title: TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells.
abstract: Leprosy enables investigation of mechanisms by which the innate immune system contributes to host defense against infection, because in one form, the disease progresses, and in the other, the infection is limited. We report that Toll-like receptor (TLR) activation of human monocytes induces rapid differentiation into two distinct subsets: DC-SIGN+ CD16+ macrophages and CD1b+ DC-SIGN- dendritic cells. DC-SIGN+ phagocytic macrophages were expanded by TLR-mediated upregulation of interleukin (IL)-15 and IL-15 receptor. CD1b+ dendritic cells were expanded by TLR-mediated upregulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) and its receptor, promoted T cell activation and secreted proinflammatory cytokines. Whereas DC-SIGN+ macrophages were detected in lesions and after TLR activation in all leprosy patients, CD1b+ dendritic cells were not detected in lesions or after TLR activation of peripheral monocytes in individuals with the progressive lepromatous form, except during reversal reactions in which bacilli were cleared by T helper type 1 (TH1) responses. In tuberculoid lepromatous lesions, DC-SIGN+ cells were positive for macrophage markers, but negative for dendritic cell markers. Thus, TLR-induced differentiation of monocytes into either macrophages or dendritic cells seems to crucially influence effective host defenses in human infectious disease.
authors.affiliation: Division of Dermatology, University of California at Los Angeles, 611 Charles Young Drive East, 536 Boyer Hall, Los Angeles, CA 90095, USA.
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Krutzik
authors.forename: Belinda
authors.initials: B
authors.lastname: Tan
authors.forename: Huiying
authors.initials: H
authors.lastname: Li
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Ochoa
authors.forename: Philip T
authors.initials: PT
authors.lastname: Liu
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Sharfstein
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.forename: Peter A
authors.initials: PA
authors.lastname: Sieling
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Rea
authors.forename: Barry R
authors.initials: BR
authors.lastname: Bloom
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
mesh_terms: D018949:Antigens, CD1 / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D003713:Dendritic Cells / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D037181:Lectins, C-Type / Q000378:metabolism; D007918:Leprosy / Q000276:immunology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D009000:Monocytes / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology; D051193:Toll-Like Receptors; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D018949:Antigens, CD1; D015815:Cell Adhesion Molecules; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C419394:CD1b antigen