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CXCR4 inhibitor attenuates allergen-induced lung inflammation by down-regulating MMP-9 and ERK1/2
Huilong Chen1, Xiangqin Xu1, Jieming Teng1
1Department of Respiratory and Critical Care Medicine, Tongji Hospital, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China.
Abstract:
Chemokine (C-X-C motif) ligand 12 (CXCL12) and its receptor chemokine receptor 4 (CXCR4) have been recognized to play a crucial role in the pathogenesis of bronchial asthma, but the underlying molecular mechanisms are yet to be fully addressed. In the present report we demonstrated that CXCL12/CXCR4 signaling mediates allergic airway inflammation through induction of matrix metalloproteinase 9 (MMP-9) in a murine asthmatic model. We noted that administration of AMD3100, a specific CXCR4 antagonist, significantly attenuated OVA-induced asthmatic responses along with reduced epithelial MMP-9 expression. Our studies in a bronchial epithelial cell line, 16HBE cells, further revealed that CXCL12/CXCR4 signaling synergizes with IL-13 to enhance epithelial MMP-9 expression. Our mechanistic studies demonstrated that CXCL12/CXCR4 enhances epithelial MMP-9 expression by inducing ERK1/2 expression and activation. Together, these studies would bring novel insight into the understanding for the role of CXCL12/CXCR4 signaling in asthmatic responses during the course of bronchial asthma development.
Insights
Chemokine CXCL12/CXCR4 signaling drives allergic airway inflammation by increasing MMP-9. Blocking CXCR4 with AMD3100 reduced asthma symptoms and MMP-9 expression in a mouse model.
Area of Science:
- Immunology
- Respiratory Medicine
- Molecular Biology
Background:
- Chemokine (C-X-C motif) ligand 12 (CXCL12) and its receptor chemokine receptor 4 (CXCR4) are implicated in bronchial asthma pathogenesis.
- The precise molecular mechanisms linking CXCL12/CXCR4 signaling to asthma remain incompletely understood.
Purpose of the Study:
- To elucidate the role of CXCL12/CXCR4 signaling in mediating allergic airway inflammation.
- To investigate the downstream molecular pathways involved in CXCL12/CXCR4-induced asthma responses.
Main Methods:
- Utilized a murine model of ovalbumin (OVA)-induced asthma.
- Administered AMD3100, a CXCR4 antagonist, to assess its therapeutic effect.
- Examined matrix metalloproteinase 9 (MMP-9) expression in epithelial cells and lung tissue.
- Investigated the synergistic effects of CXCL12/CXCR4 signaling and IL-13 in 16HBE cells.
- Analyzed the involvement of ERK1/2 signaling pathways.
Main Results:
- CXCL12/CXCR4 signaling was found to mediate allergic airway inflammation through the induction of MMP-9.
- AMD3100 treatment significantly reduced OVA-induced asthmatic responses and epithelial MMP-9 expression.
- CXCL12/CXCR4 signaling synergized with IL-13 to enhance MMP-9 expression in bronchial epithelial cells.
- CXCL12/CXCR4 signaling promotes MMP-9 expression via ERK1/2 activation.
Conclusions:
- CXCL12/CXCR4 signaling plays a significant role in the development of bronchial asthma.
- Targeting the CXCL12/CXCR4 pathway, specifically with CXCR4 antagonists, may offer a therapeutic strategy for asthma.
- Understanding the CXCL12/CXCR4-MMP-9-ERK1/2 axis provides novel insights into asthma pathogenesis.
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