Université du Québec
Macrophage activation; Leishmania-macrophage interaction.
Because of their potent microbicidal and tumoricidal capacities, macrophages play a major role in the immune response. Macrophage functions are not constitutive, being rather acquired (activation) in the presence of molecules such as cytokines or microbial-derived products. Binding of these molecules at the surface of a resting macrophage triggers intracellular signalling pathways, leading to the induction of gene expression and protein synthesis. These intracellular events culminate in the acquisition of phenotypes allowing the macrophage to perform specific immune functions.
One of my objectives is to gain a better knowledge of the molecular mechanisms leading to macrophage activation. This is essential for the development of novel pharmacological approaches based on the selective manipulation of intracellular signalling pathways. We concentrate our efforts on the role of a family of kinases known as protein kinase C (PKC).
PKCs play a key role in intracellular signalling and the regulation of gene expression. To determine to which extent individual PKC isoenzymes regulate macrophage activity, we are genetically modifying macrophage cell lines to overproduce active PKC isoenzymes, as well as dominant-negative PKC mutants.
We also investigate the interaction between the intracellular parasite Leishmania and the macrophage. Although the inside of a macrophage seems inhospitable, several intracellular microbes chose the macrophage as a host cell. Of course, these microbes evolved strategies to avoid or manipulate host immune defenses.
One of these strategies consists in modulating in their favor their host cell intracellular signalling pathways. Since Leishmania interferes with macrophage activation through inhibition of PKCs, studying the underlying mechanisms will enhance our understanding of macrophage function regulation.
Finally, in the macrophage, Leishmania resides within a lysosomal vacuole. Using genetically defined Leishmaniavirulence mutants, we have shown that this parasite can modulate the biogenesis of their vacuole using surface glycolipids. Defining the molecular composition of vacuoles induced by virulence mutants will contribute to our knowledge of basic microbial pathogenesis problems.
- Giroux M, Schmidt M, Descoteaux A. 2003. "IFN-gamma-induced MHC class II expression: transactivation of CIITA promoter IV by IRF-1 is regulated by protein kinase C-alpha." Journal of ImmunologyIn press
- Holm Å, Tejle K, Gunnarsson T, Magnusson KE, Descoteaux A, Rasmusson B. 2003. "Role of protein kinase C-alpha for uptake of unopsonized prey and phagosomal maturation in macrophages." Biochemical and Biophysical Research Communications 302: 653-658.
- Chano F, Descoteaux A. 2002. "Modulation of lipopolysaccharide-induced NF-IL6 activation by protein kinase C-alpha in a mouse macrophage cell line." European Journal of Immunology 32: 2897-2904
- Descoteaux A, Avila HA, Zhang K, Turco SJ, Beverley SM. 2002. "Leishmania LPG3 is a GRP94 homolog required for synthesis of phosphoglycans implicated in parasite virulence but not viability." The EMBO Journal 21: 4458-4469
- EstÃ¨ve PO, Chicoine E, Robledo O, Aoudjit F, Descoteaux A, Potworowski EF, St-Pierre Y. 2002. "Protein kinase C-zeta regulates, via NF-kB, the IL-1 and TNF-a induced transcription of the matrix metalloproteinase-9 gene in glioma cells." Journal of Biological Chemistry 277: 35150-35155
- Holm Å, Tejle K, Magnusson KE, Descoteaux A, Rasmusson BJ. 2001. "Leishmania donovanilipophosphoglycan causes periphagosomal actin accumulation: correlation with impaired translocation of PK C-alpha and defective phagosome maturation." Cellular Microbiology 3: 439-447.
- Duclos S, Diez R, Garin J, Papadopoulou B, Descoteaux A, Stenmark H, Desjardins M. 2000. "Rab5 regulates the kiss and run fusion between phagosomes and endosomes and the acquisition of phagosome leishmanicidal properties in RAW 264.7 macrophages." Journal of Cell Science 113: 3531-3541
- Giroux M, Descoteaux A. 2000. "Cyclooxygenase-2 expression in macrophages: regulation by protein kinase C-alpha." Journal of Immunology 165: 3985-3991
- PrivÃ© C, Descoteaux A. 2000. "Leishmania donovani promastigotes evade the activation of mitogen-activated protein kinases p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase-1/2 during infection of naive macrophages." European Journal of Immunology 30: 2235-2244
- Dermine JF, Scianimanico S, PrivÃ© C, Descoteaux A, Desjardins M. 2000. Leishmania promastigotes require lipophosphoglycan to actively modulate the fusion properties of phagosomes at an early step of phagocytosis. Cellular Microbiology 2: 115-126.