Citrullinated vimentin mediates development and progression of lung fibrosis
Department of Biochemistry and Molecular Pharmacology; Thompson Lab
Amino Acids, Peptides, and Proteins | Biochemistry | Environmental Public Health | Medicinal-Pharmaceutical Chemistry | Pulmonology | Respiratory Tract Diseases
The mechanisms by which environmental exposures contribute to the pathogenesis of lung fibrosis are unclear. Here, we demonstrate an increase in cadmium (Cd) and carbon black (CB), common components of cigarette smoke (CS) and environmental particulate matter (PM), in lung tissue from subjects with idiopathic pulmonary fibrosis (IPF). Cd concentrations were directly proportional to citrullinated vimentin (Cit-Vim) amounts in lung tissue of subjects with IPF. Cit-Vim amounts were higher in subjects with IPF, especially smokers, which correlated with lung function and were associated with disease manifestations. Cd/CB induced the secretion of Cit-Vim in an Akt1- and peptidylarginine deiminase 2 (PAD2)-dependent manner. Cit-Vim mediated fibroblast invasion in a 3D ex vivo model of human pulmospheres that resulted in higher expression of CD26, collagen, and alpha-SMA. Cit-Vim activated NF-kappaB in a TLR4-dependent fashion and induced the production of active TGF-beta1, CTGF, and IL-8 along with higher surface expression of TLR4 in lung fibroblasts. To corroborate ex vivo findings, mice treated with Cit-Vim, but not Vim, independently developed a similar pattern of fibrotic tissue remodeling, which was TLR4 dependent. Moreover, wild-type mice, but not PAD2(-/-) and TLR4 mutant (MUT) mice, exposed to Cd/CB generated high amounts of Cit-Vim, in both plasma and bronchoalveolar lavage fluid, and developed lung fibrosis in a stereotypic manner. Together, these studies support a role for Cit-Vim as a damage-associated molecular pattern molecule (DAMP) that is generated by lung macrophages in response to environmental Cd/CB exposure. Furthermore, PAD2 might represent a promising target to attenuate Cd/CB-induced fibrosis.
DOI of Published Version
Li FJ, Surolia R, Li H, Wang Z, Liu G, Kulkarni T, Massicano AVF, Mobley JA, Mondal S, de Andrade JA, Coonrod SA, Thompson PR, Wille K, Lapi SE, Athar M, Thannickal VJ, Carter AB, Antony VB. Citrullinated vimentin mediates development and progression of lung fibrosis. Sci Transl Med. 2021 Mar 17;13(585):eaba2927. doi: 10.1126/scitranslmed.aba2927. PMID: 33731433. Link to article on publisher's site
Science translational medicine
Li FJ, Mondal S, Thompson PR, Antony VB. (2021). Citrullinated vimentin mediates development and progression of lung fibrosis. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1126/scitranslmed.aba2927. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/2012