Molecular basis of carrageenan-induced cytokines production in macrophages
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(2020) 18:141
RESEARCH
Open Access
Molecular basis of carrageenan-induced cytokines production in macrophages Alexandre H. Lopes1, Rangel L. Silva1, Miriam D. Fonseca1, Francisco I. Gomes1, Alexandre G. Maganin1, Lucas S. Ribeiro2, Lucas Maciel Mauriz Marques3, Fernando Q. Cunha1, Jose C. Alves-Filho1, Dario S. Zamboni4, Norberto P. Lopes3, Bernardo S. Franklin2, Aurélie Gombault5, Fernando Silva Ramalho6, Valerie F. J. Quesniaux5, Isabelle Couillin5, Bernhard Ryffel5 and Thiago M. Cunha1*
Abstract Background: 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. Methods: 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. Results: 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. Conclusions: 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. Keywords: Carrageenan, Macrophages, IL-1β, NLRP3 Inflammasome, Pannexin-1 channel
Background Carrageenan (Cg) is a seaweed-derived sulfated polysaccharide [1, 2]. There are three major forms of carrageenan: lambda- (λ), kappa- (κ) and iota- (ι) [3, 4]. There is evidence that chronic ingestion of some subtypes of Cg, especially low-molecular weight, is associated with inflammation, intestinal cancer and ulcerations [5–7]. * Correspondence: [email protected]; [email protected] 1 Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Center for Research in Inflammatory Diseases (CRID)Av. Bandeirantes 3900, 14049-900, Ribeirão Preto, SP, Brazil Full list of author information is available at the end of the article
Furthermore, these flogistic Cg subtypes are extensively used to induce inflammation in several experimental animal models especially to study novel anti-inflammatory and analgesic drugs [8–11]. For instance, Cg injected into the rodents hindpaw causes a classical innate immune response characterized by paw oedema, neutrophil migration and pain [12, 13]. Our group has identified that Cg-induced inflammatio
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