| First Author | Mulay SR | Year | 2013 |
| Journal | J Clin Invest | Volume | 123 |
| Issue | 1 | Pages | 236-46 |
| PubMed ID | 23221343 | Mgi Jnum | J:194155 |
| Mgi Id | MGI:5471146 | Doi | 10.1172/JCI63679 |
| Citation | Mulay SR, et al. (2013) Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1beta secretion. J Clin Invest 123(1):236-46 |
| abstractText | 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-1beta 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-1beta 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-1beta-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-1beta blockade may prevent renal damage in nephrocalcinosis. |
