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.
View: Text | PDF
Research Article Immunology Pulmonology

Increased flux through the mevalonate pathway mediates fibrotic repair without injury

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

×

Figure 6

Rac1 is required for GGOH- and bleomycin-induced lung fibrosis.

Options: View larger image (or click on image) Download as PowerPoint
Rac1 is required for GGOH- and bleomycin-induced lung fibrosis. Ten days...
Ten days after exposure of WT and Rac1–/– Lyz2-Cre mice to saline or bleomycin, pumps containing vehicle or GGOH were s.c. implanted, and the mice were sacrificed 11 days later. (A) Total number of BAL cells and (B) cell differential (n = 5/group). Mac, macrophage; PMN, polymorphonuclear. (C) Mitochondrial Rac1 activity (n = 5/group). Inset in C shows Rac1 immunoblot analysis of BAL cells. (D) mtROS generation in isolated BAL cells (n = 5–6/group). (E) Active TGF-β1, (F) PDGF-BB, and (G) Ym-1 expression in BALF (n = 4–5/group). (H and I) Ten days after exposure of WT mice to saline or bleomycin, daily i.p. injections of simvastatin (SIMV) (20 mg/kg/day) were administered, and mice were sacrificed 11 days later. (H) Active TGF-β1 and (I) PDGF-BB expression in BALF (n = 4/group). (J) Representative images of lung histology with Masson’s trichrome staining (n = 5/group). Original magnification, ×2.5. (K) Hydroxyproline content (n = 5/group). Values indicate the mean ± SEM. **P < 0.001 and ***P < 0.0001, by 1-way ANOVA followed by Tukey’s multiple comparisons test.