Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion
| Autor: | Adriana Migliorini, Helen Liapis, Fay Munro, Murthy N. Darisipudi, Akosua Vilaysane, Yan Shi, Onkar P. Kulkarni, Khader Valli Rupanagudi, Daniel A. Muruve, Shrikant R. Mulay, Hans-Joachim Anders |
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| Rok vydání: | 2012 |
| Předmět: |
medicine.medical_specialty
Primary Immunodeficiency Diseases Interleukin-1beta Calcium oxalate Inflammation Biology Nephropathy Mice chemistry.chemical_compound Phagocytosis Internal medicine NLR Family Pyrin Domain-Containing 3 Protein medicine Animals Secretion Receptor Mice Knockout Innate immune system Calcium Oxalate Immunologic Deficiency Syndromes Interleukin-18 Receptors Interleukin-1 Dendritic Cells General Medicine medicine.disease CARD Signaling Adaptor Proteins Cytoskeletal Proteins Nephrocalcinosis Kidney Tubules Endocrinology chemistry Myeloid Differentiation Factor 88 Interleukin 18 medicine.symptom Apoptosis Regulatory Proteins Carrier Proteins Research Article |
| Zdroj: | Journal of Clinical Investigation. 123:236-246 |
| ISSN: | 0021-9738 |
| Popis: | Nephrocalcinosis, acute calcium oxalate (CaOx) nephropathy, and renal stone disease can lead to inflammation and subsequent renal failure, but the underlying pathological mechanisms remain elusive. Other crystallopathies, such as gout, atherosclerosis, and asbestosis, trigger inflammation and tissue remodeling by inducing IL-1β secretion, leading us to hypothesize that CaOx crystals may induce inflammation in a similar manner. In mice, intrarenal CaOx deposition induced tubular damage, cytokine expression, neutrophil recruitment, and renal failure. We found that CaOx crystals activated murine renal DCs to secrete IL-1β through a pathway that included NLRP3, ASC, and caspase-1. Despite a similar amount of crystal deposits, intrarenal inflammation, tubular damage, and renal dysfunction were abrogated in mice deficient in MyD88; NLRP3, ASC, and caspase-1; IL-1R; or IL-18. Nephropathy was attenuated by DC depletion, ATP depletion, or therapeutic IL-1 antagonism. These data demonstrated that CaOx crystals trigger IL-1β–dependent innate immunity via the NLRP3/ASC/caspase-1 axis in intrarenal mononuclear phagocytes and directly damage tubular cells, leading to the release of the NLRP3 agonist ATP. Furthermore, these results suggest that IL-1β blockade may prevent renal damage in nephrocalcinosis. |
| Databáze: | OpenAIRE |
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