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Master's Dissertation
DOI
https://doi.org/10.11606/D.60.2020.tde-21092021-044227
Document
Author
Full name
Luana Henrique de Macêdo
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2020
Supervisor
Committee
Faccioli, Lucia Helena (President)
Nunes, Anderson de Sá
Pucca, Manuela Berto
Title in Portuguese
O papel do receptor CD14 na regulação metabólica de macrófagos estimulados com peçonha do escorpião Tityus serrulatus
Keywords in Portuguese
CD14
Macrófagos
Metabolismo
Tityus serrulatus
Abstract in Portuguese
A peçonha do escorpião Tityus serrulatus (TsV) é constituída por diversos compostos, os quais interagem com células do sistema imune inato e desencadeiam cascatas de sinalização que culminam no processo inflamatório. Em humanos, o envenenamento induz alterações em diversos órgãos, desregula canais iônicos e pode levar o paciente a óbito. Estudos recentes do nosso grupo descreveram que os macrófagos estão entre as principais células da imunidade inata que reconhecem o TsV. Esse reconhecimento é feito por diversos receptores de reconhecimento de padrões moleculares (PRRs), destacando-se o receptor CD14 presente na superfície dessas células, o qual quando ativado induz a produção de mediadores pró-inflamatórios. Recentemente foi observado que CD14 está associado a regulação metabólica de forma geral, visto que animais deficientes para essa molécula não se tornam obesos, e não desenvolvem resistência à insulina ou complicações cardíacas associadas à obesidade. Porém os mecanismos moleculares pelos quais o CD14 coordena a atividade metabólica de células do sistema imune ainda não foram elucidados. Desta forma propomos investigar o papel do CD14 no metabolismo de macrófagos derivados de medula óssea e macrófagos peritoneais de camundongos C57BL/6 e CD14-/- após estimulo in vitro com TsV ou LPS. As alterações metabólicas, induzidas por LPS ou TsV, foram comparadas entre os macrófagos diferenciados da medula óssea (BMDMs), entre os residentes na cavidade peritoneal (MPs). Para tal finalidade, utilizamos a tecnologia de espectrometria de massas de alta resolução acoplada a cromatografia líquida, instrumentação de estado-da-arte no campo da metabolômica e biologia de sistemas. Os dados foram analisados por meio de programas de biologia computacional especificamente delineados para análises estatísticas e análises funcionais. Nossos resultados demonstraram que a molécula CD14 contribui para a perturbação de vias metabólicas distintas entre BMDMs e MPs, as quais diferem de acordo com o estímulo utilizado, mas que incluem metabolismo de aminoácidos, ácidos graxos, vitaminas e ciclo da ureia. Os resultados deste projeto apresentam grande potencial para o delineamento de novas estratégias terapêuticas no envenenamento por TsV e doenças/condições relacionadas.
Title in English
The role of CD14 receptor on the metabolic regulation of macrophages stimulated with the venom from Tityus serrulatus scorpion
Keywords in English
CD14
Macrophage
Metabolism
Tityus serrulatus
Abstract in English
The venom of Tituys serrulatus scorpion (TsV) is constituted by several compounds, which interact with innate immune cells and trigger signaling cascades that culminate on the inflammatory process. In humans, TsV envenomings induce alterations in several organs, deregulate ionic channels and can be fatal. Recent studies from our group described that macrophages are one of the main innate immune cells to recognize TsV. This process is performed by pattern recognition receptors (PRRs), in which the CD14 receptor is presented in macrophage surfaces, which when activated, results in the production of pro-inflammatory mediators. Recent observations implicate CD14 on a general metabolic regulation, since CD14-deficient animals do not become obese and they do not develop insulin resistance or cardiac complications associated to obesity. However, the molecular mechanisms by which CD14 coordinates the metabolic activity of immune system cells have not been elucidated. In this project, we investigate the role of CD14 on the metabolism of bone marrow derived macrophages (BMDMs) and peritoneal macrophages (MPs) of C57BL/6 and CD14-/- after the stimulation with TsV or LPS. We evaluated metabolic alterations resulting from the two stimuli, which were also compared between different bone marrow derived macrophages or residents in the peritoneal cavity. For this purpose, we used high resolution mass spectrometry coupled with liquid chromatography, a state- of-art technology on the field of metabolomics and systems biology. The data were analyzed using computational biology programs specifically designed for statistical analysis and functional analysis. The data were analyzed using computational biology programs specifically designed for statistical analysis and functional analysis. Our results demonstrated that the CD14 molecule contributes to the disturbance of different metabolic pathways between BMDMs and MPs, which are different according to the stimulus received, but include metabolism of amino acids, fatty acids, vitamins and urea cycle. This project has great potential for the design of new therapeutic strategies in TsV poisoning and related diseases/conditions.
 
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Release Date
2022-08-10
Publishing Date
2021-09-24
 
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