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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 4

mtROS is required for Rac1-mediated profibrotic polarization of BAL cells.

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mtROS is required for Rac1-mediated profibrotic polarization of BAL cell...
mtROS generation in BAL cells from (A) healthy subjects (n = 6) or patients with IPF (n = 6) and from (B) saline- (n = 6) or bleomycin-exposed (n = 6) mice. (C) mtROS generation in THP-1 cells expressing empty control or Rac1WT and treated with vehicle or GGOH (n = 3). (D) Ten days after exposure of mice to saline or bleomycin, pumps containing vehicle or GGOH were implanted s.c. into mice, and the mice were sacrificed 11 days later. Data show mtROS generation in isolated MDMs (n = 5 mice/group). (E) mtROS generation in isolated BAL cells from bleomycin- or saline-exposed WT or Rac1–/– Lyz2-Cre mice (saline, n = 4 mice; bleomycin n = 6 mice). Inset shows immunoblot analysis. (F) Nuclear immunoblot analysis of transfected THP-1 cells treated with vehicle or GGOH (n = 3). (G) mtROS generation in transfected THP-1 cells (n = 5). Inset shows Rieske immunoblot analysis. Nuclear immunoblot analysis of THP-1 cells expressing (H) scrambled or Rieske siRNA and empty control or Rac1WT (n = 3) and (I) empty, Rac1CA, or Rac1DN. Arg1 promoter activity in transfected (J) THP-1 cells (n = 3) and (K) MH-S cells (n = 3). Inset in J shows KLF4 and HIF-2α immunoblot analysis. mRNA expression of (L) Tgfb1 (n = 3) and (M) Chil3 (n = 3) in MH-S cells expressing empty control, Rac1WT, or Rac1C189S. mRNA expression of (N) Tgfb1 (n = 3) and (O) Retnla (n = 3) in transfected THP-1 cells. Inset in N shows GGDPS immunoblot analysis. Values indicate the mean ± SEM. *P < 0.05, **P < 0.001, and ***P < 0.0001, by 2-tailed Student’s t test (A and B) and 1-way ANOVA followed by Tukey’s multiple comparisons test (C–E, G, and J–O). Scr, scrambled siRNA.

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