title: Inflammasome activation by cystine crystals: implications for the pathogenesis of cystinosis.
abstract: Intralysosomal cystine crystal accumulation, due to mutations in the CTNS gene, is a hallmark of nephropathic cystinosis, but the role of these crystals in disease pathogenesis remains unclear. We hypothesized that, similar to other host-derived crystalline moieties, cystine crystals can induce IL-1β production through inflammasome activation. Thus, we investigated the proinflammatory effects of cystine crystals in primary human PBMCs. LPS-primed PBMCs stimulated with cystine crystals secreted IL-1β in a dose-dependent manner. Similarly to IL-1β secretion induced by other crystalline inflammasome activators, cystine crystal-induced IL-1β secretion required activation of caspase-1. Additionally, exogenous cystine crystals were internalized by monocytes, and inhibition of phagocytosis, cathepsin B leakage, generation of reactive oxygen species, and potassium efflux reduced cystine crystal-induced IL-1β secretion. Patients with cystinosis had higher levels of circulating IL-1β and IL-18 compared with controls. Analysis of inflammasome-related gene expression in PBMCs from patients with cystinosis revealed a significant increase in IL-1β and CASP-1 transcript levels compared with controls. Moreover, knockout of cystinosin in mice led to significant increases in serum IL-18 levels and kidney expression of inflammasome-related genes (Casp-1, Pycard, Il-18, Il18r1, Il1r1, and Il1rl2). Taken together, these data demonstrate that cystine crystals are endogenous inflammasome-activating stimuli, suggesting a novel role for cystine crystals in the pathogenesis of nephropathic cystinosis.
authors: Division of Rheumatology, prencipegiusi@libero.it.
authors: Giusi
authors: G
authors: Prencipe
authors: Division of Rheumatology.
authors: Ivan
authors: I
authors: Caiello
authors: Department of Pediatrics, Division of Genetics, University of California, San Diego, California; and.
authors: Stephanie
authors: S
authors: Cherqui
authors: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California.
authors: Thomas
authors: T
authors: Whisenant
authors: Confocal Microscopy Core Facility, Research Laboratories, and.
authors: Stefania
authors: S
authors: Petrini
authors: Department of Nephrology and Urology, Bambino Gesù Children's Hospital, Roma, Italy;
authors: Francesco
authors: F
authors: Emma
authors: Division of Rheumatology.
authors: Fabrizio
authors: F
authors: De Benedetti
mesh_terms: D000293:Adolescent; D000328:Adult; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003460:Crystallization; D003553:Cystine / Q000737:chemistry* / Q000378:metabolism*; D003554:Cystinosis / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D006801:Humans; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism*; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D055815:Young Adult
chemical_list: D026921:Amino Acid Transport Systems, Neutral; C111445:CTNS protein, human; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; C534463:cystinosin protein, mouse; D003553:Cystine
keywords: chronic kidney disease; genetic renal disease; immunology