Molecular aspects involved in leukocytes microbicidal and inflammatory activities in the lung

• Grant number: 06/03982-5
• Support Opportunities: Research Projects - Thematic Grants
• Start date: June 01, 2007
• End date: May 31, 2013
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Sônia Jancar
• Grantee: Sônia Jancar
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Pesquisadores principais: Niels Olsen Saraiva Câmara
• Associated researchers: Carlos Henrique Cardoso Serezani ; Fábio Henrique Kwasniewski ; Joilson de Oliveira Martins ; Pamella Huey Mei Wang ; Reinaldo Correia da Silva ; Richardt Gama Landgraf
• Associated scholarship(s): 12/01874-1 - Study about the association of the receptor CD36 and the Platelet-Activating Factor Receptor on the membrane of macrophages, BP.IC; 10/09120-0 - Modulation of dendritic cell phenotype by the Platelet-Activating Factor Receptor (PAFR) and the consequences for the immune response, BP.DD; 10/09388-3 - Molecular and cellular aspects of the lung inflammation caused by sepsis in diabetic and non diabetic rats, BP.DD; + associated scholarships 09/05290-1 - INTERACTION BETWEEN SCAVENGER RECEPTOR CD36 AND PAF RECEPTOR IN MACROPHAGES: LOCATION AND COMMON SIGNALING PATHWAYS., BP.PD; 09/03368-3 - The PAF receptor on macrophage polarization to M1 and M2 phenotype: localization, interactions and signaling pathways, BP.DR; 09/06539-3 - Role of LTB4 and LTD4 in killing of Candida albicans by alveolar macrophages, BP.IC; 08/03722-9 - Mollecular aspects of pentraxin 3 and leukotrienes in phagocytosis and microbicidal activity of alveolar macrophages, BP.DR - associated scholarships

Abstract

The recognition of microorganisms by phagocytes involves complexes of receptors (PRRs) that recognize molecular patterns associated with pathogens (PAMPs), receptors for opsins (Fc gamma to C3b), toll type receptors, in addition to receptors for inflammatory mediators. Evidence exists of interactions between receptors of innate immunity, Fc gamma receptors and receptors for eicosanoids, and that these interactions influence the effector functions of the macrophages, such as phagocytosis and microbicide activity. These interactions can occur between the receptors present in lipidic rafts and/or G proteins involved which lead to induction via different transduction paths of signal elicited by the activation of these receptors. Recently, we demonstrated that leukotriene B4 increases the microbicide activity of alveolar macrophages infected with Klebsiella pneumoniae (opsonized with antibodies) and that this increase is dependent on the activation of PKC - delta and subsequent activation of the NADPH oxidase. It is not known, however, if the leukotrienes interfere with the formation of the phagolysosome, an important step in the control of infection by macrophages. Thus, the first part of this project aims to characterize the signaling paths activated in alveolar macrophages by activation of the Fc gamma receptors, toll type receptors and receptors for leukotrienes, individually or in association, and the consequences in phagocytosis, formation of phagosome and microbicide activity. In pulmonary inflammation the leukocytes that migrate to the lung are fundamental in the induction and resolution of the inflammatory process but they can also be important effectors of tissue lesion. As examples of inflammation mediated by leukocytes in the lung we have allergic asthma where the effector cells are the lymphocytes and eosinophils, pulmonary inflammation stemming from reperfusion after ischemia, in which the effector cell of the lesions is the neutrophil and pulmonary inflammation by LPS which represents a model of inflammation caused by activation of toll type receptors in macrophages. The activation of these cells so that they become effectors of lesion involves signaling through a vast range of receptors. Previous works in our laboratory showed that, in immunomediated inflammation, the pathological events depend on interactions involving receptors for prostaglandins, leukotrienes, PAF, bradykinin and endothelins. Thus, the second part of this project aims to determine the signaling paths activated in the course of allergic pulmonary inflammation (asthma) and non-allergic (LPS and pulmonary inflammation stemming from ischemia/reperfusion), the most relevant pathological events in each model (migration of eosinophils and T gamma/delta and NK T lymphocytes, bronchial hyperactivity, formation of mucous, endothelial lesion and tissue remodeling) and the effect of the lipidic mediators (prostaglandins, leukotrienes and PAF), IL17, bradikinin, endothelins, insulin and proteins related to cell stress (UPR, HO-1 and HSP70) in the signaling paths and in pathological events selected in each of the models. A better understanding of how these receptors function when in concert and of how the different signaling paths interfere some with the others, would permit us to develop new strategies for manipulating the functions of the leukocytes. This could lead to new forms of pharmacological intervention to increase natural immunity against pathogenetic microorganisms or inhibit the harmful effects of inflammation. (AU)

Scientific publications

(12)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

RIOS, FRANCISCO J.; KOGA, MARIANNA M.; PECENIN, MATEUS; FERRACINI, MATHEUS; GIDLUND, MAGNUS; JANCAR, S.. Oxidized LDL Induces Alternative Macrophage Phenotype through Activation of CD36 and PAFR. Mediators of Inflammation, 2013. (06/03982-5)

WANG‚ P.H.M.; CENEDEZE‚ M.A.; CAMPANHOLLE‚ G.; MALHEIROS‚ D.M.A.C.; DE MOURA TORRES‚ H.A.; PESQUERO‚ J.B.; PACHECO-SILVA‚ A.; C{\=A}MARA‚ N.O.S.. Deletion of bradykinin B1 receptor reduces renal fibrosis. International Immunopharmacology, v. 9, n. 6, p. 653-657, 2009. (04/08311-6, 06/03982-5, 07/07139-3)

FEITOZA, CARLA Q.; GONALVES, GISELLE M.; SEMEDO, PATRICIA; CENEDEZE, MARCOS A.; PINHEIRO, HELADY S.; BERALDO, FELIPE CAETANO; DOS SANTOS, OSCAR FERNANDO PAVAO; TEIXEIRA, VICENTE DE PAULA A.; DOS REIS, MARLENE A.; MAZZALI, MARILDA; et al. Inhibition of COX 1 and 2 prior to Renal Ischemia/Reperfusion Injury Decreases the Development of Fibrosis. Molecular Medicine, v. 14, n. 11-12, p. 724-730, NOV-DEC 2008. (06/03982-5, 07/07139-3)

FERRACINI, MATHEUS; RIOS, FRANCISCO J. O.; PECENIN, MATEUS; JANCAR, SONIA. Clearance of Apoptotic Cells by Macrophages Induces Regulatory Phenotype and Involves Stimulation of CD36 and Platelet-Activating Factor Receptor. Mediators of Inflammation, 2013. (06/03982-5, 09/03368-3)

WANG, PAMELLA H. M.; CAMPANHOLLE, GABRIELA; CENEDEZE, MARCOS A.; FEITOZA, CARLA Q.; GONCALVES, GISELLE M.; LANDGRAF, RICHARDT G.; JANCAR, SONIA; PESQUERO, JOAO B.; PACHECO-SILVA, ALVARO; CAMARA, NIELS O. S.. Brabykinin B1 Receptor Antagonism Is Beneficial in Renal Ischemia-Reperfusion Injury. PLoS One, v. 3, n. 8, p. e3050, 2008. (07/07139-3, 06/03982-5, 04/08311-6)

RIOS, FRANCISCO J. O.; KOGA, MARIANA M.; FERRACINI, MATHEUS; JANCAR, SONIA. Co-Stimulation of PAFR and CD36 Is Required for oxLDL-Induced Human Macrophages Activation. PLoS One, v. 7, n. 5, p. e36632, 2012. (09/05290-1, 06/03982-5)

RIOS, FRANCISCO J. O.; FERRACINI, MATHEUS; PECENIN, MATEUS; KOGA, MARIANNA M.; WANG, YAJUAN; KETELHUTH, DANIEL F. J.; JANCAR, S.. Uptake of oxLDL and IL-10 Production by Macrophages Requires PAFR and CD36 Recruitment into the Same Lipid Rafts. PLoS One, v. 8, n. 10, OCT 9 2013. (06/03982-5)

CAMPANHOLLE, GABRIELA; LANDGRAF, RICHARDT G.; BORDUCCHI, ERICA; SEMEDO, PATRICIA; WANG, PAMELA H. M.; AMANO, MARIANE T.; RUSSO, MOMTCHILO; PACHECO-SILVA, ALVARO; JANCAR, SONIA; CAMARA, NIELS O. S.. Bradykinin inducible receptor is essential to lipopolysaccharide-induced acute lung injury in mice. European Journal of Pharmacology, v. 634, n. 1-3, p. 132-137, MAY 25 2010. (07/07139-3, 06/03982-5)

CAMPANHOLLE, G.; LANDGRAF, R. G.; GONCALVES, G. M.; PAIVA, V. N.; MARTINS, J. O.; WANG, P. H. M.; MONTEIRO, R. M. M.; SILVA, R. C.; CENEDEZE, M. A.; TEIXEIRA, V. P. A.; et al. Lung inflammation is induced by renal ischemia and reperfusion injury as part of the systemic inflammatory syndrome. Inflammation Research, v. 59, n. 10, p. 861-869, OCT 2010. (07/07139-3, 06/03982-5)

FEITOZA, CARLA Q.; SEMEDO, PATRICIA; GONCALVES, GISELLE M.; CENEDEZE, MARCOS A.; PINHEIRO, HELADY S.; PAVAO DOS SANTOS, OSCAR FERNANDO; LANDGRAF, RICHARDT GAMA; PACHECO-SILVA, ALVARO; SARAIVA CAMARA, NIELS OLSEN. Modulation of inflammatory response by selective inhibition of cyclooxygenase-1 and cyclooxygenase-2 in acute kidney injury. Inflammation Research, v. 59, n. 3, p. 167-175, MAR 2010. (06/03982-5, 07/07139-3)

RIOS, FRANCISCO J.; KOGA, MARIANNA M.; PECENIN, MATEUS; FERRACINI, MATHEUS; GIDLUND, MAGNUS; JANCAR, S.. Oxidized LDL Induces Alternative Macrophage Phenotype through Activation of CD36 and PAFR. Mediators of Inflammation, v. 2013, p. 8-pg., 2013-01-01. (06/03982-5)

FERRACINI, MATHEUS; RIOS, FRANCISCO J. O.; PECENIN, MATEUS; JANCAR, SONIA. Clearance of Apoptotic Cells by Macrophages Induces Regulatory Phenotype and Involves Stimulation of CD36 and Platelet-Activating Factor Receptor. Mediators of Inflammation, v. 2013, p. 8-pg., 2013-01-01. (06/03982-5, 09/03368-3)