Effects of liver X receptor agonist treatment on pulmonary inflammation and host defense.
Liver X receptor (LXR) alpha and beta are members of the nuclear receptor superfamily of ligand-activated transcription factors. Best known for triggering "reverse cholesterol transport" gene programs upon their activation by endogenous oxysterols, LXRs have recently also been implicated in regulation of innate immunity. In this study, we define a role for LXRs in regulation of pulmonary inflammation and host defense and identify the lung and neutrophil as novel in vivo targets for pharmacologic LXR activation. LXR is expressed in murine alveolar macrophages, alveolar epithelial type II cells, and neutrophils. Treatment of mice with TO-901317, a synthetic LXR agonist, reduces influx of neutrophils to the lung triggered by inhaled LPS, intratracheal KC chemokine, and intratracheal Klebsiella pneumoniae and impairs pulmonary host defense against this bacterium. Pharmacologic LXR activation selectively modulates airspace cytokine expression induced by both LPS and K. pneumoniae. Moreover, we report for the first time that LXR activation impairs neutrophil motility and identify inhibition of chemokine-induced RhoA activation as a putative underlying mechanism. Taken together, these data define a novel role for LXR in lung pathophysiology and neutrophil biology and identify pharmacologic activation of LXR as a potential tool for modulation of innate immunity in the lung.
Smoak
Kathleen
K
Laboratory of Respiratory Biology, Department of Health and Human Services, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Madenspacher
Jennifer
J
Jeyaseelan
Samithamby
S
Williams
Belinda
B
Dixon
Darlene
D
Poch
Katie R
KR
Nick
Jerry A
JA
Worthen
G Scott
GS
Fessler
Michael B
MB
D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D002464:Cell Migration Inhibition / Q000187:drug effects / Q000276:immunology; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D005260:Female; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage*; D007113:Immunity, Innate / Q000187:drug effects; D018836:Inflammation Mediators / Q000819:agonists* / Q000378:metabolism / Q000502:physiology; D007710:Klebsiella Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000071518:Liver X Receptors; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D013449:Sulfonamides / Q000008:administration & dosage*; D020298:U937 Cells; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D018836:Inflammation Mediators; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides