title: Bacterial clearance and survival are dependent on CXC chemokine receptor-2 ligands in a murine model of pulmonary Nocardia asteroides infection.
abstract: Survival from murine pulmonary nocardiosis is highly dependent on CXC chemokine receptor-2 (CXCR2) ligand-mediated neutrophil chemotaxis and subsequent clearance of the infectious agent Nocardia asteroides. Intratracheal inoculation of N. asteroides rapidly up-regulated the CXC chemokines macrophage inflammatory protein-2 (MIP-2) and KC within 24 h, with levels remaining elevated through day 3 before returning to near baseline levels by day 7. Coinciding with elevated MIP-2 and KC were the rapid recruitment of neutrophils and clearance of the organism. Anti-Ly-6G Ab-mediated neutrophil depletion before bacterial challenge resulted in strikingly increased mortality to N. asteroides infection. The relative contribution of MIP-2 in neutrophil recruitment was examined by anti-MIP-2 Ab treatment before nocardial infection. MIP-2 neutralization had no detrimental effects on survival, neutrophil recruitment, or bacterial clearance, suggesting the usage of additional or alternative CXCR2-binding ligands. The importance of the CXC family of chemokines was determined by the administration of an anti-CXCR2 Ab capable of blocking ligand binding in vivo. Anti-CXCR2 treatment greatly increased mortality by preventing neutrophil migration into the lung. Paralleling this impaired neutrophil recruitment was a 100-fold increase in lung bacterial burden. Combined, these observations indicate a critical role for neutrophils and CXC chemokines during nocardial pneumonia. These data directly link CXCR2 ligands and neutrophil recruitment and lend further support to the concept of CXC chemokine redundancy. For infections highly dependent on neutrophils, such as nocardial pneumonia, this is of critical importance.
authors.affiliation: Department of Internal Medicine, Division of Pulmonary Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA. tmoore@umich.edu
authors.forename: T A
authors.initials: TA
authors.lastname: Moore
authors.forename: M W
authors.initials: MW
authors.lastname: Newstead
authors.forename: R M
authors.initials: RM
authors.lastname: Strieter
authors.forename: B
authors.initials: B
authors.lastname: Mehrad
authors.forename: B L
authors.initials: BL
authors.lastname: Beaman
authors.forename: T J
authors.initials: TJ
authors.lastname: Standiford
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000950:Antigens, Ly / Q000276:immunology; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis; D019743:Chemokines, CXC; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D007106:Immune Sera / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D007442:Intubation, Intratracheal; D007700:Kinetics; D008024:Ligands; D008168:Lung / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D015846:Monokines / Q000096:biosynthesis; D009503:Neutropenia / Q000276:immunology / Q000382:microbiology; D020556:Neutrophil Infiltration; D009617:Nocardia Infections / Q000276:immunology* / Q000382:microbiology* / Q000401:mortality / Q000473:pathology; D009616:Nocardia asteroides / Q000276:immunology*; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000382:microbiology* / Q000401:mortality / Q000473:pathology; D019707:Receptors, Chemokine / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D018123:Receptors, Interleukin / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D023063:Receptors, Interleukin-8B
chemical_list: D000950:Antigens, Ly; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; D016207:Cytokines; D007106:Immune Sera; D008024:Ligands; D015846:Monokines; D019707:Receptors, Chemokine; D018123:Receptors, Interleukin; D023063:Receptors, Interleukin-8B; C074302:keratinocyte-derived chemokines