Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis
| Autor: | Sabine Charron, Vincent Lagente, Lizette Fick, Jürg Tschopp, Sandra Girre, Isabelle Couillin, Virginie Pétrilli, Paméla Gasse, Nicolas Riteau, Bernhard Ryffel, Valérie F. J. Quesniaux |
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| Přispěvatelé: | Immunologie et Embryologie Moléculaires (IEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Institute of Immunology and Infectious Disease and Molecular Medicine, Department of Biochemistry [Lausanne], Université de Lausanne (UNIL), Détoxication et réparation tissulaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Lausanne = University of Lausanne (UNIL), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Pulmonary Fibrosis
Interleukin-1beta NALP3 Critical Care and Intensive Care Medicine MESH: Uric Acid chemistry.chemical_compound Mice 0302 clinical medicine Fibrosis MESH: Interleukin-1beta Pulmonary fibrosis Medicine MESH: Animals Lung 0303 health sciences biology MESH: Enzyme-Linked Immunosorbent Assay Inflammasome Lung Injury respiratory system MESH: Bleomycin 3. Good health 030220 oncology & carcinogenesis MESH: Lung Injury [SDV.IMM]Life Sciences [q-bio]/Immunology medicine.symptom Bronchoalveolar Lavage Fluid medicine.drug MESH: Myeloid Differentiation Factor 88 Pulmonary and Respiratory Medicine MESH: Pneumonia MESH: Allopurinol Allopurinol Inflammation Enzyme-Linked Immunosorbent Assay MESH: Carrier Proteins Lung injury Bleomycin 03 medical and health sciences NLR Family Pyrin Domain-Containing 3 Protein Animals MESH: Lung MESH: Mice 030304 developmental biology MESH: Pulmonary Fibrosis business.industry MESH: Bronchoalveolar Lavage Fluid MESH: Biological Markers nutritional and metabolic diseases Pneumonia medicine.disease respiratory tract diseases Uric Acid Disease Models Animal chemistry Immunology Myeloid Differentiation Factor 88 Cancer research biology.protein Uric acid MESH: Disease Models Animal business Carrier Proteins Biomarkers |
| Zdroj: | American Journal of Respiratory and Critical Care Medicine American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, 2009, 179 (10), pp.903-13. ⟨10.1164/rccm.200808-1274OC⟩ American Journal of Respiratory and Critical Care Medicine, 2009, 179 (10), pp.903-13. ⟨10.1164/rccm.200808-1274OC⟩ |
| ISSN: | 1073-449X 1535-4970 |
| Popis: | International audience; RATIONALE: Lung injury leads to pulmonary inflammation and fibrosis through myeloid differentiation primary response gene 88 (MyD88) and the IL-1 receptor 1 (IL-1R1) signaling pathway. The molecular mechanisms by which lung injury triggers IL-1beta production, inflammation, and fibrosis remain poorly understood. OBJECTIVES: To determine if lung injury depends on the NALP3 inflammasome and if bleomycin (BLM)-induced lung injury triggers local production of uric acid, thereby activating the NALP3 inflammasome in the lung. Methods: Inflammation upon BLM administration was evaluated in vivo in inflammasome-deficient mice. Pulmonary uric acid accumulation, inflammation, and fibrosis were analyzed in mice treated with the inhibitor of uric acid synthesis or with uricase, which degrades uric acid. MEASUREMENTS AND MAIN RESULTS: Lung injury depends on the NALP3 inflammasome, which is triggered by uric acid locally produced in the lung upon BLM-induced DNA damage and degradation. Reduction of uric acid levels using the inhibitor of uric acid synthesis allopurinol or uricase leads to a decrease in BLM-induced IL-1beta production, lung inflammation, repair, and fibrosis. Local administration of exogenous uric acid crystals recapitulates lung inflammation and repair, which depend on the NALP3 inflammasome, MyD88, and IL-1R1 pathways and Toll-like receptor (TLR)2 and TLR4 for optimal inflammation but are independent of the IL-18 receptor. CONCLUSIONS: Uric acid released from injured cells constitutes a major endogenous danger signal that activates the NALP3 inflammasome, leading to IL-1beta production. Reducing uric acid tissue levels represents a novel therapeutic approach to control IL-1beta production and chronic inflammatory lung pathology. |
| Databáze: | OpenAIRE |
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