational modification, geranylgeranylation, of the C-terminal cysteine residue. We found that by supplying more substrate for geranylgeranylation, Rac1 activation was substantially increased, resulting in profibrotic polarization by increasing flux through the mevalonate pathway. The increased flux was secondary to greater levels of acetyl-CoA from metabolic reprogramming to β oxidation. The polarization mediated fibrotic repair in the absence of injury by enhancing macrophage/fibroblast signaling. These observations suggest that targeting the mevalonate pathway may abrogate the role of macrophages in dysregulated fibrotic repair.

Authors

Jennifer L. Larson-Casey, Mudit Vaid, Linlin Gu, Chao He, Guo-Qiang Cai, Qiang Ding, Dana Davis, Taylor F. Berryhill, Landon S. Wilson, Stephen Barnes, Jeffrey D. Neighbors, Raymond J. Hohl, Kurt A. Zimmerman, Bradley K. Yoder, Ana Leda F. Longhini, Vidya Sagar Hanumanthu, Ranu Surolia, Veena B. Antony, A. Brent Carter

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Figure 1

Mitochondrial Rac1 activity is increased in IPF BAL cells.

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Mitochondrial Rac1 activity is increased in IPF BAL cells.
Immunoblot an...
Immunoblot analysis of Rac1 expression in isolated (A) mitochondria or (B) cytosol fractions from BAL cells obtained from healthy subjects (n = 4) or patients with IPF (n = 4). (C) Mitochondrial Rac1 activity in BAL cells from healthy subjects (n = 6) or patients with IPF (n = 5). BAL cells from healthy subjects (n = 6–7) or patients with IPF (n = 6–8) were analyzed for mRNA expression of (D) ARG1 and (E) PDGFB. (F) Arginase 1 activity in BAL cells from healthy subjects (n = 5) or patients with IPF (n = 8). (G) Rac1 activity in BAL cells isolated at the indicated time points from mice exposed to saline or bleomycin (n = 3–4 mice/time point). Immunoblot analysis of Rac1 expression in isolated (H) mitochondria or (I) cytosolic fractions from BAL cells obtained from mice treated with saline (n = 4) or bleomycin (n = 5). (J) Mitochondrial Rac1 activity in BAL cells from saline- (n = 5) or bleomycin-exposed (n = 5) mice. (K) PDGF-BB and (L) IL-10 were measured in BALF from saline- or bleomycin-exposed mice at the indicated time points (n = 3–4 mice/time point). Values indicate the mean ± SEM. *P < 0.05, **P < 0.001, and ***P < 0.0001, by 2-tailed Student’s t test (C–F and J) and 2-way ANOVA with Bonferroni’s post test (G, K, and L).
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