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Doctoral Thesis
DOI
10.11606/T.42.2012.tde-12112012-092250
Document
Author
Full name
Mariana Morato Marques
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2012
Supervisor
Committee
Negro, Sonia Jancar (President)
Calich, Vera Lucia Garcia
Campa, Ana
Condino Neto, Antonio
Medeiros, Alexandra Ivo de
Title in Portuguese
Leucotrienos como moduladores da imunidade inata a fungos.
Keywords in Portuguese
Candida albicans
Fagocitose
Fungos
Leucotrienos
Abstract in Portuguese
Leucotrienos (LTs) são mediadores lipídicos derivados do ácido araquidônico. Existem evidências que receptores da imunidade inata interagem com receptores para LTs amplificando funções efetoras de macrófagos. Investigamos se LTs modulam a fagocitose e a atividade microbicida via receptores Manose, Dectina -1 e PTX3 em macrófagos alveolares (AMs) e os mecanismos moleculares envolvidos. Nossos resultados mostram que: 1) AMs sintetizam LTs quando fagocitam C. albicans, Zy e Zy-PTX3; 2) LTs potencializam a fagocitose de C. albicans e Zy, mas não de Zy-PTX3. Este efeito dos LTs depende: do reconhecimento via receptor manose (LTB4) e Dectina-1 (LTD4); da integridade de lipid rafts; da ação em mecanismos de polimerização de actina; do aumento dos níveis de F-actina por inativação da Cofilina-1; da ativação das LIMKs, que regulam Cofilina-1; da ativação de PKCd e PI3K3) LTs aumentam a capacidade de AMs em matar C. albicans por ativação de NADPH oxidase. Em conjunto, mostramos que LTs potencializam programas de sinalização específicos para determinados PRRs.
Title in English
Leukotrienes as modulators of innate immunity to fungi.
Keywords in English
Candida albicans
Fungi
Leukotrienes
Phagocytosis
Abstract in English
Leukotrienes (LTs) are lipid mediators derived from arachidonic acid. There is evidence that innate immunity receptors and leukotrienes receptors interact and amplify macrophage effector functions. We investigated if LTs receptors modulate phagocytosis and microbicidal activity mediated by Mannose receptor, Dectin-1 and PTX3 in alveolar macrophages (AMs) and the molecular mechanisms involved. Our results showed that: 1) AMs produce LTs when stimulated with C.albicans, Zy, Zy-PTX3; 2) LTs enhance phagocytosis of C.albicans and Zymosan, but not Zy-PTX3. This is dependent on: recognition via mannose receptor (LTB4) and Dectin-1 (LTD4); integrity of lipid rafts; its action on actin polimerization mechanisms; enhancement of F-actin levels by induction of Cofilin-1 inactivation; activation of LIMKs that regulate Cofilin-1; activation of PKCd and PI3K3) LTs enhance killing of C.albicans by activation of NADPH oxidase. Taken together, our results showed that LTs specifically influence signaling programs of keys PRRs.
 
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Publishing Date
2013-02-08
 
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