Dataset Information

Proteomic analysis of lungs in early experimental model of Chronic obstructive pulmonary disease (COPD)

ABSTRACT: Rationale: Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disease lacking disease modifying treatment. The role of CXCL12/CXCR4 axis has been demonstrated in acute exacerbation of COPD. The interest of study early COPD has been recently pointed out. Objectives: To study the role of the CXCL12/CXCR4 axis in both human and mouse model of early COPD. Methods: Blood and lung tissue were obtained from both COPD patients and mice exposed to cigarette smoke (CS) for 10 weeks and intranasal instillations of polyinosinic–polycytidylic acid (poly(I:C)) to mimic exacerbations for 5 weeks. Measurements and Main Results: Exposed mice presented mild airway obstruction, peri-bronchial fibrosis and right heart remodeling. The level of CXCR4 expressing cells was increased in the blood of exposed mice, as well as in the blood of patients with mild COPD. Lung CXCL12 expression was higher both in exposed mice and COPD patients. The densities of fibrocytes expressing CXCR4 were increased in the blood and in the bronchial submucosa of exposed mice. Conditional inactivation of CXCR4 at adult stage as well as pharmacological inhibition of CXCR4 with plerixafor injections improved lung function and inflammation and protected against CS and poly-(I:C)-induced airway and cardiac remodeling. CXCR4-/- and plerixafor-treated mice also had reduced levels of CXCR4-expressing circulating cells and a lower density of peri-bronchial fibrocytes. Conclusions: We demonstrated that targeting CXCR4 has beneficial effects in an animal model of early COPD, and provide a framework to translate preclinical findings to clinical settings within a drug repurposing approach.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Lung

DISEASE(S): Chronic Obstructive Pulmonary Disease

SUBMITTER: Dupuy Jean-William

LAB HEAD: Isabelle Dupin

PROVIDER: PXD040105 | Pride | 2025-05-12

REPOSITORIES: pride

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Publications

CXCR4 Blockade Alleviates Pulmonary and Cardiac Outcomes in Early COPD.

Dupin Isabelle I Henrot Pauline P Maurat Elise E Abohalaka Reshed R Chaigne Sébastien S El Hamrani Dounia D Eyraud Edmée E Prevel Renaud R Esteves Pauline P Campagnac Marilyne M Dubreuil Marielle M Cardouat Guillaume G Bouchet Clément C Ousova Olga O Dupuy Jean-William JW Trian Thomas T Thumerel Matthieu M Begueret Hugues H Girodet Pierre-Olivier PO Marthan Roger R Zysman Maeva M Freund-Michel Véronique V Berger Patrick P

American journal of respiratory cell and molecular biology 20250408

Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disease lacking effective treatment. Focusing on early COPD should help to discover disease modifying therapies. We examined the role of the CXCL12/CXCR4 axis in early COPD using human samples and murine models. Blood samples and lung tissues from both individuals with early COPD and controls were analyzed for CXCL12 and CXCR4 levels. To generate an early-like COPD model, 10-week-old male C57BL/6J mice were exposed to cigare ...[more]

PMID: 40198797

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Project description:Nathaniel L. Coggins, Danielle Trakimas, S. Laura Chang, Anna Ehrlich, Paramita Ray, Kathryn E. Luker, Jennifer J. Linderman & Gary D. Luker. CXCR7 controls competition for recruitment of β-arrestin 2 in cells expressing both CXCR4 and CXCR7. PLoS ONE 9, 6 (2014). Chemokine CXCL12 promotes growth and metastasis of more than 20 different human cancers, as well as pathogenesis of other common diseases. CXCL12 binds two different receptors, CXCR4 and CXCR7, both of which recruit and signal through the cytosolic adapter protein β-arrestin 2. Differences in CXCL12-dependent recruitment of β-arrestin 2 in cells expressing one or both receptors remain poorly defined. To quantitatively investigate parameters controlling association of β-arrestin 2 with CXCR4 or CXCR7 in cells co-expressing both receptors, we used a systems biology approach combining real-time, multi-spectral luciferase complementation imaging with computational modeling. Cells expressing only CXCR4 maintain low basal association with β-arrestin 2, and CXCL12 induces a rapid, transient increase in this interaction. In contrast, cells expressing only CXCR7 have higher basal association with β-arrestin 2 and exhibit more gradual, prolonged recruitment of β-arrestin 2 in response to CXCL12. We developed and fit a data-driven computational model for association of either CXCR4 or CXCR7 with β-arrestin 2 in cells expressing only one type of receptor. We then experimentally validated model predictions that co-expression of CXCR4 and CXCR7 on the same cell substantially decreases both the magnitude and duration of CXCL12-regulated recruitment of β-arrestin 2 to CXCR4. Co-expression of both receptors on the same cell only minimally alters recruitment of β-arrestin 2 to CXCR7. In silico experiments also identified β-arrestin 2 as a limiting factor in cells expressing both receptors, establishing that CXCR7 wins the "competition" with CXCR4 for CXCL12 and recruitment of β-arrestin 2. These results reveal how competition for β-arrestin 2 controls integrated responses to CXCL12 in cells expressing both CXCR4 and CXCR7. These results advance understanding of normal and pathologic functions of CXCL12, which is critical for developing effective strategies to target these pathways therapeutically.

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