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Molecular basis of carrageenan-induced cytokines production in macrophages

2020; BioMed Central; Volume: 18; Issue: 1 Linguagem: Inglês

10.1186/s12964-020-00621-x

1478-811X

Alexandre H. Lopes, Rangel L. Silva, Miriam M. Fonseca, Francisco Isaac Fernandes Gomes, Alexandre G.M. Maganin, Lucas S. Ribeiro, Lucas Maciel Mauriz Marques, Fernando Q. Cunha, José C. Alves‐Filho, Dario S. Zamboni, Norberto Peporine Lopes, Bernardo S. Franklin, Aurélie Gombault, Fernando Silva Ramalho, Valérie Quesniaux, Isabelle Couillin, Bernhard Ryffel, Thiago M. Cunha,

Inflammasome and immune disorders

Low molecular weight carrageenan (Cg) is a seaweed-derived sulfated polysaccharide widely used as inflammatory stimulus in preclinical studies. However, the molecular mechanisms of Cg-induced inflammation are not fully elucidated. The present study aimed to investigate the molecular basis involved in Cg-induced macrophages activation and cytokines production.Primary culture of mouse peritoneal macrophages were stimulated with Kappa Cg. The supernatant and cell lysate were used for ELISA, western blotting, immunofluorescence. Cg-induced mouse colitis was also developed.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 Pannexin-1/P2X7/K+ efflux signaling. In vivo, Cg-induced colitis was reduced in mice in the absence of NLRP3 inflammasome components.In conclusion, we unravel a critical role of the NLRP3 inflammasome in Cg-induced pro-inflammatory cytokines production and colitis, which is an important discovery on the pro-inflammatory properties of this sulfated polysaccharide for pre-clinical studies. Video abstract Carrageenan (Cg) is one the most used flogistic stimulus in preclinical studies. Nevertheless, the molecular basis of Cg-induced inflammation is not totally elucidated. Herein, Lopes et al. unraveled the molecular basis for Cg-induced macrophages production of biological active IL-1β. The Cg-stimulated macrophages produces pro-IL-1β depends on TLR4/TRIF/Syk/ROS, whereas its processing into mature IL-1β is dependent on the canonical NLRP3 inflammasome.