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Molecular basis of carrageenan-induced cytokines production in macrophages.

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-1?. While Cg-induced TNF production/secretion depends on TLR4/MyD88 signaling, the production of pro-IL-1? relies on TLR4/TRIF/SYK/reactive oxygen species (ROS) signaling pathway. The maturation of pro-IL1? into IL-1? 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. 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-1?. The Cg-stimulated macrophages produces pro-IL-1? depends on TLR4/TRIF/Syk/ROS, whereas its processing into mature IL-1? is dependent on the canonical NLRP3 inflammasome.

SUBMITTER: Lopes AH

PROVIDER: S-EPMC7487827 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Molecular basis of carrageenan-induced cytokines production in macrophages.

Lopes Alexandre H AH Silva Rangel L RL Fonseca Miriam D MD Gomes Francisco I FI Maganin Alexandre G AG Ribeiro Lucas S LS Marques Lucas Maciel Mauriz LMM Cunha Fernando Q FQ Alves-Filho Jose C JC Zamboni Dario S DS Lopes Norberto P NP Franklin Bernardo S BS Gombault Aurélie A Ramalho Fernando Silva FS Quesniaux Valerie F J VFJ Couillin Isabelle I Ryffel Bernhard B Cunha Thiago M TM

Cell communication and signaling : CCS 20200907 1

<h4>Background</h4>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.<h4>Methods</h4>Primary culture of mouse peritoneal macrophages were stimulated with Kappa Cg. The supernatant and cell ...[more]

PMID: 32894139

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Project description:Periodontitis is a very common oral inflammatory disease that results in the destruction of supporting connective and osseous tissues of the teeth. Although the exact etiology is still unclear, Gram-negative bacteria, especially Porphyromonas gingivalis in subgingival pockets are thought to be one of the major etiologic agents of periodontitis. Endothelin (ET) is a family of three 21-amino acid peptides, ET-1, -2, and -3, that activate G protein-coupled receptors, ETA and ETB. Endothelin is involved in the occurrence and progression of various inflammatory diseases. Previous reports have shown that ET-1 and its receptors, ETA and ETB are expressed in the periodontal tissues and, that ET-1 levels in gingival crevicular fluid are increased in periodontitis patients. Moreover, P. gingivalis infection has been shown to induce the production of ET-1 along with other inflammatory cytokines. Despite these studies, however, the functional significance of endothelin in periodontitis is still largely unknown. In this study, we explored the cellular and molecular mechanisms of ET-1 action in periodontitis using human gingival epithelial cells (HGECs). ET-1 and ETA, but not ETB, were abundantly expressed in HGECs. Stimulation of HGECs with P. gingivalis or P. gingivalis lipopolysaccharide increased the expression of ET-1 and ETA suggesting the activation of the endothelin signaling pathway. Production of inflammatory cytokines, IL-1?, TNF?, and IL-6, was significantly enhanced by exogenous ET-1 treatment, and this effect depended on the mitogen-activated protein kinases via intracellular Ca2+ increase, which resulted from the activation of the phospholipase C/inositol 1,4,5-trisphosphate pathway. The inhibition of the endothelin receptor-mediated signaling pathway with the dual receptor inhibitor, bosentan, partially ameliorated alveolar bone loss and immune cell infiltration. These results suggest that endothelin plays an important role in P. gingivalis-mediated periodontitis. Thus, endothelin antagonism may be a potential therapeutic approach for periodontitis treatment.

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Molecular basis of carrageenan-induced cytokines production in macrophages.

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Molecular basis of carrageenan-induced cytokines production in macrophages.

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