A Regulatory Role of Chemokine Receptor CXCR3 in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Emphysema.

Abstract

Chronic obstructive pulmonary disease (COPD)/pulmonary emphysema is driven by the dysregulated airway inflammation and primarily influenced by the interaction between cigarette smoking (CS) and the individual's susceptibility. The inflammation in COPD involves both innate and adaptive immunity. By binding to its specific ligands, chemokine receptor CXCR3 plays an important role in regulating tissue inflammation and damage. In acute animal model challenged with either CS or pathogens, CXCR3 knockout (KO) attenuated lung inflammation and pathology. However, the role of CXCR3 in CS-induced chronic airway inflammation and pulmonary emphysema remains unknown. In this present study, we investigated the effect of CXCR3 in CS-induced pulmonary emphysema in an animal model, and the association between CXCR3 single nucleotide polymorphisms (SNPs) and COPD susceptibility in human subjects. We found that after chronic exposure to side stream CS (SSCS) for 24 weeks, CXCR3 KO mice demonstrated significant airspace enlargement expressed by mean linear intercept (Lm) compared with the wild-type (WT) mice. Consistently, CXCR3 KO mice had significantly higher BAL fluid macrophages and neutrophils, TNFα, and lung homogenate MMP-9 and MMP-12. Through genetic analysis of CXCR3 polymorphisms in a cohort of COPD patients with Han Chinese ethnicity, one CXCR3 SNP, rs2280964, was found to be genetically related to COPD susceptibility. Furthermore, CXCR3 SNP rs2280964 was significantly associated with the levels of serum MMP-9 in COPD patients. Our data from both animal and human studies revealed a novel role of CXCR3 possibly via influencing MMP9 production in the pathogenesis and progression of CS-associated COPD/pulmonary emphysema.

• Authors: Lun Li, Yi Liu, Chin Chiu, Yang Jin, Weixun Zhou, Min Peng, Lung-Chi Chen, Qinghua Sun, Jinming Gao
• Journal: Inflammation (Inflammation) Vol. 44 Issue 3 Pg. 985-998 (Jun 2021) ISSN: 1573-2576 [Electronic] United States
• PMID: 33415536 (Publication Type: Journal Article)

Chemical References

• CXCR3 protein, human
• Cxcr3 protein, mouse
• Receptors, CXCR3
• Tnf protein, mouse
• Tumor Necrosis Factor-alpha
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse
• Matrix Metalloproteinase 12
• matrix metallopeptidase 12, mouse

Topics

• Adult
• Aged
• Animals
• Case-Control Studies
• China
• Disease Models, Animal
• Female
• Genetic Association Studies
• Genetic Predisposition to Disease
• Humans
• Lung (immunology, metabolism, pathology)
• Macrophages, Alveolar (immunology, metabolism)
• Male
• Matrix Metalloproteinase 12 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Neutrophils (immunology, metabolism)
• Phenotype
• Polymorphism, Single Nucleotide
• Pulmonary Disease, Chronic Obstructive (genetics, immunology, metabolism, pathology)
• Pulmonary Emphysema (genetics, immunology, metabolism, pathology)
• Receptors, CXCR3 (genetics, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• Mice