NK cells regulate CXCR2+ neutrophil recruitment during acute lung injury.
A critical step in the pathogenesis of acute lung injury (ALI) is excessive recruitment of polymorphonuclear neutrophils (PMNs) into the lungs, causing significant collateral tissue damage. Defining the molecular and cellular steps that control neutrophil infiltration and activation during ALI is therefore of important therapeutic relevance. Based on previous findings implicating the transcription factor Tbet in mucosal Th1-inflammation, we hypothesized a detrimental role for Tbet during ALI. In line with our hypothesis, initial studies of endotoxin-induced lung injury revealed a marked protection of Tbet-/-mice, including attenuated neutrophilia compared to WT counterparts. Surprisingly, subsequent studies identified natural killer (NK) cells as the major source of pulmonary Tbet during ALI. In addition, a chemokine screen suggested that mature Tbet+NK-cells are critical for the production of pulmonary CXCL1 and -2, thereby contributing to pulmonary PMN recruitment. Indeed, both NK-cell Ab depletion and adoptive transfer studies provide evidence for NK cells in the orchestration of neutrophil recruitment during endotoxin-induced ALI. Taken together, these findings identify a novel role for Tbet+NK-cells in initiating the early events of noninfectious pulmonary inflammation.
Organ Protection Program, Department of Anesthesiology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA.|Clinic for Anesthesiology, University Hospital of Ludwig-Maximilians-University, Munich, Germany.
Sandra
S
Hoegl
Organ Protection Program, Department of Anesthesiology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA.|Department of Anesthesiology and Intensive Care Medicine, University Hospital, Bonn, Germany; and.
Heidi
H
Ehrentraut
Organ Protection Program, Department of Anesthesiology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA.
Kelley S
KS
Brodsky
Organ Protection Program, Department of Anesthesiology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA.|Integrated Department of Immunology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA.
Francisco
F
Victorino
Division of Gastroenterology and Hepatology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA.
Lucy
L
Golden-Mason
Organ Protection Program, Department of Anesthesiology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA.
Holger K
HK
Eltzschig
Organ Protection Program, Department of Anesthesiology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA.|Mucosal Inflammation Program, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA.
Eóin N
EN
McNamee
D055371:Acute Lung Injury / Q000150:complications / Q000276:immunology* / Q000473:pathology*; D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008070:Lipopolysaccharides; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000276:immunology*; D011014:Pneumonia / Q000150:complications / Q000276:immunology / Q000473:pathology; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000378:metabolism; D000098815:T-bet Transcription Factor
D000906:Antibodies; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D023063:Receptors, Interleukin-8B; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor
CXCR2; chemokine; mucosal; natural killer cell; pulmonary inflammation