ABSTRACT
Lung type 2 pneumocytes (T2Ps) and alveolar macrophages (AMs) play crucial roles in the synthesis, recycling and catabolism of surfactant material, a lipid/protein fluid essential for respiratory function. The liver X receptors (LXR), LXRα and LXRß, are transcription factors important for lipid metabolism and inflammation. While LXR activation exerts anti-inflammatory actions in lung injury caused by lipopolysaccharide (LPS) and other inflammatory stimuli, the full extent of the endogenous LXR transcriptional activity in pulmonary homeostasis is incompletely understood. Here, using mice lacking LXRα and LXRß as experimental models, we describe how the loss of LXRs causes pulmonary lipidosis, pulmonary congestion, fibrosis and chronic inflammation due to defective de novo synthesis and recycling of surfactant material by T2Ps and defective phagocytosis and degradation of excess surfactant by AMs. LXR-deficient T2Ps display aberrant lamellar bodies and decreased expression of genes encoding for surfactant proteins and enzymes involved in cholesterol, fatty acids, and phospholipid metabolism. Moreover, LXR-deficient lungs accumulate foamy AMs with aberrant expression of cholesterol and phospholipid metabolism genes. Using a house dust mite aeroallergen-induced mouse model of asthma, we show that LXR-deficient mice exhibit a more pronounced airway reactivity to a methacholine challenge and greater pulmonary infiltration, indicating an altered physiology of LXR-deficient lungs. Moreover, pretreatment with LXR agonists ameliorated the airway reactivity in WT mice sensitized to house dust mite extracts, confirming that LXR plays an important role in lung physiology and suggesting that agonist pharmacology could be used to treat inflammatory lung diseases.
Subject(s)
Homeostasis , Liver X Receptors , Macrophages, Alveolar , Pneumonia , Pulmonary Surfactants , Signal Transduction , Animals , Liver X Receptors/metabolism , Liver X Receptors/genetics , Pulmonary Surfactants/metabolism , Mice , Pneumonia/metabolism , Pneumonia/pathology , Macrophages, Alveolar/metabolism , Mice, Inbred C57BL , Mice, Knockout , Lung/metabolism , Lung/pathology , Alveolar Epithelial Cells/metabolism , Asthma/metabolism , Asthma/pathology , Asthma/genetics , Cholesterol/metabolism , Lipid Metabolism , PhagocytosisABSTRACT
Macrophages are immune cells that play crucial roles in host defense against pathogens by triggering their exceptional phagocytic and inflammatory functions. Macrophages that reside in healthy tissues also accomplish important tasks to preserve organ homeostasis, including lipid uptake/efflux or apoptotic-cell clearance. Both homeostatic and inflammatory functions of macrophages require the precise stability of lipid-rich microdomains located at the cell membrane for the initiation of downstream signaling cascades. Caveolin-1 (Cav-1) is the main protein responsible for the biogenesis of caveolae and plays an important role in vascular inflammation and atherosclerosis. The Liver X receptors (LXRs) are key transcription factors for cholesterol efflux and inflammatory gene responses in macrophages. Although the role of Cav-1 in cellular cholesterol homeostasis and vascular inflammation has been reported, the connection between LXR transcriptional activity and Cav-1 expression and function in macrophages has not been investigated. Here, using gain and loss of function approaches, we demonstrate that LXR-dependent transcriptional pathways modulate Cav-1 expression and compartmentation within the membrane during macrophage activation. As a result, Cav-1 participates in LXR-dependent cholesterol efflux and the control of inflammatory responses. Together, our data show modulation of the LXR-Cav-1 axis could be exploited to control exacerbated inflammation and cholesterol overload in the macrophage during the pathogenesis of lipid and immune disorders, such as atherosclerosis.
Subject(s)
Caveolin 1/biosynthesis , Cholesterol/metabolism , Liver X Receptors/biosynthesis , Macrophages/metabolism , ATP Binding Cassette Transporter 1/metabolism , Animals , Anti-Inflammatory Agents , Apolipoprotein A-I/metabolism , Atherosclerosis/metabolism , Caveolin 1/genetics , Cell Membrane/metabolism , Detergents , Gene Expression , Green Fluorescent Proteins/metabolism , Humans , Inflammation , Mice , Mice, Inbred C57BL , RAW 264.7 Cells , Signal Transduction , Transcription, GeneticABSTRACT
A zoonotic, opportunistic out-break of tropical rat mite Ornithonyssus bacoti [Acari: Macronyssidae; Ornithonyssus bacoti (Hirst)] in an animal facility, is described. Immunocompetent mice [Mus musculus (Linnaeus)] and rat [Rattus norvegicus (Berkenhout)] strains in a conventional health status facility suffered from scratching and allopecia and staff members suffered from pruritic, erythemato-papular lesions, presumed to be allergic in origin. O. bacoti was identified and treatment with a 0.1% ivermectin solution led to its complete erradication. Safety assessment revealed no signs of acute toxicity in any animal strain. Following this inexpensive strategy, 7 wk after the initial dose, samples were negative for the presence of acari. At the time of this report, 26 months after diagnosis, O. bacoti remains undetected.
