title: The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens.
abstract: Macrophages orchestrate innate immunity by phagocytosing pathogens and coordinating inflammatory responses. Effective defence requires the host to discriminate between different pathogens. The specificity of innate immune recognition in Drosophila is mediated by the Toll family of receptors; Toll mediates anti-fungal responses, whereas 18-wheeler mediates anti-bacterial defence. A large number of Toll homologues have been identified in mammals, and Toll-like receptor 4 is critical in responses to Gram-negative bacteria. Here we show that Toll-like receptor 2 is recruited specifically to macrophage phagosomes containing yeast, and that a point mutation in the receptor abrogates inflammatory responses to yeast and Gram-positive bacteria, but not to Gram-negative bacteria. Thus, during the phagocytosis of pathogens, two classes of innate immune receptors cooperate to mediate host defence: phagocytic receptors, such as the mannose receptor, signal particle internalization, and the Toll-like receptors sample the contents of the vacuole and trigger an inflammatory response appropriate to defence against the specific organism.
authors.affiliation: Department of Immunology, University of Washington, Seattle 98195, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Underhill
authors.forename: A
authors.initials: A
authors.lastname: Ozinsky
authors.forename: A M
authors.initials: AM
authors.lastname: Hajjar
authors.forename: A
authors.initials: A
authors.lastname: Stevens
authors.forename: C B
authors.initials: CB
authors.lastname: Wilson
authors.forename: M
authors.initials: M
authors.lastname: Bassetti
authors.forename: A
authors.initials: A
authors.lastname: Aderem
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D029721:Drosophila Proteins; D008264:Macrophages / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88; D010587:Phagocytosis; D010588:Phagosomes / Q000378:metabolism*; D017354:Point Mutation; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012475:Salmonella / Q000378:metabolism; D015398:Signal Transduction; D013211:Staphylococcus aureus / Q000378:metabolism; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015003:Yeasts / Q000378:metabolism; D015054:Zymosan / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D029721:Drosophila Proteins; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D015054:Zymosan