Elevated MicroRNA-33 in Sarcoidosis and a Carbon Nanotube Model of Chronic Granulomatous Disease
| Autor: | Mark R. Bowling, Marc A. Judson, Michael B. Fessler, Anagha Malur, Christopher J. Wingard, Barbara P. Barna, Mary Jane Thomassen, Larry Dobbs, Kathryn M. Verbanac, Matthew McPeek |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Sarcoidosis Clinical Biochemistry Granulomatous Disease Chronic Models Biological Proinflammatory cytokine 03 medical and health sciences 0302 clinical medicine Chronic granulomatous disease microRNA Macrophages Alveolar medicine Animals Humans Receptor Molecular Biology Original Research ATP Binding Cassette Transporter Subfamily G Member 1 medicine.diagnostic_test biology Chemistry Nanotubes Carbon Membrane Transport Proteins Cell Biology medicine.disease Lipids Mice Inbred C57BL Disease Models Animal MicroRNAs 030104 developmental biology Bronchoalveolar lavage 030228 respiratory system ABCG1 ABCA1 Immunology biology.protein Alveolar macrophage Cancer research lipids (amino acids peptides and proteins) Bronchoalveolar Lavage Fluid ATP Binding Cassette Transporter 1 |
| Popis: | We established a murine model of multiwall carbon nanotube (MWCNT)-induced chronic granulomatous disease, which resembles human sarcoidosis pathology. At 60 days after oropharyngeal MWCNT instillation, bronchoalveolar lavage (BAL) cells from wild-type mice exhibit an M1 phenotype with elevated proinflammatory cytokines and reduced peroxisome proliferator-activated receptor γ (PPARγ)-characteristics also present in human sarcoidosis. Based upon MWCNT-associated PPARγ deficiency, we hypothesized that the PPARγ target gene, ATP-binding cassette (ABC) G1, a lipid transporter with antiinflammatory properties, might also be repressed. Results after MWCNT instillation indicated significantly repressed ABCG1, but, surprisingly, lipid transporter ABCA1 was also repressed, suggesting a possible second pathway. Exploration of potential regulators revealed that microRNA (miR)-33, a lipid transporter regulator, was strikingly elevated (13.9 fold) in BAL cells from MWCNT-instilled mice but not sham control mice. Elevated miR-33 was also detected in murine granulomatous lung tissue. In vitro studies confirmed that lentivirus-miR-33 overexpression repressed both ABCA1 and ABCG1 (but not PPARγ) in cultured murine alveolar macrophages. BAL cells of patients with sarcoidosis also displayed elevated miR-33 together with reduced ABCA1 and ABCG1 messenger RNA and protein compared with healthy control subjects. Moreover, miR-33 was elevated within sarcoidosis granulomatous tissue. The findings suggest that alveolar macrophage miR-33 is up-regulated by proinflammatory cytokines and may perpetuate chronic inflammatory granulomatous disease by repressing antiinflammatory functions of ABCA1 and ABCG1 lipid transporters. The results also suggest two possible pathways for transporter dysregulation in granulomatous disease-one associated with intrinsic PPARγ status and the other with miR-33 up-regulation triggered by environmental challenges, such as MWCNT. |
| Databáze: | OpenAIRE |
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