Enhanced susceptibility of staggerer (RORalphasg/sg) mice to lipopolysaccharide-induced lung inflammation.
The retinoid-related orphan receptor alpha (RORalpha), a member of the ROR subfamily of nuclear receptors, has been implicated in the control of a number of physiological processes, including the regulation of several immune functions. To study the potential role of RORalpha in the regulation of innate immune responses in vivo, we analyzed the induction of airway inflammation in response to lipopolysaccharide (LPS) challenge in wild-type and staggerer (RORalpha(sg/sg)) mice, a natural mutant strain lacking RORalpha expression. Examination of hematoxylin and eosin-stained lung sections showed that RORalpha(sg/sg) mice displayed a higher degree of LPS-induced inflammation than wild-type mice. Bronchoalveolar lavage (BAL) was performed at 3, 16, and 24 h after LPS exposure to monitor the increase in inflammatory cells and the level of several cytokines/chemokines. The increased susceptibility of RORalpha(sg/sg) mice to LPS-induced airway inflammation correlated with a higher number of total cells and neutrophils in BAL fluids from LPS-treated RORalpha(sg/sg) mice compared with those from LPS-treated wild-type mice. In addition, IL-1beta, IL-6, and macrophage inflammatory protein-2 were appreciably more elevated in BAL fluids from LPS-treated RORalpha(sg/sg) mice compared with those from LPS-treated wild-type mice. The enhanced susceptibility of RORalpha(sg/sg) mice appeared not to be due to a repression of IkappaBalpha expression. Our observations indicate that RORalpha(sg/sg) mice are more susceptible to LPS-induced airway inflammation and are in agreement with the hypothesis that RORalpha functions as a negative regulator of LPS-induced inflammatory responses.
Stapleton
Cliona M
CM
Division of Intramural Research, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Jaradat
Maisa
M
Dixon
Darlene
D
Kang
Hong Soon
HS
Kim
Seong-Chul
SC
Liao
Grace
G
Carey
Michelle A
MA
Cristiano
Joey
J
Moorman
Michael P
MP
Jetten
Anton M
AM
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D020556:Neutrophil Infiltration; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators