MARCO, TLR2, and CD14 Are Required for Macrophage Cytokine Responses to Mycobacterial Trehalose Dimycolate and Mycobacterium tuberculosis

• DOI: 10.1371/journal.ppat.1000474
• Publication Date: 2009-06-11T22:12:09Z
• Authors: Dawn M. E. Bowdish; Kaori Sakamoto; Mi-Jeong Kim; Mariliis Kroos; Subhankar Mukhopa...; Cynthia A. Leifer; Karl Tryggvason; Siamon Gordon; David G. Russell
• Keywords: 0301 basic medicine; Cytoplasm; interleukin 1beta; receptor binding; Lipopolysaccharide Receptors; animal cell; Mice; 0302 clinical medicine; toll like receptor 4; toll like receptor 2; Cricetinae; Phagosomes; cytokine; animal; enzyme phosphorylation; Biology (General); Receptors, Immunologic; tumor necrosis factor alpha; mitogen activated protein kinase; TLR2 protein; C57BL mouse; immunoglobulin receptor; article; Scavenger Receptors, Class A; phagosome; Microspheres; unclassified drug; TLR4 protein; 3. Good health; immunoglobulin enhancer binding protein; marco receptor; cytokine production; Cord Factors; Cytokines; signal transduction; Research Article; Signal Transduction; 570; QH301-705.5; animal experiment; interleukin 6; 610; protein localization; CHO Cells; 03 medical and health sciences; Cricetulus; Animals; Humans; controlled study; human; protein expression; mouse; cord factor; nonhuman; myeloid differentiation factor 88; human cell; Macrophages; enzyme activation; Mycobacterium tuberculosis; CD14 antigen; RC581-607; scavenger receptor A; Toll-Like Receptor 2; Mice, Inbred C57BL; mitogen activated protein kinase 3; MARCO protein; protein MD 2; peritoneum macrophage; mitogen activated protein kinase 1; Microscopy, Fluorescence; microsphere; Immunologic diseases. Allergy

Virtually all of the elements Mycobacterium tuberculosis (Mtb) pathogenesis, including pro-inflammatory cytokine production, granuloma formation, cachexia, and mortality, can be induced by its predominant cell wall glycolipid, trehalose 6,6′-dimycolate (TDM/cord factor). TDM mediates these potent inflammatory responses via interactions with macrophages both in vitro vivo a myeloid differentiation factor 88 (MyD88)-dependent manner phosphorylation mitogen activated protein kinases (MAPKs), implying involvement toll-like receptors (TLRs). However, specific TLRs or binding for have yet to identified. Herein, we demonstrate that macrophage receptor collagenous structure (MARCO), class A scavenger receptor, is utilized preferentially "tether" activate TLR2 signaling pathway. TDM-induced signaling, as measured nuclear factor-kappa B (NF-κB)-luciferase reporter assay, required MARCO addition CD14. was used over highly homologous (SRA), which TLR4, well their respective accessory molecules, order slight increase NF-κB occur. Consistent observations, from MARCO−/− MARCO−/−SRA−/− mice are defective activation extracellular signal-related kinase 1/2 (ERK1/2) subsequent production response TDM. These results show MARCO-expressing secrete cytokines cooperation between TLR2/CD14, whereas other subtypes (e.g. bone marrow–derived) may rely somewhat less effectively on SRA, TLR4/MD2. Macrophages also produce markedly lower levels infection virulent Mtb. observations identify essential TDM, explain differential various populations, differ expression receptors, novel component TLR signaling.