Enhanced susceptibility of staggerer (ROR{alpha}sg/sg) mice to lipopolysaccharide-induced lung inflammation

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 289; no. 1; pp. L144 - L152
• Main Authors: Stapleton, Cliona M, Jaradat, Maisa, Dixon, Darlene, Kang, Hong Soon, Kim, Seong-Chul, Liao, Grace, Carey, Michelle A, Cristiano, Joey, Moorman, Michael P, Jetten, Anton M
• Format: Journal Article
• Language: English
• Published: United States 01.07.2005
• Subjects: Animals; Bronchoalveolar Lavage Fluid - cytology; Cytokines - biosynthesis; Female; I-kappa B Proteins - metabolism; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Lipopolysaccharides - toxicity; Male; Mice; Mice, Knockout; Mice, Neurologic Mutants; Neutrophil Infiltration; Nuclear Receptor Subfamily 1, Group F, Member 1; Pneumonia - chemically induced; Pneumonia - metabolism; Pneumonia - pathology; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Trans-Activators - genetics; Trans-Activators - metabolism
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00348.2004

Division of Intramural Research, Laboratory of Respiratory Biology, 1 Cell Biology Section and 3 Molecular and Cellular Biology Section, 2 Laboratory of Pathology, and 4 Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina Submitted 16 September 2004 ; accepted in final form 14 March 2005 The retinoid-related orphan receptor (ROR ), 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 ROR 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 (ROR sg/sg ) mice, a natural mutant strain lacking ROR expression. Examination of hematoxylin and eosin-stained lung sections showed that ROR 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 ROR sg/sg mice to LPS-induced airway inflammation correlated with a higher number of total cells and neutrophils in BAL fluids from LPS-treated ROR sg/sg mice compared with those from LPS-treated wild-type mice. In addition, IL-1 , IL-6, and macrophage inflammatory protein-2 were appreciably more elevated in BAL fluids from LPS-treated ROR sg/sg mice compared with those from LPS-treated wild-type mice. The enhanced susceptibility of ROR sg/sg mice appeared not to be due to a repression of I B expression. Our observations indicate that ROR sg/sg mice are more susceptible to LPS-induced airway inflammation and are in agreement with the hypothesis that ROR functions as a negative regulator of LPS-induced inflammatory responses. retinoid-related orphan receptor ; innate immune response; nuclear receptor Address for reprint requests and other correspondence: A. M. Jetten, Laboratory of Respiratory Biology, Cell Biology Section, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T. W. Alexander Dr., Research Triangle Park, NC 27709 (E-mail: jetten{at}niehs.nih.gov )