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      Human CD14 dim Monocytes Patrol and Sense Nucleic Acids and Viruses via TLR7 and TLR8 Receptors

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          Summary

          Monocytes are effectors of the inflammatory response to microbes. Human CD14 + monocytes specialize in phagocytosis and production of reactive oxygen species and secrete inflammatory cytokines in response to a broad range of microbial cues. Here, we have characterized the functions of human monocytes that lack CD14 (CD14 dim) and express CD16. CD14 dim monocytes were genetically distinct from natural killer cells. Gene expression analyses indicated similarities with murine patrolling Gr1 dim monocytes, and they patrolled the endothelium of blood vessels after adoptive transfer, in a lymphocyte function-associated antigen-1-dependent manner. CD14 dim monocytes were weak phagocytes and did not produce ROS or cytokines in response to cell-surface Toll-like receptors. Instead, they selectively produced TNF-α, IL-1β, and CCL3 in response to viruses and immune complexes containing nucleic acids, via a proinflammatory TLR7-TLR 8-MyD88-MEK pathway. Thus, CD14 dim cells are bona fide monocytes involved in the innate local surveillance of tissues and the pathogenesis of autoimmune diseases.

          Abstract

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          Highlights

          ► Human CD14 dim monocytes patrol the vasculature ► CD14 dim monocytes respond poorly to TLR1, TLR2, and TLR4 agonists ► CD14 dim monocytes respond to viruses and nucleic acids via TLR7-8-MyD88-MEK pathway

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          Most cited references35

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          Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.

          Interferons (IFNs) are critical for protection from viral infection, but the pathways linking virus recognition to IFN induction remain poorly understood. Plasmacytoid dendritic cells produce vast amounts of IFN-alpha in response to the wild-type influenza virus. Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-like receptor 7 (TLR7) and MyD88. Single-stranded RNA (ssRNA) molecules of nonviral origin also induce TLR7-dependent production of inflammatory cytokines. These results identify ssRNA as a ligand for TLR7 and suggest that cells of the innate immune system sense endosomal ssRNA to detect infection by RNA viruses.
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            Recognition of single-stranded RNA viruses by Toll-like receptor 7.

            Viral infection of mammalian host results in the activation of innate immune responses. Toll-like receptors (TLRs) have been shown to mediate the recognition of many types of pathogens, including viruses. The genomes of viruses possess unique characteristics that are not found in mammalian genomes, such as high CpG content and double-stranded RNA. These genomic nucleic acids serve as molecular signatures associated with viral infections. Here we show that TLR7 recognizes the single-stranded RNA viruses, vesicular stomatitis virus and influenza virus. The recognition of these viruses by plasmacytoid dendritic cells and B cells through TLR7 results in their activation of costimulatory molecules and production of cytokines. Moreover, this recognition required intact endocytic pathways. Mice deficient in either the TLR7 or the TLR adaptor protein MyD88 demonstrated reduced responses to in vivo infection with vesicular stomatitis virus. These results demonstrate microbial ligand recognition by TLR7 and provide insights into the pathways used by the innate immune cells in the recognition of viral pathogens.
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              Monocyte-mediated defense against microbial pathogens.

              Circulating blood monocytes supply peripheral tissues with macrophage and dendritic cell (DC) precursors and, in the setting of infection, also contribute directly to immune defense against microbial pathogens. In humans and mice, monocytes are divided into two major subsets that either specifically traffic into inflamed tissues or, in the absence of overt inflammation, constitutively maintain tissue macrophage/DC populations. Inflammatory monocytes respond rapidly to microbial stimuli by secreting cytokines and antimicrobial factors, express the CCR2 chemokine receptor, and traffic to sites of microbial infection in response to monocyte chemoattractant protein (MCP)-1 (CCL2) secretion. In murine models, CCR2-mediated monocyte recruitment is essential for defense against Listeria monocytogenes, Mycobacterium tuberculosis, Toxoplasma gondii, and Cryptococcus neoformans infection, implicating inflammatory monocytes in defense against bacterial, protozoal, and fungal pathogens. Recent studies indicate that inflammatory monocyte recruitment to sites of infection is complex, involving CCR2-mediated emigration of monocytes from the bone marrow into the bloodstream, followed by trafficking into infected tissues. The in vivo mechanisms that promote chemokine secretion, monocyte differentiation and trafficking, and finally monocyte-mediated microbial killing remain active and important areas of investigation.
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                Author and article information

                Journal
                Immunity
                Immunity
                Immunity
                Cell Press
                1074-7613
                1097-4180
                24 September 2010
                24 September 2010
                : 33
                : 3
                : 375-386
                Affiliations
                [1 ]Centre for Molecular and Cellular Biology of inflammation, Division of Immunology Infection and Inflammatory Diseases, King's College London, SE1 1UL London, UK
                [2 ]U838 INSERM, Université Paris Descartes, 75015 Paris, France
                [3 ]Plateforme Bio-informatique & Département de biostatistiques AP-HP, Hôpital Necker - Enfants Malades, Université Paris Descartes, 75015 Paris, France
                [4 ]Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA
                [5 ]Singapore Immunology Network, SIgN (BMSI, A STAR), Immunos, 138648 Singapore
                [6 ]Pediatric Immuno-Hematology Unit, Hôpital Necker-Enfants Malades, Université Paris Descartes, 75015 Paris, France
                [7 ]Louise Coote Lupus Unit, St Thomas Hospital, King's College London, SE1 7EH London, UK
                [8 ]Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U550 and University Paris Descartes, Necker Medical School, 75015 Paris, France
                Author notes
                []Corresponding author frederic.geissmann@ 123456kcl.ac.uk
                [9]

                These authors contributed equally to this work

                Article
                IMMUNI1957
                10.1016/j.immuni.2010.08.012
                3063338
                20832340
                eb45aa25-72fc-441e-b0f1-be75a3f87a4b
                © 2010 ELL & Excerpta Medica.

                This document may be redistributed and reused, subject to certain conditions.

                History
                : 26 May 2010
                : 27 July 2010
                : 20 August 2010
                Categories
                Article

                Immunology
                Immunology

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