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      PAMPs and DAMPs: signal 0s that spur autophagy and immunity

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          Summary

          Pathogen‐associated molecular pattern molecules ( PAMPs) are derived from microorganisms and recognized by pattern recognition receptor ( PRR)‐bearing cells of the innate immune system as well as many epithelial cells. In contrast, damage‐associated molecular pattern molecules ( DAMPs) are cell‐derived and initiate and perpetuate immunity in response to trauma, ischemia, and tissue damage, either in the absence or presence of pathogenic infection. Most PAMPs and DAMPs serve as so‐called ‘Signal 0s’ that bind specific receptors [Toll‐like receptors, NOD‐like receptors, RIG‐I‐like receptors, AIM2‐like receptors, and the receptor for advanced glycation end products ( RAGE)] to promote autophagy. Autophagy, a conserved lysosomal degradation pathway, is a cell survival mechanism invoked in response to environmental and cellular stress. Autophagy is inferred to have been present in the last common eukaryotic ancestor and only to have been lost by some obligatory intracellular parasites. As such, autophagy represents a unifying biology, subserving survival and the earliest host defense strategies, predating apoptosis, within eukaryotes. Here, we review recent advances in our understanding of autophagic molecular mechanisms and functions in emergent immunity.

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          Most cited references 220

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          The danger model: a renewed sense of self.

          For over 50 years immunologists have based their thoughts, experiments, and clinical treatments on the idea that the immune system functions by making a distinction between self and nonself. Although this paradigm has often served us well, years of detailed examination have revealed a number of inherent problems. This Viewpoint outlines a model of immunity based on the idea that the immune system is more concerned with entities that do damage than with those that are foreign.
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            RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates.

            Double-stranded RNA (dsRNA) produced during viral replication is believed to be the critical trigger for activation of antiviral immunity mediated by the RNA helicase enzymes retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). We showed that influenza A virus infection does not generate dsRNA and that RIG-I is activated by viral genomic single-stranded RNA (ssRNA) bearing 5'-phosphates. This is blocked by the influenza protein nonstructured protein 1 (NS1), which is found in a complex with RIG-I in infected cells. These results identify RIG-I as a ssRNA sensor and potential target of viral immune evasion and suggest that its ability to sense 5'-phosphorylated RNA evolved in the innate immune system as a means of discriminating between self and nonself.
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              HMG-1 as a late mediator of endotoxin lethality in mice.

              Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.
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                Author and article information

                Journal
                Immunol Rev
                Immunol. Rev
                10.1111/(ISSN)1600-065X
                IMR
                Immunological Reviews
                John Wiley and Sons Inc. (Hoboken )
                0105-2896
                1600-065X
                14 August 2012
                September 2012
                : 249
                : 1 , Metabolism and Autophagy in the Immune System ( doiID: 10.1111/imr.2012.249.issue-1 )
                : 158-175
                Affiliations
                [ 1 ] Department of Surgery University of Pittsburgh Cancer Institute Pittsburgh PA USA
                [ 2 ] Department of Microbiology and Molecular Genetics University of Pittsburgh Pittsburgh PA USA
                Author notes
                [* ] Correspondence to:

                Michael T. Lotze

                Department of Surgery

                G.21 Hillman Cancer Center

                University of Pittsburgh Cancer Institute

                University of Pittsburgh

                Pittsburgh, PA 15213, USA

                Tel.: +1 412 623 5977

                Fax: +1 412 623 1212

                e‐mail: LotzMT@ 123456upmc.edu

                [†]

                Daolin Tang and Michael Lotze contributed equally as senior authors

                Article
                IMR1146
                10.1111/j.1600-065X.2012.01146.x
                3662247
                22889221
                © 2012 John Wiley & Sons A/S

                This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

                Page count
                Pages: 18
                Product
                Funding
                Funded by: National Cancer Institute
                Award ID: 1P01 CA 101944
                Categories
                Invited Review
                Invited Reviews
                Custom metadata
                2.0
                September 2012
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.0 mode:remove_FC converted:15.04.2020

                pamps, damps, autophagy, apoptosis, immunity, inflammation

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