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

Area of Science:

• Nephrology
• Immunology
• Toxicology

Background:

• Nephrogenic systemic fibrosis (NSF) is a severe fibrotic condition linked to gadolinium-based contrast agents (GBCAs) in patients with kidney disease.
• The exact fibrotic mechanisms of NSF remain unclear, though other fibrotic agents activate the NLRP3 inflammasome.

Purpose of the Study:

• To investigate the role of GBCAs and released gadolinium (Gd) in activating the NLRP3 inflammasome.
• To elucidate the mechanisms underlying Gd-induced fibrosis in NSF.

Main Methods:

• In vitro studies using mouse-derived macrophages incubated with Gd compounds to assess IL-1β secretion and inflammasome activation.
• In vivo studies involving GBCA injection in mice to analyze inflammatory cell recruitment.
• Analysis of macrophage polarization (IL-4 vs. IFNγ) and gene expression related to inflammasome activity.

Main Results:

• Gadolinium (Gd) and GBCAs activate the NLRP3 inflammasome and induce IL-1β secretion in macrophages.
• Gd administration in vivo promoted neutrophil and inflammatory monocyte recruitment.
• IL-4-polarized macrophages showed greater activation by Gd compared to IFNγ-polarized macrophages.

Conclusions:

• Gd released from GBCAs initiates a NLRP3 inflammasome-dependent inflammatory response contributing to NSF.
• The preferential activation of IL-4-polarized macrophages aligns with the fibrotic nature of NSF.