Citrullinated vimentin mediates development and progression of lung fibrosis

Abstract

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 α-SMA. Cit-Vim activated NF-κB in a TLR4-dependent fashion and induced the production of active TGF-β1, 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.

Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis

“…The content of Cd and CB in IPF lung tissue increased significantly and was directly proportional to the amounts of citrullinated vimentin (Cit-Vim). Under activation of Akt1 and peptidylarginine deiminase 2 (PAD2), Cd/CB can induce Vim citrullination and Cit-Vim secretion, which in turn triggers fibroblasts to infiltrate lung microspheres, promotes increased expression of collagen and α-smooth muscle actin (α-SMA), and induces lung fibrosis ( Li et al, 2021 ).…”

A Vimentin-Targeting Oral Compound with Host-Directed Antiviral and Anti-Inflammatory Actions Addresses Multiple Features of COVID-19 and Related Diseases

“…The roles of vimentin in tissue injury and fibrosis have been well established in the literature. Citrullinated vimentin mediates development and progression of lung fibrosis ( 39 ). Vimentin knockout (KO) or inhibition of vimentin has been shown to decrease collagen production ( 40 ), reduce lung injury, and protect the lung from developing fibrosis ( 22 , 41 ).…”

A vimentin-targeting oral compound with host-directed antiviral and anti-inflammatory actions addresses multiple features of COVID-19 and related diseases

“…The roles of vimentin in tissue injury and fibrosis have been well-established in the literature. Citrullinated vimentin mediates development and progression of lung fibrosis (39). Vimentin KO or inhibiting vimentin has been shown to decrease collagen production (40), reduce lung injury and protect the lung from developing fibrosis (22, 41).…”