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Doctoral Thesis
DOI
10.11606/T.9.2016.tde-21102016-172133
Document
Author
Full name
Marina Reis de Moura Campos
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2008
Supervisor
Committee
Negro, Sonia Jancar (President)
Almeida, Sandro Rogerio de
Kwasniewski, Fábio Henrique
Lima, Wothan Tavares de
Starobinas, Nancy
Title in Portuguese
Ação dos leucotrienos na fagocitose via receptores Fc e manose em macrófagos alveolares e mecanismos moleculares envolvidos
Keywords in Portuguese
Candida albicans
Fagocitose
Imunologia
Leucotrienos
Macrófagos
Abstract in Portuguese
Os leucotrienos aumentam a fagocitose e a atividade microbicida contra uma série de patógenos. Em macrófagos alveolares, LTB4 e LTD4 aumentam a fagocitose via FcγR de modo dependente de PKC. Entretanto, o papel das isoformas específicas da PKC, das MAPK, e da PI3K neste processo, ainda não é conhecido. Além disso, pouco se sabe sobre a importância dos leucotrienos na fagocitose via outros receptores. Os objetivos deste trabalho são: a) ampliar o conhecimento sobre as vias de sinalização ativadas pelos leucotrienos durante a fagocitose de hemácias opsonizadas por IgG; b) avaliar o efeito dos leucotrienos na fagocitose de Candida albicans, por macrófagos alveolares e as vias de sinalização intracelular envolvidas. Observou-se que os leucotrienos endogenamente produzidos ou adicionados aos macrófagos alveolares, aumentam a fagocitose via FcγR e para isso utilizam distintas vias de sinalização intracelular. A ação do LTB4 envolveu predominantemente a via ERK1/2 e PKCα. E com menor intensidade da PKCδ. A ação do LTD4 envolveu exclusivamente a via p38 e PKCδ. Ambos leucotrienos utilizaram a PI3K para aumentar a fagocitose via FcγR. Na fagocitose de C.albicans, os macrófagos alveolares produziram LTB4. Tanto o LTB4 quanto o LTD4 endógenos contribuíram para a fagocitose da C.albicans que ocorre predominantemente via receptor manose. A fagocitose via receptor manose foi potencializada pela adição tahto do LTB4 quanto do LTD4 cγ de modo dependente da ativação da PKCδ e da PI3K. As vias da PKCα., ERK1/2 e p38 não estão envolvidas na potencialização da fagocitose de C.albicans por leucotrienos. O esclarecimento das moléculas sinalizadoras envolvidas na interação de macrófagos alveolares com patógenos poderá contribuir para o desenvolvimento de alvos específicos e refinados no controle e tratamento de infecções pulmonares. Analisados em conjunto, os resultados mostram que os leucotrienos são importantes moduladores das funções dos macrófagos alveolares, por aumentar a fagocitose tanto através dos receptores para Fcγ como do receptor manose. Além disso, os LTB4 e LTD4 ativam programas de sinalização distintos para potencializar a fagocitose via receptor Fcγ, enquanto na fagocitose via receptor manose os LTB4 e LTD4 usam as mesmas vias.
Title in English
Action of leukotrienes in phagocytosis via mannose receptors fc in alveolar macrophages and molecular mechanisms involved
Keywords in English
Candida albicans
Immunology
Leukotrienes
Macrophages
Phagocytosis
Abstract in English
Leukotrienes enhance phagocytosis and microbicidal activity against several pathogens. In alveolar macrophages, LTB4 and cysteinyl LT both enhance Fcγ receptor - mediated phagocytosis. While both LTB4 and LTD4 enhances phagocytosis dependent on PKC activity, only LTB4 requires the protein tyrosine kinase syk to do so. However, the role of specific PKC isoforms, MAPKs (p38 and ERK1/2), and PI3K in mediating LT-enhanced FcγR-mediated phagocytosis is unknown. In addition, the importance of LT in the phagocytosis via other receptors is also understudied. In the present work we sought to determine the importance of the above kinases during IgG-opsonized phagocytosis and if both classes of LT enhance the ingestion of C. albicans; the receptors and the molecular mechanisms involved. Studies with isoform-selective inhibitors indicated that LTB4 effects were dependent on both PKCα. And PKCδ, while LTD4 effects were exclusively due to PKCδ activation. Although both exogenous LTB4 and LTD4 enhanced p38 and ERK1/2 activation, LTB4 required only ERK1/2, while LTD4 required only p38 activation. Activation by both LT was dependent on PI3K activation. It was found that exogenously added LTB4 and LTD4 both enhanced PKC& and PKCα. Phosphorylation during FcγR engagement. Regarding the studies concerning the importance of LT in the ingestion of C.albicans, both endogenous and exogenous LTB4 and LTD4 enhanced C.albicans phagocytosis. LT effects were dependent exclusively on PKCδ and P13K. We also demonstrated that the LT effect on C.albicans was due to the mannose receptor activation. Taken together, leukotrienes are potente immunomodulators of the phagocyte function, by enhancing phagocytosis both via FcγR and mannose receptor. Moreover, LT receptors activate different signaling programs to enhance FcγR-mediated phagocytosis, while the signaling elicited to enhance C.albicans ingestion is similar for both classes of LTs. Thus the nature of the signaling elicited by the phagocytic receptors dictates the signaling induced by LT.
 
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Publishing Date
2016-10-21
 
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