title: CXCL1 contributes to host defense in polymicrobial sepsis via modulating T cell and neutrophil functions.
abstract: Severe bacterial sepsis leads to a proinflammatory condition that can manifest as septic shock, multiple organ failure, and death. Neutrophils are critical for the rapid elimination of bacteria; however, the role of neutrophil chemoattractant CXCL1 in bacterial clearance during sepsis remains elusive. To test the hypothesis that CXCL1 is critical to host defense during sepsis, we used CXCL1-deficient mice and bone marrow chimeras to demonstrate the importance of this molecule in sepsis. We demonstrate that CXCL1 plays a pivotal role in mediating host defense to polymicrobial sepsis after cecal ligation and puncture in gene-deficient mice. CXCL1 appears to be essential for restricting bacterial outgrowth and death in mice. CXCL1 derived from both hematopoietic and resident cells contributed to bacterial clearance. Moreover, CXCL1 is essential for neutrophil migration, expression of proinflammatory mediators, activation of NF-κB and MAPKs, and upregulation of adhesion molecule ICAM-1. rIL-17 rescued impaired host defenses in cxcl1(-/-) mice. CXCL1 is important for IL-17A production via Th17 differentiation. CXCL1 is essential for NADPH oxidase-mediated reactive oxygen species production and neutrophil extracellular trap formation. This study reveals a novel role for CXCL1 in neutrophil recruitment via modulating T cell function and neutrophil-related bactericidal functions. These studies suggest that modulation of CXCL1 levels in tissues and blood could reduce bacterial burden in sepsis.
authors.affiliation: Laboratory of Lung Biology, Department of Pathobiological Sciences, Center for Experimental Infectious Disease Research, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803;
authors.forename: Liliang
authors.initials: L
authors.lastname: Jin
authors.affiliation: Laboratory of Lung Biology, Department of Pathobiological Sciences, Center for Experimental Infectious Disease Research, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803;
authors.forename: Sanjay
authors.initials: S
authors.lastname: Batra
authors.affiliation: Program in Physiology and Experimental Medicine, SickKids Research Institute, Toronto, Ontario M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; and.
authors.forename: David Nobuhiro
authors.initials: DN
authors.lastname: Douda
authors.affiliation: Program in Physiology and Experimental Medicine, SickKids Research Institute, Toronto, Ontario M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; and.
authors.forename: Nades
authors.initials: N
authors.lastname: Palaniyar
authors.affiliation: Laboratory of Lung Biology, Department of Pathobiological Sciences, Center for Experimental Infectious Disease Research, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112 jey@lsu.edu.
authors.forename: Samithamby
authors.initials: S
authors.lastname: Jeyaseelan
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D054360:Chemokine CXCL1 / Q000097:blood / Q000235:genetics / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000097:blood / Q000235:genetics / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018805:Sepsis / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; C098680:Il17a protein, mouse; D020381:Interleukin-17; D016328:NF-kappa B; D048049:Extracellular Signal-Regulated MAP Kinases