CXCR4 inhibitor attenuates allergen-induced lung inflammation by down-regulating MMP-9 and ERK1/2.
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.
Department 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.
Huilong
H
Chen
Department 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.
Xiangqin
X
Xu
Department 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.
Jieming
J
Teng
Department 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.
Sheng
S
Cheng
Department 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.
Hansvin
H
Bunjhoo
Department 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.
Yong
Y
Cao
Department 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.
Jin
J
Liu
Department 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.
Jungang
J
Xie
The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China.
Congyi
C
Wang
Department 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.
Yongjian
Y
Xu
Department 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.
Weining
W
Xiong
D000485:Allergens; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D001596:Benzylamines; D001980:Bronchi / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000378:metabolism; D000080027:Cyclams; D004195:Disease Models, Animal; D015536:Down-Regulation; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D005260:Female; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010047:Ovalbumin; D011014:Pneumonia / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D000485:Allergens; D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D001596:Benzylamines; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D018793:Interleukin-13; D019718:Receptors, CXCR4; D010047:Ovalbumin; C535150:MAPK1 protein, human; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C088327:plerixafor
Asthma; CXCL12; CXCR4; MMP-9