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Doctoral Thesis
DOI
10.11606/T.42.2016.tde-25022016-095353
Document
Author
Full name
Silvia Lucena Lage
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2015
Supervisor
Committee
Bortoluci, Karina Ramalho (President)
Basso, Alexandre Salgado
Pontillo, Alessandra
Rosa, Daniela Santoro
Weinlich, Ricardo
Title in Portuguese
Papel de inflamassomas e vias lisossomais na morte celular e resposta imune induzidas pela flagelina.
Keywords in Portuguese
Adjuvantes
Flagelina
Inflamassomas
Lisossomas
Sinalização da IL-1
Abstract in Portuguese
A flagelina é um agonista natural do sensor TLR5 e do inflamassoma NAIP/NLRC4 que é responsável pela secreção de IL-1β e IL-18 e pela indução de morte celular necrótica, via ativação da caspase-1. Entretanto, nós observamos que a inserção da flagelina de B. subtilis no citosol celular por meio de vesículas lipídicas, induz um processo atípico de morte nos macrófagos peritoneais (PMs) deficientes em NLRC4, ASC e caspase-1/11. A morte dos PMs manteve seu resultado antimicrobiano, sendo acompanhada da liberação de IL-1α. A morte celular e a secreção das citocinas IL-1α e IL-1β, foi mediada por catepsinas lisossomais, sugerindo uma cooperação entre a via lisossomal e os inflamassomas nas respostas induzidas pela flagelina. Além disso, a flagelina de S. typhimurium foi capaz de induzir dano lisossomal e secreção de IL-1α e IL-1β mediada pelo eixo caspase-catepsinas, na ausência de carreadores, e estas citocinas tiveram um impacto na imunidade adaptativa induzida pela flagelina, no modelo de ativação de linfócitos T específicos por células dendríticas, in vitro.
Title in English
Role of inflammasomes and lysosomal pathway in cell death and immunity induced by flagellin.
Keywords in English
Adjuvancy
Flagellin
IL-1 signaling
Inflammasomes
Lysosomes
Abstract in English
Flagellin is a natural agonist of TLR5 and NAIP/NLRC4 inflammasome that is responsible for IL-1β and IL-18 secretion and for the induction of a necrotic cell death, both mediated by caspase-1. However, we observed that flagellin from B. subtilis inserted into lipid vesicles, induced an atypical cell death in peritoneal macrophages (PMs) in the absence of NLRC4, ASC and caspase-1/11. This inflammasome-independent cell death retained its antimicrobial outcome, being accompanied with IL-1α secretion. Importantly, cell death and caspase-1-dependent IL-1α and IL-1β secretion were regulated by lysosomal cathepsins, suggesting a cooperation between the inflammasome and lysosomal pathway in response to flagellin. We also observed that flagellin from S. typhimurium is able to induce lysosomal damage and IL-1α and IL-1β secretion by PMs in the absence of a carrier, through a caspase-catepsins-dependent manner, and that cytokines were important to the ability of flagellin in to induce adaptive immune response by antigen-specific T cells.
 
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Release Date
2018-02-24
Publishing Date
2016-02-25
 
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