title: Glycopeptidolipids from Mycobacterium avium promote macrophage activation in a TLR2- and MyD88-dependent manner.
abstract: The Toll-like receptors (TLRs) are key components in the immune response against numerous pathogens. Previous studies have indicated that TLR2 plays an essential role in promoting immune responses against mycobacterial infections. Prior work has also shown that mice deficient in TLR2 are more susceptible to infection by Mycobacterium tuberculosis, Mycobacterium bovis bacillus Calmette-Guerin, and Mycobacterium avium. Therefore, it is important to define the molecules expressed by pathogenic mycobacteria, which bind the various TLRs. Although a number of TLR agonists have been characterized for M. tuberculosis, no specific TLR ligand has been identified in M. avium. We have found that glycopeptidolipids (GPLs), which are highly expressed surface molecules on M. avium, can stimulate the nuclear factor-kappaB pathway as well as mitogen-activated protein kinase p38 and Jun N-terminal kinase activation and production of proinflammatory cytokines when added to murine bone marrow-derived macrophages. This stimulation was dependent on TLR2 and myeloid differentiation primary-response protein 88 (MyD88) but not TLR4. M. avium express apolar and serovar-specific (ss)GPLs, and it is the expression of the latter that determines the serotype of a particular M. avium strain. It is interesting that the ssGPLs activated macrophages in a TLR2- and MyD88-dependent manner, and no macrophage activation was observed when using apolar GPLs. ssGPLs also differed in their ability to activate macrophages with Serovars 1 and 2 stimulating inhibitor of kappaB p38 and phosphorylation and tumor necrosis factor alpha (TNF-alpha) secretion, while Serovar 4 failed to stimulate p38 activation and TNF-alpha production. Our studies indicate that ssGPLs can function as TLR2 agonists and promote macrophage activation in a MyD88-dependent pathway.
authors.affiliation: Department of Biological Sciences, Center for Tropical Disease Research and Training, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Sweet
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Schorey
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D006017:Glycolipids / Q000494:pharmacology*; D006020:Glycopeptides / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008262:Macrophage Activation / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009162:Mycobacterium avium / Q000737:chemistry*; D053594:Myeloid Differentiation Factor 88; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006017:Glycolipids; D006020:Glycopeptides; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C495345:TLR4 protein, human; C439524:TNF protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C010762:peptidoglycolipids; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases