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Cells Innate Immunity and Its Regulation by Mast Innate Immunity and Its Regulation by Mast Cells Ashley L. St. John and Soman N. Abraham This information is current as J Immunol 2013; 190:4458-4463; ; of September 24, 2021. doi: 10.4049/jimmunol.1203420 http://www.jimmunol.org/content/190/9/4458 Downloaded from References This article cites 83 articles, 31 of which you can access for free at: http://www.jimmunol.org/content/190/9/4458.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 24, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Innate Immunity and Its Regulation by Mast Cells x Ashley L. St. John*,† and Soman N. Abraham*,†,‡, Mast cells (MCs), which are granulated tissue-resident plement split products) (5, 6) can potentiate signals received cells of hematopoietic lineage, constitute a major sen- through PRRs (7–11). Some responses prompt direct killing sory arm of the innate immune system. In this review of pathogens, such as complement activation, antimicrobial we discuss the evidence supporting the dual role of peptides (AMPs), and phagocytosis/degradation by host cells MCs, both as sentinels for invading pathogens and as (3, 12). Both uninfected cells that detect pathogen-derived regulatory cells throughout the course of acute inflam- products or infected cells may indirectly initiate the clear- mation, from its initiation to resolution. This versatility ance of pathogens through the recruitment of neutrophils, NK is dependent on the ability of MCs to detect pathogens cells, and others from the circulation. PRRs can also trigger apoptosis or pyroptosis (13), resulting in the death of infected and danger signals and release a unique panel of medi- Downloaded from ators to promote pathogen-specific clearance mecha- cells, further facilitating infection clearance. These processes nisms, such as through cellular recruitment or vascular are coordinated to resolve infection and, conversely, to avoid permeability. It is increasingly understood that MCs immune pathology. There is growing evidence that mast cells (MCs) are key regulatory cells capable of coordinating and also contribute to the regulated contraction of immune integrating many branches of the innate immune system. activation that occurs within tissues as inflammation resolves. This overarching regulatory control over in- Properties of MCs that allow innate immune regulation http://www.jimmunol.org/ nate immune processes has made MCs successful targets to purposefully enhance or, alternatively, suppress MC MCs act as professional immune sentinels owing to several at- responses in multiple therapeutic contexts. The Jour- tributes involving a heightened capacity to detect pathogens, nal of Immunology, 2013, 190: 4458–4463. adaptations to promote communication within the tissue and to distant sites, and their prime location as first responders to pathogen colonization. As previously reviewed, the close as- sociation of MCs with both epithelial and endothelial bar- Initiation of innate immune responses to pathogens riers strategically places them among the first cells to encounter by guest on September 24, 2021 Immediate responses to pathogens are typically initiated in pathogens (5, 14) along with other innate immune cells on the epithelial tissues, such as the skin, intestinal/urogenital epi- front lines of infection, including DCs and Mfs. Initial de- thelium, and nasal mucosa where environmental pathogens tection may not be due to direct pathogen exposure, as MCs are first encountered. Pathogens may also be injected into the also sense danger signals emanating from the surrounding circulation by insect vectors or gain access owing to surgery or tissue, including epithelial, endothelial, and tissue-resident medical interventions. Immunosurveillance for pathogens re- immune cells. lies on a wide array of pattern recognition receptors (PRRs), Depending on the balance of activating stimuli perceived by which are hard-wired to recognize both extra- and intracellular MCs, they release a panel of inflammatory mediators with a pathogens and pathogen-derived products (1, 2). Most cells degree of specialization for the type of pathogen detected. express PRRs, although nonimmune cells generally have fewer Stimuli such as many whole bacteria, parasite products, and types of PRRs or other mechanisms to limit unwarranted even the structure of certain viruses can induce release of an activation. PRR-initiated signaling induces epithelial, endo- MC’s cytoplasmic granules (15–17). At a site of infection in thelial, or local immune cells, including dendritic cells (DCs), vivo, host and pathogen-associated products likely have a monocytes, and macrophages (Mfs), to release cytokines and/ combinatorial effect to promote extensive degranulation. Re- or antimicrobial agents (e.g., cathelicidin, b-defensins) (3, lease of vesicle-encased granules into the surrounding tissue as 4). Additionally, danger signals released from injured or dying vesicle-free particles usually begins within seconds of exposure cells (e.g., ATP, heat shock proteins, bradykinins, and com- to degranulating stimuli. Granules are packed with inflam- *Program in Emerging Infectious Diseases, Duke–National University of Singapore, Address correspondence and reprint requests to Dr. Ashley St. John, Program in Emerg- Singapore 169857; †Department of Pathology, Duke University Medical Center, Dur- ing Infectious Diseases, Duke–National University of Singapore Graduate Medical School, ham, NC 27710; ‡Department of Immunology, Duke University Medical Center, Level 9, 8 College Road, Singapore 169857. E-mail address: ashley.st.john@duke-nus. x Durham, NC 27710; and Department of Molecular Genetics and Microbiology, Duke edu.sg University Medical Center, Durham, NC 27710 Abbreviations used in this article: AMP, antimicrobial peptide; DC, dendritic cell; DLN, Received for publication December 14, 2012. Accepted for publication February 28, draining lymph node; Mf, macrophage; MC, mast cell; NLR, Nod-like receptor; PRR, 2013. pattern recognition receptor. This work was supported by National Medical Research Council of Singapore Grant Ó NIG/1053/2011, the Duke–National University of Singapore Signature Research Pro- Copyright 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 gram funded by the Ministry of Health, Singapore, the Duke University/Duke–National University of Singapore Collaborative Initiative, and National Institutes of Health Grants U01-AI082107, R01-AI096305, and R56-DK095198. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1203420 The Journal of Immunology 4459 matory mediators, including heparin, proteases, TNF, hista- (Fig. 1A). Few functional differences have been described mine, and others. The dense granule structure promotes their between rodent and human MCs, and yet there are differences travel through lymphatics to draining lymph nodes (DLNs), in TLR expression and cellular distribution. Human MCs ex- where they trigger the recruitment and sequestration of APCs press TLR1–TLR9 (22–24), although there have been varia- and T cells (18). However, extracellular granules contribute to tions in detection among many studies. TLR stimulation innate immunity, as well, by protecting inflammatory media- generally produces signaling below the threshold required to tors from dilution or degradation and allowing the slow release generate calcium flux and granule exocytosis, except, poten- of associated products (19). In vivo, many particles also remain tially, peptidoglycan stimulation through TLR2 (27). TLR- trapped at the site of activation due to anatomical barriers (18). induced signaling in MCs, similar to other cells, results in DCs and Mfs can phagocytose extracellular MC granules stimulus-specific transcriptional activation and production (20), which may be a mechanism of communicating to APCs of cytokines/chemokines (5) and also attunes other MC re- within the site of infection or DLN. sponses. For example, pretreatment of MCs with TLR ago- Delayed in comparison with degranulation responses, MCs nists results in sensitization and enhanced degranulation in release de novo–produced inflammatory mediators (e.g., cyto- response to IgE cross-linking through Fc«R1 (28). Eiocosinoid kines, chemokines) requiring transcriptional changes with a pathways are also activated by TLR signaling (29). In some time course similar to other tissue-resident immune cells such contexts, MCs may be one of the only cells proximal to an as DCs and Mfs. However, the MC-produced lipid media- infection site capable of detecting certain pathogen-asso- tors, eiocosanoids (i.e., leukotrienes and PGs), only require ciated motifs. For example, in the lung, MCs express TLR10 Downloaded from enzymatic events to occur downstream of activating signaling and TLR7,
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