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.
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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