Carrageenan Triggers NLRP3 Inflammasome Activation and IL-1β Production by Macrophages
39 Pages Posted: 20 Jun 2019More...
Background: Carrageenan (Cg) is a seaweed-derived sulfated polysaccharide widely used as a food additive with the inflammatory property. However, the molecular mechanisms of Cg-induced inflammation are not fully elucidated. The present study aimed to investigate the IL-1β production depends on TLR4/TRIF cascade and subsequent NLRP3 inflammasome activation.
Methods: The undergoing mechanisms in which Cg-mediated macrophages activation were determined by ELISA, Pharmacological approachs and immunolabeling assay. The expression of IL-1β and caspase-1 activity were examined by quantitative PCR and western blotting analyses. The in vivo effect of Cg was investigated in a model of colitis.
Findings: Here we show that Cg activates peritoneal macrophages to produce pro-inflammatory cytokines such as TNF and IL-1β. While Cg-induced TNF production/secretion depends on TLR4/MyD88 signaling, the production of pro-IL-1β relies on TLR4/TRIF/SYK/reactive oxygen species (ROS) signaling pathway. The maturation of pro-IL1β into IL-1β is dependent on canonical NLRP3 inflammasome activation via Pannexin1/P2X7/K+ efflux signaling. In vivo, Cg-induced colitis was reduced in mice in the absence of NLRP3 inflammasome.
Interpretation: We unravel a critical role of the NLRP3 inflammasome in Cg-induced IL-1β secretion and colitis, which is an important discovery on the pro-inflammatory properties of this sulfated polysaccharide for pre-clinical studies and potential undesired effects used as a food additive.
Funding: The research leading to these results received funding from São Paulo Research Foundation (FAPESP) under grant agreements n° 2013/08216-2 (Center for Research in Inflammatory Disease) and 2011/19670-0 (Thematic Project), CNPq n. 141150/2013-0, and from Centre National de la Recherche Scientifique (CNRS) and European Regional Development Fund (FEDER n°2016-00110366).
Declaration of Interests: All authors declare no Conflict of Interest.
Ethics Approval Statement: Animal care and handling procedures were in accordance with Ethics Committee on Animal Experimentation of the Ribeirão Preto Medical School, University of São Paulo. Approval for ethical animal care and use was obtained before the beginning of this study (Process nº 180/2016).
Keywords: Carrageenan, Macrophages, IL-1β, NLRP3 Inflammasome, Pannexin-1 channel
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