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ScienceDirect Innate immunity Editorial overview Seth L Masters and Dominic De Nardo Current Opinion in Immunology 2014, 26:v–vi For a complete overview see the Issue Available online 1st February 2014 0952-7915/$ – see front matter, # 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.coi.2013.12.006

Seth L Masters The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia e-mail: [email protected] Seth Masters is a VESKI innovation fellow and head of a laboratory in the Inflammation Division at the Walter and Eliza Hall Institute in Melbourne, Australia. The Masters laboratory studies innate immunity with a particular emphasis on the inflammasome, and translates this toward therapies for infectious and autoinflammatory disease. This research has earned Dr. Masters awards from the Australian Institute of Policy and Science, the International Cytokine Society, the Irish Society of Immunology and the International Society of Systemic Autoinflammatory Diseases.

Dominic De Nardo Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany e-mail: [email protected] Dominic De Nardo received his PhD from the University of Melbourne in Australia where he developed an interest in macrophages and the innate immune system. He is currently a postdoctoral research fellow at the Institute of Innate Immunity under the guidance of Prof. Eicke Latz. His current research interests focus on the activation and regulation of innate immune receptors and their signaling pathways.

Innate immunity is an ancient system considered the first line of host defense against so called ‘danger signals’. These danger signals come in a wide variety of forms, such as highly conserved components of microbes (pattern-associated molecular patterns — PAMPs) or altered host molecules (danger-associated molecular patterns — DAMPS). The innate immune system has the ability to rapidly detect these danger signals via the expression of families of pattern recognition receptors (PRRs). To date, the vertebrate innate immune system comprises: Toll-like receptors (TLRs), Nod-like receptor (NLRs), Rig-I-like receptors (RLRs), C-type lectin receptors (CLRs), and the cytosolic DNA receptors. Upon activation, some of these innate receptors form large oligomeric signaling platforms further classified as ‘inflammasomes’. The localization of PRRs is reflective of the specific ligands they sense. For instance, TLRs are expressed on both the cell surface and endosomal membranes where they respond mainly to bacterial components; while in contrast, the cytosolic PRRs recognize danger signals that gain direct access to the cytosol or escape lysosomal degradation. Such a system enables multiple levels of detection against an array of dangers. In general, the activation of these receptors leads to induction of specific signal transduction or proteolytic pathways, ultimately resulting in the production of inflammatory mediators (e.g. cytokines, chemokines, type I interferon’s) that coordinate further recruitment of immune cells and lymphocytes to sites of inflammation, and ensure an appropriate inflammatory response to a specific insult. Signals emanating from the activation of these receptors are critical not only for the clearance of invading microorganisms and the restoration of tissue homeostasis, but also for activation of the adaptive immune system following antigen presentation. Understanding in the field of innate immunology and its underlying molecular mechanisms has grown rapidly since its relatively recent discovery. During this time the critical importance of the innate immune system to the host has become ever more apparent. This innate immunity volume of Current Opinion in Immunology explores some of the most exciting recent advances, findings and concepts in the field from leaders in their respective topics. Studies that solve the structural components of innate immune signaling pathways provide us with an essential molecular understanding of how cells can recognize ligands and transduce signals. In this issue, Sam Xiao and colleagues, present a unified view of PRR function, from sensing, through to receptor oligomerization and signaling output. This highlights auto-inhibition as a common theme for retaining PRRs in a non-active conformation, and the modules that can be targeted by posttranslational modification to alter PRR function.


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Defense against microbes by innate immune receptors often requires the integration of multiple cellular processes including phagocytosis and autophagy in a tightly regulated manner. The review article by Julien Moretti and Julie Blander describes recent advances in our understanding of the molecular mechanisms of phagocytosis during the activation of innate immune receptors. Phagocytosis involves uptake and destruction of microbes within intracellular compartments and can be regulated by PRRs, and likewise can also dictate the magnitude of inflammatory responses from these receptors. In the case of some TLRs, phagocytosis is directly involved in their activation but phagocytic processes can also mediate canonical and non-canonical pathways leading to cytosolic inflammasome activation. Autophagy is another critical process that is required for degradation of cellular components and is widely linked to innate immunity. The contribution by Miguel Sanjuan and colleagues reviews this process in relation to innate immunity, providing interesting insights into LC3-associated phagocytosis (LAP), a non-canonical autophagy pathway that integrates autophagy machinery into a phagocytic pathway induced by PRR activation. The RNA endonuclease activity of Dicer is highly conserved across species and facilities multiple cellular functions including the maturation of miRNAs, and the cleavage of dsRNAs into siRNAs for incorporation into RNA-induced silencing complexes (RISCs). In insects and worms these processes are critical for innate anti-viral functions. Evelyn Kurt-Jones and colleagues review these concepts and in addition summarize a growing body of evidence suggesting that Dicer may also have anti-viral activity in mammals. Furthermore, the authors discuss the current limitations facing scientists examining the role of Dicer in mammalian anti-viral immunity. In contrast, Fitzgerald and Caffrey tackle long noncoding RNA, which have a number of functions, including acting as sponges to deplete miRNA. This will clearly be important for regulation of the host innate immune response, but could also directly target viral miRNA species. Moreover, lncRNA may collaborate with the innate immune system to direct an appropriate adaptive immune response, which the authors discuss in more detail. The three reviews from Vince, Croker and Kono are testament to the rapidly emerging concepts surrounding

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initiation of cell death pathways by activation of inflammasomes. In particular, the non-canonical inflammasome containing Caspase-11 has shot to prominence as a new pathway activated downstream of intracellular LPS to trigger pyroptosis. This, and the related pyroptosis driven by Caspase-1, may be critically over stimulated during sepsis and provide an entirely novel mechanism to be targeted in that disease. Croker et al. propose this ‘death storm’, to supplant the ‘cytokine storm’ theory, which has so far failed to generate clinically validated targets in sepsis and septic shock. Like pyroptosis, necroptosis is a programmed form of inflammatory cell death, reviewed in this issue by James Vince and colleagues. This review highlights where this pathway, primarily regulated by RIP3, is likely to be relevant in disease and where its inflammatory functions can be separated from necroptotic cell death. Hajime Kono and colleagues further discuss IL-1-driven sterile inflammation in response to endogenous danger signals released from dead or dying cells, and review the known ligands, receptors, and pathways activated in this context. The microbiota is a dense prokaryotic ecosystem existing symbiotically within the gastrointestinal tract of its eukaryotic host. As such, the innate immune system has coevolved with the microbiota in a way that allows for sufficient host defense while maintaining homeostasis within this delicate environment. Dysfunction in either system can lead to local and systemic diseases. In this issue of Current Opinion in Immunology, Eran Elinav and colleagues explore the current concepts and provide perspectives on both the mutualistic relationship of the microbiota and innate immune receptors, as well as the influence of the intestinal microbiota on the function of immune cells. A number of the topics covered in this issue have significant clinical bearing. Of note, genetically programmed modes of inflammatory cell death are likely to be critical during sepsis and chronic inflammatory disease, long and short RNA species are heavily implicated in the innate response to viral infection, and our commensal microbiota likely have an impact on all immune-related pathologies. We are excited to present these recent advances in this series of Current Opinions in Immunology, and would like to thank all the authors for their insightful and interesting contributions.


Innate immunity.

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