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.

A Tissue-Specific Role for Nlrp3 in Tubular Epithelial Repair after Renal Ischemia/Reperfusion

“…The cytosolic innate immune receptor Nlrp3 is able to sense cellular damage 13 and mediates renal inflammation and pathological characteristics after IR 14e16 or nephrocalcinosis. 17 Next to the detrimental role of Nlrp3 in different renal disease models and consistent with the dual role of TLR2, Nlrp3 was shown to protect against loss of colonic epithelial integrity. 18 We, therefore, speculate that Nlrp3, which contributes to sterile renal inflammation during acute renal IR injury, might also drive subsequent tubular repair.…”

Inflammasome Activation by Cystine Crystals

“…Our data suggest that cystine crystals may not be inert but rather a trigger of inflammation, as recently demonstrated for calcium oxalate crystals in nephrocalcinosis. 17 Elevated circulating levels of IL-1b and IL-18 in cystinotic patients and elevated inflammasome-related gene expression both in PBMCs from patients and in kidney tissue from Ctns 2/2 mice support the hy pothesis that inflammasome activation may contribute to the development of the interstitial inflammation and fibrosis leading to ESRD observed in cystinotic patients and mice. Interestingly, the inflammasome-regulated cytokines IL-1b and IL-18 are implicated in several animal models or human forms of CKD.…”

Synchronized renal tubular cell death involves ferroptosis

“…Having identified ferroptosis to be of relevance in acute postischemic injury, we sought to investigate another model of acute renal failure, oxalate nephropathy, which has recently been established (30). Intrarenal CaOx crystal deposition was identical in all groups ( Fig.…”