期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 123, 期 1, 页码 236-246出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI63679
关键词
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资金
- Deutsche Forschungsgemeinschaft [GRK 1202, AN372/9-2]
- NIH/NIDCD [P30DC04665 SEM]
- Pathology and Immunology Electron Microscopy Research Core lab, Washington University School of Medicine
- Heuser Lab, Department of Cell Biology, Washington University School of Medicine
- NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS [P30DC004665] Funding Source: NIH RePORTER
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-1 beta 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-1 beta through a pathway that included NLRP3, AS C, 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-1 beta-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-1(3 blockade may prevent renal damage in nephrocalcinosis.
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