Lung-specific overexpression of CC chemokine ligand (CCL) 2 enhances the host defense to Streptococcus pneumoniae infection in mice: role of the CCL2-CCR2 axis.
Mononuclear phagocytes are critical components of the innate host defense of the lung to inhaled bacterial pathogens. The monocyte chemotactic protein CCL2 plays a pivotal role in inflammatory mononuclear phagocyte recruitment. In this study, we tested the hypothesis that increased CCL2-dependent mononuclear phagocyte recruitment would improve lung innate host defense to infection with Streptococcus pneumoniae. CCL2 transgenic mice that overexpress human CCL2 protein in type II alveolar epithelial cells and secrete it into the alveolar air space showed a similar proinflammatory mediator response and neutrophilic alveolitis to challenge with S. pneumoniae as wild-type mice. However, CCL2 overexpressing mice showed an improved pneumococcal clearance and survival compared with wild-type mice that was associated with substantially increased lung mononuclear phagocyte subset accumulations upon pneumococcal challenge. Surprisingly, CCL2 overexpressing mice developed bronchiolitis obliterans upon pneumococcal challenge. Application of anti-CCR2 Ab MC21 to block the CCL2-CCR2 axis in CCL2 overexpressing mice, though completely abrogating bronchiolitis obliterans, led to progressive pneumococcal pneumonia. Collectively, these findings demonstrate the importance of the CCL2-CCR2 axis in the regulation of both the resolution/repair and remodelling processes after bacterial challenge and suggest that overwhelming innate immune responses may trigger bronchiolitis obliterans formation in bacterial lung infections.
Winter
Christine
C
Department of Pulmonary Medicine, Laboratory for Experimental Lung Research, Hannover School of Medicine, Hannover 30625, Germany.
Taut
Katharina
K
Srivastava
Mrigank
M
Länger
Florian
F
Mack
Matthias
M
Briles
David E
DE
Paton
James C
JC
Maus
Regina
R
Welte
Tobias
T
Gunn
Michael D
MD
Maus
Ulrich A
UA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001989:Bronchiolitis Obliterans / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008168:Lung / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010586:Phagocytes / Q000276:immunology; D011008:Pneumococcal Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics / Q000502:physiology*; D013296:Streptococcus pneumoniae
D000911:Antibodies, Monoclonal; C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D008024:Ligands; D054390:Receptors, CCR2; D019707:Receptors, Chemokine