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      Plasmacytoid dendritic cells sense skin injury and promote wound healing through type I interferons

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          Abstract

          Cutaneous injury in mice drives transient TLR7- and TLR9-mediated production of type I interferon by plasmacytoid dendritic cells, which is required for re-epithelialization of the skin.

          Abstract

          Plasmacytoid dendritic cells (pDCs) are specialized type I interferon (IFN-α/β)–producing cells that express intracellular toll-like receptor (TLR) 7 and TLR9 and recognize viral nucleic acids in the context of infections. We show that pDCs also have the ability to sense host-derived nucleic acids released in common skin wounds. pDCs were found to rapidly infiltrate both murine and human skin wounds and to transiently produce type I IFNs via TLR7- and TLR9-dependent recognition of nucleic acids. This process was critical for the induction of early inflammatory responses and reepithelization of injured skin. Cathelicidin peptides, which facilitate immune recognition of released nucleic acids by promoting their access to intracellular TLR compartments, were rapidly induced in skin wounds and were sufficient but not necessary to stimulate pDC activation and type I IFN production. These data uncover a new role of pDCs in sensing tissue damage and promoting wound repair at skin surfaces.

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          Most cited references 40

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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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            Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function.

            MyD88, originally isolated as a myeloid differentiation primary response gene, is shown to act as an adaptor in interleukin-1 (IL-1) signaling by interacting with both the IL-1 receptor complex and IL-1 receptor-associated kinase (IRAK). Mice generated by gene targeting to lack MyD88 have defects in T cell proliferation as well as induction of acute phase proteins and cytokines in response to IL-1. Increases in interferon-gamma production and natural killer cell activity in response to IL-18 are abrogated. In vivo Th1 response is also impaired. Furthermore, IL-18-induced activation of NF-kappaB and c-Jun N-terminal kinase (JNK) is blocked in MyD88-/- Th1-developing cells. Taken together, these results demonstrate that MyD88 is a critical component in the signaling cascade that is mediated by IL-1 receptor as well as IL-18 receptor.
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              The nature of the principal type 1 interferon-producing cells in human blood.

              Interferons (IFNs) are the most important cytokines in antiviral immune responses. "Natural IFN-producing cells" (IPCs) in human blood express CD4 and major histocompatibility complex class II proteins, but have not been isolated and further characterized because of their rarity, rapid apoptosis, and lack of lineage markers. Purified IPCs are here shown to be the CD4(+)CD11c- type 2 dendritic cell precursors (pDC2s), which produce 200 to 1000 times more IFN than other blood cells after microbial challenge. pDC2s are thus an effector cell type of the immune system, critical for antiviral and antitumor immune responses.
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                Author and article information

                Journal
                J Exp Med
                J. Exp. Med
                jem
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                20 December 2010
                : 207
                : 13
                : 2921-2930
                Affiliations
                [1 ]Department of Immunology , [2 ]Department of Melanoma Medical Oncology , and [3 ]Department of Dermatology, the University of Texas M. D. Anderson Cancer Center, Houston, TX 77030
                [4 ]Graduate School of Biomedical Sciences, University of Texas at Houston, Houston, TX 77030
                [5 ]Division of Dermatology, University of California, San Diego, La Jolla, CA 92093
                [6 ]Department of Dermatology, Heinrich-Heine University, Duesseldorf 40225, Germany
                [7 ]Control of Hypersensitivity Diseases, Finnish Institute of Occupational Health, FIN-00250 Helsinki, Finland
                [8 ]Skin and Allergy Hospital, Helsinki University Central Hospital, FIN-00290 Helsinki, Finland
                [9 ]SBI Biotech Co., Ltd., Ginkgo Biomedical Research Institute, Kawasaki 216-0001, Japan
                [10 ]Pharmacology and Toxicology, College of Pharmacy, the University of Texas, Austin, TX 78712
                Author notes
                CORRESPONDENCE Michel Gilliet: michel.gilliet@ 123456chuv.ch

                S. Meller and C. Conrad contributed equally to this paper.

                Article
                20101102
                10.1084/jem.20101102
                3005239
                21115688
                © 2010 Gregorio et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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