Gadolinium-based compounds induce NLRP3-dependent IL-1β production and peritoneal inflammation
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Gadolinium-based compounds induce NLRP3-dependent IL-1β production and peritoneal inflammation. / Schmidt-Lauber, Christian; Bossaller, Lukas; Abujudeh, Hani H; Vladimer, Gregory I; Christ, Anette; Fitzgerald, Katherine A; Latz, Eicke; Gravallese, Ellen M; Marshak-Rothstein, Ann; Kay, Jonathan.
In: ANN RHEUM DIS, Vol. 74, No. 11, 11.2015, p. 2062-9.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Gadolinium-based compounds induce NLRP3-dependent IL-1β production and peritoneal inflammation
AU - Schmidt-Lauber, Christian
AU - Bossaller, Lukas
AU - Abujudeh, Hani H
AU - Vladimer, Gregory I
AU - Christ, Anette
AU - Fitzgerald, Katherine A
AU - Latz, Eicke
AU - Gravallese, Ellen M
AU - Marshak-Rothstein, Ann
AU - Kay, Jonathan
N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
PY - 2015/11
Y1 - 2015/11
N2 - OBJECTIVE: 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)-1β release with the subsequent development of fibrosis, we evaluated the effects of GBCAs on inflammasome activation.METHODS: Bone marrow derived macrophages from C57BL/6, Nlrp3(-/-) and Asc(-/-) mice were incubated with three Gd-containing compounds and IL-1β activation and secretion was detected by ELISA and western blot analysis. Inflammasome activation and regulation was investigated in IL-4- and interferon (IFN)γ-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).RESULTS: Free Gd and GBCAs activate the NLRP3 inflammasome and induce IL-1β 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 IFNγ-polarised macrophages, which preferentially expressed genes known to downregulate inflammasome activity.CONCLUSIONS: 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.
AB - OBJECTIVE: 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)-1β release with the subsequent development of fibrosis, we evaluated the effects of GBCAs on inflammasome activation.METHODS: Bone marrow derived macrophages from C57BL/6, Nlrp3(-/-) and Asc(-/-) mice were incubated with three Gd-containing compounds and IL-1β activation and secretion was detected by ELISA and western blot analysis. Inflammasome activation and regulation was investigated in IL-4- and interferon (IFN)γ-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).RESULTS: Free Gd and GBCAs activate the NLRP3 inflammasome and induce IL-1β 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 IFNγ-polarised macrophages, which preferentially expressed genes known to downregulate inflammasome activity.CONCLUSIONS: 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.
KW - Animals
KW - Apoptosis Regulatory Proteins/genetics
KW - CARD Signaling Adaptor Proteins
KW - Carrier Proteins/drug effects
KW - Contrast Media/adverse effects
KW - Disease Models, Animal
KW - Gadolinium/adverse effects
KW - Gadolinium DTPA/adverse effects
KW - Inflammasomes/drug effects
KW - Interleukin-1beta/drug effects
KW - Macrophages/drug effects
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - NLR Family, Pyrin Domain-Containing 3 Protein
KW - Nephrogenic Fibrosing Dermopathy/chemically induced
KW - Organometallic Compounds/adverse effects
KW - Peritoneum/drug effects
KW - Peritonitis/chemically induced
U2 - 10.1136/annrheumdis-2013-204900
DO - 10.1136/annrheumdis-2013-204900
M3 - SCORING: Journal article
C2 - 24914072
VL - 74
SP - 2062
EP - 2069
JO - ANN RHEUM DIS
JF - ANN RHEUM DIS
SN - 0003-4967
IS - 11
ER -
