Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion.

Abstract

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.

• Authors: Shrikant R Mulay, Onkar P Kulkarni, Khader V Rupanagudi, Adriana Migliorini, Murthy N Darisipudi, Akosua Vilaysane, Daniel Muruve, Yan Shi, Fay Munro, Helen Liapis, Hans-Joachim Anders
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 123 Issue 1 Pg. 236-46 (Jan 2013) ISSN: 1558-8238 [Electronic] United States
• PMID: 23221343 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• CARD Signaling Adaptor Proteins
• Carrier Proteins
• Cytoskeletal Proteins
• Interleukin-18
• Interleukin-1beta
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Pycard protein, mouse
• Receptors, Interleukin-1
• Calcium Oxalate

Topics

• Animals
• Apoptosis Regulatory Proteins
• CARD Signaling Adaptor Proteins
• Calcium Oxalate (immunology, metabolism)
• Carrier Proteins (genetics, immunology, metabolism)
• Cytoskeletal Proteins (genetics, immunology, metabolism)
• Dendritic Cells (immunology, metabolism)
• Immunologic Deficiency Syndromes (genetics, immunology, metabolism)
• Inflammation (genetics, immunology, metabolism)
• Interleukin-18 (genetics, immunology, metabolism)
• Interleukin-1beta (genetics, immunology, metabolism)
• Kidney Tubules (immunology, metabolism, pathology)
• Mice
• Mice, Knockout
• Myeloid Differentiation Factor 88 (genetics, immunology, metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nephrocalcinosis (genetics, immunology, metabolism, pathology)
• Phagocytosis
• Primary Immunodeficiency Diseases
• Receptors, Interleukin-1 (genetics, immunology, metabolism)