The autocrine CXCR4/CXCL12 axis contributes to lung fibrosis through modulation of lung fibroblast activity

Abstract

12 (CXCR4/CXCL12) axis has been implicated in the pathogenesis of pulmonary fibrosis. However, the mechanisms governing this remain to be determined. The current study demonstrated that human lung fibroblasts (HLFs) exhibit high CXCL12 expression and also exhibit high expression of its corresponding receptor CXCR4. Exogenous CXCL12 was revealed to significantly promote the migration and proliferation of HLFs, and potentiate CXCR4 expression. These effects were demonstrated to be inhibited by AMD3100, which is an antagonist of CXCR4. Lung and bronchoalveolar lavage fluid CXCR4 and CXCL12 expression was upregulated by in vivo bleomycin administration, which was partially inhibited by pre-treatment with AMD3100. AMD3100 also reduced lung collagen content in the bleomycin model. Inhibiting CXCR4 was indicated to ameliorate the lung compliance and resistance of pulmonary fibrosis. In conclusion, the results of the present study suggested that autocrine CXCR4/CXCL12 axis is an important mechanism underlying the pathogenesis of idiopathic pulmonary fibrosis, and may serve as a potential therapeutic target that can be used in the treatment of pulmonary disease.

Impact of Human Cytomegalovirus and Human Herpesvirus 6 Infection on the Expression of Factors Associated with Cell Fibrosis and Apoptosis: Clues for Implication in Systemic Sclerosis Development

“…By summarizing the results obtained in this in vitro study on the modulation of several pro-fibrotic factors induced by HCMV and/or HHV-6A, it is worthy to note that although a number of them are often altered in different autoimmune diseases [ 89 ], most of them have been described to be up- or downregulated in SSc, as already highlighted above [ 15 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 ].…”

“…Among them, CXCR4 (upmodulated by both viruses) is overexpressed the skin of SSc patients [ 60 ] and is known to contribute to fibrosis [ 60 , 61 ].…”

Comparative Transcriptome Analyses Reveal a Transcriptional Landscape of Human Silicosis Lungs and Provide Potential Strategies for Silicosis Treatment

“…Subsequently, the activation of Th2 cells and related signaling pathways, such as OX40L/OX40 signaling, can promote fibrotic changes ( So et al, 2006 ). Furthermore, the regulation of C-X-C motif chemokine receptor 4/C-X-C motif chemokine ligand 12 (CXCR4/CXCL12) axis could maintain the Th2 bias, and enhance the expression of cytokines with profibrotic effect such as IL-4 and IL-10 ( Piao et al, 2012 ; Li et al, 2020 ). Additionally, research on B cells in silicosis has mainly focused on IL-10 producing regulatory B cells (B10 cells).…”

Multi-organ Proteomic Landscape of COVID-19 Autopsies

“…It has been reported as a pre-B cell growth factor and would contribute to lymphopoiesis and embryogenesis homeostatic processes via regulating the migration of cells 179 . Moreover, exogenous CXCL12 would promote the migration and proliferation of human lung fibroblasts and CXCR4/CXCL12 plays an important role in IPF 180 . The upregulated CXCL12 in the thyroid may be an underlying factor for fibrosis.…”