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Doctoral Thesis
DOI
10.11606/T.42.2014.tde-27112014-084955
Document
Author
Full name
Thaís Boccia da Costa
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2014
Supervisor
Committee
Bortoluci, Karina Ramalho (President)
Barboza, Renato
Keller, Alexandre de Castro
Peron, Jean Pierre Schatzmann
Pontillo, Alessandra
Title in Portuguese
Papel dos inflamassomas na ativação de células dendríticas e na modulação da resposta imune adaptativa.
Keywords in Portuguese
S. typhimurium
Caspase-1
Flagelina
IL-1a
Inflamassoma
MyD88
Abstract in Portuguese
O reconhecimento da flagelina pelos NLRs Naip5 e NLRC4 leva à formação do complexo multiproteico denominado inflamassoma que culmina na ativação da caspase-1, com consequente clivagem da forma inativa das citocinas pró-inflamatórias IL-1b e IL-18 e morte da célula infectada. Neste trabalho pudemos observar que in vitro, a maturação de BMDCs com a estimulação com flagelina citosólica, inserida em vesículas lipídicas que permitem a transfecção da flagelina para o citosol, foi independente da ativação de NLRC4, caspase-1 e TLR5, mas somente de MyD88. Já a ativação de linfócitos T por estas BMDCs ativadas por flagelina citosólica é dependente de caspase-1 e MyD88. A neutralização da citocina IL-1a, levou à inibição da ativação de linfócitos T, indicando a contribuição desta para a montagem de resposta imune. A neutralização de IL-1a também levou a uma redução na produção de IL-12, que seria a citocina responsável pela polarização dos linfócitos para Th1. A imunização com flagelina leva ao desenvolvimento de imunidade protetora contra o desafio com S. typhimurium, igualmente dependente de caspase-1 e MyD88. Podemos dizer que a flagelina induz resposta imune tanto in vivo quanto in vitro e que, em ambos os casos, há a participação das moléculas caspase-1 e MyD88.
Title in English
Role of inflammasome activation in the maturation of dendritic cells and in the development of adaptive imune response.
Keywords in English
S. typhimurium
Caspase-1
Flagellin
IL-1a
Inflammasome
MyD88
Abstract in English
TLR5 activates inflammatory genes through MyD88 pathway whereas NLRC4 and NAIP5 assemble multiprotein complexes called inflammasomes, leading to caspase-1 activation and secretion of proinflammatory cytokines IL-1 and IL-18. Cytosolic flagellin (FLA-BSDot) induced upregulation of costimulatory molecules independent on TLR5, NLRC4 and Caspase-1, but dependent on MyD88. In addition, FLA-BSDot-stimulated OVA-pulsed BMDCs induced proliferation and production of IFN by OT-II splenocytes, dependent on caspase-1 and MyD88. FLA-BSDot stimulation leads to the secretion of IL-1 and IL-1. Neutralization of IL-1 inhibited BMDCs maturation in response to FLA-BSDot and led to decreased IFN production by OT-II splenocytes. Searching for the effector mechanism by which IL-1 induces Th1 polarization in response to FLA-BSDot, we observed a significant reduction in IL-12 production when IL-1 was neutralized. Also, we could see that adaptive immune responses induced by flagellin in vivo was protective against S.typhimurium lethal challenge, showing again a role for caspase-1 and MyD88. From these data we can infer that caspase-1 and MyD88 are both involved in the adaptive response induced by flagelin both in vitro and in vivo.
 
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Release Date
2016-12-03
Publishing Date
2014-12-11
 
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