title: MARCO, TLR2, and CD14 are required for macrophage cytokine responses to mycobacterial trehalose dimycolate and Mycobacterium tuberculosis.
abstract: Virtually all of the elements of 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 and in vivo in a myeloid differentiation factor 88 (MyD88)-dependent manner via phosphorylation of the mitogen activated protein kinases (MAPKs), implying involvement of toll-like receptors (TLRs). However, specific TLRs or binding receptors for TDM have yet to be identified. Herein, we demonstrate that the macrophage receptor with collagenous structure (MARCO), a class A scavenger receptor, is utilized preferentially to "tether" TDM to the macrophage and to activate the TLR2 signaling pathway. TDM-induced signaling, as measured by a nuclear factor-kappa B (NF-kappaB)-luciferase reporter assay, required MARCO in addition to TLR2 and CD14. MARCO was used preferentially over the highly homologous scavenger receptor class A (SRA), which required TLR2 and TLR4, as well as their respective accessory molecules, in order for a slight increase in NF-kappaB signaling to occur. Consistent with these observations, macrophages from MARCO(-/-) or MARCO(-/-)SRA(-/-) mice are defective in activation of extracellular signal-related kinase 1/2 (ERK1/2) and subsequent pro-inflammatory cytokine production in response to TDM. These results show that MARCO-expressing macrophages secrete pro-inflammatory cytokines in response to TDM by cooperation between MARCO and TLR2/CD14, whereas other macrophage subtypes (e.g. bone marrow-derived) may rely somewhat less effectively on SRA, TLR2/CD14, and TLR4/MD2. Macrophages from MARCO(-/-) mice also produce markedly lower levels of pro-inflammatory cytokines in response to infection with virulent Mtb. These observations identify the scavenger receptors as essential binding receptors for TDM, explain the differential response to TDM of various macrophage populations, which differ in their expression of the scavenger receptors, and identify MARCO as a novel component required for TLR signaling.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: Dawn M E
authors.initials: DM
authors.lastname: Bowdish
authors.forename: Kaori
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Kim
authors.forename: Mariliis
authors.initials: M
authors.lastname: Kroos
authors.forename: Subhankar
authors.initials: S
authors.lastname: Mukhopadhyay
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Leifer
authors.forename: Karl
authors.initials: K
authors.lastname: Tryggvason
authors.forename: Siamon
authors.initials: S
authors.lastname: Gordon
authors.forename: David G
authors.initials: DG
authors.lastname: Russell
mesh_terms: D000818:Animals; D016466:CHO Cells; D003311:Cord Factors / Q000276:immunology*; D006224:Cricetinae; D003412:Cricetulus; D016207:Cytokines / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008863:Microspheres; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010588:Phagosomes / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D051117:Scavenger Receptors, Class A / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D003311:Cord Factors; D016207:Cytokines; D018950:Lipopolysaccharide Receptors; C490460:MARCO protein, human; C092228:Marco protein, mouse; D011971:Receptors, Immunologic; D051117:Scavenger Receptors, Class A; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4