title: Monocyte chemoattractant protein 1 regulates pulmonary host defense via neutrophil recruitment during Escherichia coli infection.
abstract: Neutrophil accumulation is a critical event to clear bacteria. Since uncontrolled neutrophil recruitment can cause severe lung damage, understanding neutrophil trafficking mechanisms is important to attenuate neutrophil-mediated damage. While monocyte chemoattractant protein 1 (MCP-1) is known to be a monocyte chemoattractant, its role in pulmonary neutrophil-mediated host defense against Gram-negative bacterial infection is not understood. We hypothesized that MCP-1/chemokine (C-C motif) ligand 2 is important for neutrophil-mediated host defense. Reduced bacterial clearance in the lungs was observed in MCP-1(-/-) mice following Escherichia coli infection. Neutrophil influx, along with cytokines/chemokines, leukotriene B(4) (LTB(4)), and vascular cell adhesion molecule 1 levels in the lungs, was reduced in MCP-1(-/-) mice after infection. E. coli-induced activation of NF-κB and mitogen-activated protein kinases in the lung was also reduced in MCP-1(-/-) mice. Administration of intratracheal recombinant MCP-1 (rMCP-1) to MCP-1(-/-) mice induced pulmonary neutrophil influx and cytokine/chemokine responses in the presence or absence of E. coli infection. Our in vitro migration experiment demonstrates MCP-1-mediated neutrophil chemotaxis. Notably, chemokine receptor 2 is expressed on lung and blood neutrophils, which are increased upon E. coli infection. Furthermore, our findings show that neutrophil depletion impairs E. coli clearance and that exogenous rMCP-1 after infection improves bacterial clearance in the lungs. Overall, these new findings demonstrate that E. coli-induced MCP-1 causes neutrophil recruitment directly via chemotaxis as well as indirectly via modulation of keratinocyte cell-derived chemokine, macrophage inflammatory protein 2, and LTB(4).
authors.affiliation: Laboratory of Lung Biology, Department of Pathobiological Sciences, and Center for Experimental Infectious Disease Research, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
authors.forename: Gayathriy
authors.initials: G
authors.lastname: Balamayooran
authors.forename: Sanjay
authors.initials: S
authors.lastname: Batra
authors.forename: Theivanthiran
authors.initials: T
authors.lastname: Balamayooran
authors.forename: Shanshan
authors.initials: S
authors.lastname: Cai
authors.forename: Samithamby
authors.initials: S
authors.lastname: Jeyaseelan
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology / Q000382:microbiology; D018932:Chemokine CCL2 / Q000276:immunology* / Q000378:metabolism*; D054426:Chemokine CXCL2 / Q000032:analysis; D004926:Escherichia coli / Q000276:immunology*; D004927:Escherichia coli Infections / Q000276:immunology* / Q000382:microbiology; D007975:Leukotriene B4 / Q000032:analysis; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054426:Chemokine CXCL2; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1; D007975:Leukotriene B4; D020928:Mitogen-Activated Protein Kinases