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Gadolinium-based compounds induce NLRP3-dependent IL-1? production and peritoneal inflammation.

ABSTRACT: Nephrogenic systemic fibrosis (NSF) is a progressive fibrosing disorder that may develop in patients with chronic kidney disease after administration of gadolinium (Gd)-based contrast agents (GBCAs). In the setting of impaired renal clearance of GBCAs, Gd deposits in various tissues and fibrosis subsequently develops. However, the precise mechanism by which fibrosis occurs in NSF is incompletely understood. Because other profibrotic agents, such as silica or asbestos, activate the nucleotide-binding oligomerisation domain (NOD)-like receptor protein 3 (NLRP3) inflammasome and initiate interleukin (IL)-1? release with the subsequent development of fibrosis, we evaluated the effects of GBCAs on inflammasome activation.Bone marrow derived macrophages from C57BL/6, Nlrp3(-/-) and Asc(-/-) mice were incubated with three Gd-containing compounds and IL-1? activation and secretion was detected by ELISA and western blot analysis. Inflammasome activation and regulation was investigated in IL-4- and interferon (IFN)?-polarised macrophages by ELISA, quantitative real time (qRT)-PCR and NanoString nCounter analysis. Furthermore, C57BL/6 and Nlrp3(-/-)mice were intraperitoneally injected with GBCA and recruitment of inflammatory cells to the peritoneum was analysed by fluorescence-activated cell sorting (FACS).Free Gd and GBCAs activate the NLRP3 inflammasome and induce IL-1? secretion in vitro. Gd-diethylenetriaminepentaacetic acid also induces the recruitment of neutrophils and inflammatory monocytes to the peritoneum in vivo. Gd activated IL-4-polarised macrophages more effectively than IFN?-polarised macrophages, which preferentially expressed genes known to downregulate inflammasome activity.These data suggest that Gd released from GBCAs triggers a NLRP3 inflammasome-dependent inflammatory response that leads to fibrosis in an appropriate clinical setting. The preferential activation of IL-4-differentiated macrophages is consistent with the predominantly fibrotic presentation of NSF.

SUBMITTER: Schmidt-Lauber C

PROVIDER: S-EPMC4428954 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Gadolinium-based compounds induce NLRP3-dependent IL-1β production and peritoneal inflammation.

Schmidt-Lauber Christian C Bossaller Lukas L Abujudeh Hani H HH Vladimer Gregory I GI Christ Anette A Fitzgerald Katherine A KA Latz Eicke E Gravallese Ellen M EM Marshak-Rothstein Ann A Kay Jonathan J

Annals of the rheumatic diseases 20140609 11

<h4>Objective</h4>Nephrogenic systemic fibrosis (NSF) is a progressive fibrosing disorder that may develop in patients with chronic kidney disease after administration of gadolinium (Gd)-based contrast agents (GBCAs). In the setting of impaired renal clearance of GBCAs, Gd deposits in various tissues and fibrosis subsequently develops. However, the precise mechanism by which fibrosis occurs in NSF is incompletely understood. Because other profibrotic agents, such as silica or asbestos, activate ...[more]

PMID: 24914072

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Project description:Crystalline cellulose nanocrystals (CNCs) have emerged as novel materials for a wide variety of important applications such as nanofillers, nanocomposites, surface coatings, regenerative medicine and potential drug delivery. CNCs have a needle-like structure with sizes in the range of 100-200 nm long and 5-20 nm wide and a mean aspect ratio 10-100. Despite the great potential applicability of CNCs, very little is known about their potential immunogenicity. Needle-like materials have been known to evoke an immune response in particular to activate the (NOD-like receptor, pyrin domain-containing 3)-inflammasome/IL-1? (Interleukin 1?) pathway. In this study we evaluated the capacity of unmodified CNC and its cationic derivatives CNC-AEM (aminoethylmethacrylate)1, CNC-AEM2, CNC-AEMA(aminoethylmethacrylamide)1 and CNC-AEMA2 to stimulate NLRP3-inflammasome/IL-1? pathway and enhance the production of mitochondrial reactive oxygen species (ROS). Mouse macrophage cell line (J774A.1) was stimulated for 24 h with 50 µg/mL with unmodified CNC and its cationic derivatives. Alternatively, J774A1 or PBMCs (peripheral blood mononuclear cells) were stimulated with CNC-AEMA2 in presence or absence of LPS (lipopolysaccharide). IL-1? secretion was analyzed by ELISA, mitochondrial function by JC-1 staining and ATP content. Intracellular and mitochondrial reactive oxygen species (ROS) were assessed by DCF-DA (2',7'-dichlorodihydrofluorescein diacetate) and MitoSOX, respectively. Mitochondrial ROS and extracellular ATP were significantly increased in cells treated with CNC-AEMA2, which correlates with the strongest effects on IL-1? secretion in non-primed cells. CNC-AEMA2 also induced IL-1?secretion in LPS-primed and non-primed PBMCs. Our data suggest that the increases in mitochondrial ROS and ATP release induced by CNC-AEMA2 may be associated with its capability to evoke immune response. We demonstrate the first evidence that newly synthesized cationic cellulose nanocrystal derivative, CNC-AEMA2, has immunogenic properties, which may lead to the development of a potential non-toxic and safe nanomaterial to be used as a novel adjuvant for vaccines.

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Gadolinium-based compounds induce NLRP3-dependent IL-1? production and peritoneal inflammation.

Publications

Gadolinium-based compounds induce NLRP3-dependent IL-1β production and peritoneal inflammation.

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