HIV-1 Protein gp120 Induces Mouse Lung Fibroblast-to-Myofibroblast Transdifferentiation via CXCR4 Activation

• Type of Material: Article
• Authors: Lucian Marts, Emory University; David Guidot, Emory University; Viranuj Sueblinvong, Emory University
• Language: English
• Date: 2019-06-01
• Publisher: Elsevier Science Inc.
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.amjms.2019.03.006
• Title of Journal or Parent Work: American Journal of the Medical Sciences
• Volume: 357
• Issue: 6
• Start Page: 483
• End Page: 491
• Grant/Funding Information: NIH T32 HL116271 for LTM, NIH K08 AA021404-01 for VS, NIH R01 HL125042 for DMG.
• Keywords: Fibrosis; Myofibroblast; General & Internal Medicine; Risk; Envelope glycoprotein; Life Sciences & Biomedicine; Differentiation; CXCR4; Chemokine receptor; Targets; gp120; Medicine, General & Internal; Science & Technology; Antagonist; AMD3100; Fibroblast
• Research Categories: Biology, Bioinformatics; Health Sciences, Health Care Management; Health Sciences, Medicine and Surgery

Abstract

Background: Individuals with HIV have ∼2-fold increased risk of developing pulmonary fibrosis. The mechanism(s) by which this occurs has yet to be determined. HIV-1 protein gp120 activates CXCR4 in the lymphocyte, promoting a variety of intracellular signaling pathways including those common to TGFβ1 associated with lung fibroblast-to-myofibroblast transdifferentiation. We hypothesized that gp120 promotes pulmonary fibrotic changes via activation of CXCR4 in the lung fibroblast. Methods: Mouse primary lung fibroblasts (PLFs) were cultured ± gp120, then analyzed for α-SMA expression and stress fiber formation. In parallel, PLFs were cultured ± gp120 ± AMD3100 (a CXCR4 antagonist), and α-SMA, pan and phospho-Akt, and total and phospho-MAPK (or ERK1/2) protein expression was quantified. Finally, lungs and PLFs from wild-type and HIV-1 transgenic mice were analyzed for hydroxyproline and α-SMA content. Results: gp120 treatment increased α-SMA expression and myofibroblast differentiation in PLFs. gp120 treatment activated phosphorylation of ERK1/2, but not PI3K-Akt. Pretreatment with AMD3100 inhibited gp120-induced ERK1/2 phosphorylation and gp120-induced α-SMA expression. In parallel, there was a significant increase in hydroxyproline content in lungs from older HIV-1 transgenic mice and a >3-fold increase in α-SMA expression in PLFs isolated from HIV-1 transgenic mice. Conclusions: gp120 induces α-SMA expression and fibroblast-to-myofibroblast transdifferentiation by activating the CXCR4-ERK1/2 signaling pathway in mouse PLFs. Lungs of older HIV-1 transgenic mice contain higher hydroxyproline content and their PLFs have a striking increase in α-SMA expression. These results suggest a mechanism by which individuals with HIV are at increased risk of developing pulmonary fibrotic changes as they age.