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


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          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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          Pathogen recognition and innate immunity.

          Microorganisms that invade a vertebrate host are initially recognized by the innate immune system through germline-encoded pattern-recognition receptors (PRRs). Several classes of PRRs, including Toll-like receptors and cytoplasmic receptors, recognize distinct microbial components and directly activate immune cells. Exposure of immune cells to the ligands of these receptors activates intracellular signaling cascades that rapidly induce the expression of a variety of overlapping and unique genes involved in the inflammatory and immune responses. New insights into innate immunity are changing the way we think about pathogenesis and the treatment of infectious diseases, allergy, and autoimmunity.
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            A role for mitochondria in NLRP3 inflammasome activation.

            An inflammatory response initiated by the NLRP3 inflammasome is triggered by a variety of situations of host 'danger', including infection and metabolic dysregulation. Previous studies suggested that NLRP3 inflammasome activity is negatively regulated by autophagy and positively regulated by reactive oxygen species (ROS) derived from an uncharacterized organelle. Here we show that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome. Resting NLRP3 localizes to endoplasmic reticulum structures, whereas on inflammasome activation both NLRP3 and its adaptor ASC redistribute to the perinuclear space where they co-localize with endoplasmic reticulum and mitochondria organelle clusters. Notably, both ROS generation and inflammasome activation are suppressed when mitochondrial activity is dysregulated by inhibition of the voltage-dependent anion channel. This indicates that NLRP3 inflammasome senses mitochondrial dysfunction and may explain the frequent association of mitochondrial damage with inflammatory diseases.
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              The inflammasomes.

              Inflammasomes are molecular platforms activated upon cellular infection or stress that trigger the maturation of proinflammatory cytokines such as interleukin-1beta to engage innate immune defenses. Strong associations between dysregulated inflammasome activity and human heritable and acquired inflammatory diseases highlight the importance this pathway in tailoring immune responses. Here, we comprehensively review mechanisms directing normal inflammasome function and its dysregulation in disease. Agonists and activation mechanisms of the NLRP1, NLRP3, IPAF, and AIM2 inflammasomes are discussed. Regulatory mechanisms that potentiate or limit inflammasome activation are examined, as well as emerging links between the inflammasome and pyroptosis and autophagy. 2010 Elsevier Inc. All rights reserved.

                Author and article information

                Immunol Rev
                Immunol. Rev
                Immunological Reviews
                John Wiley and Sons Inc. (Hoboken )
                14 August 2012
                September 2012
                : 249
                : 1 , Metabolism and Autophagy in the Immune System ( doiID: 10.1111/imr.2012.249.issue-1 )
                : 158-175
                [ 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

                © 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
                Funded by: National Cancer Institute
                Award ID: 1P01 CA 101944
                Invited Review
                Invited Reviews
                Custom metadata
                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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