The beta-glucan receptor dectin-1 functions together with TLR2 to mediate macrophage activation by mycobacteria.
Pattern recognition receptors (PRRs) play an essential role in a macrophage's response to mycobacterial infections. However, how these receptors work in concert to promote this macrophage response remains unclear. In this study, we used bone marrow-derived macrophages isolated from mannose receptor (MR), complement receptor 3 (CR3), MyD88, Toll-like receptor 4 (TLR4), and TLR2 knockout mice to examine the significance of these receptors in mediating a macrophage's response to a mycobacterial infection. We determined that mitogen-activated protein kinase (MAPK) activation and tumor necrosis factor-alpha (TNF-alpha) production in macrophage infected with Mycobacterium avium or M smegmatis is dependent on myeloid differentiation factor 88 (MyD88) and TLR2 but not TLR4, MR, or CR3. Interestingly, the TLR2-mediated production of TNF-alpha by macrophages infected with M smegmatis required the beta-glucan receptor dectin-1. A similar requirement for dectin-1 in TNF-alpha production was observed for macrophages infected with M bovis Bacillus Calmette-Guerin (BCG), M phlei, M avium 2151-rough, and M tuberculosis H37Ra. The limited production of TNF-alpha by virulent M avium 724 and M tuberculosis H37Rv was not dependent on dectin-1. Furthermore, dectin-1 facilitated interleukin-6 (IL-6), RANTES (regulated on activation, normal T expressed and secreted), and granulocyte colony-stimulating factor (G-CSF) production by mycobacteria-infected macrophages. These are the first results to establish a significant role for dectin-1, in cooperation with TLR2, to activate a macrophage's proinflammatory response to a mycobacterial infection.
Yadav
Mahesh
M
Department of Biological Sciences, Center for Tropical Disease Research and Training, University of Notre Dame, 130 Galvin Life Science Center, Notre Dame, IN 46556, USA.
Schorey
Jeffrey S
JS
D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D037181:Lectins, C-Type; D008262:Macrophage Activation / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009162:Mycobacterium avium / Q000472:pathogenicity*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D000099181:Dectin-1
D048049:Extracellular Signal-Regulated MAP Kinases; D037181:Lectins, C-Type; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D000099181:Dectin-1; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse