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      Targeted anti–IL-1β platelet microparticles for cardiac detoxing and repair

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          Abstract

          Platelet microparticles are used to deliver IL-1β antibodies to myocardial infarction for cardiac detoxing and repair.

          Abstract

          An acute myocardial infarction (AMI) induces a sterile inflammatory response that facilitates further heart injury and promotes adverse cardiac remodeling. Interleukin-1β (IL-1β) plays a central role in the sterile inflammatory response that results from AMI. Thus, IL-1β blockage is a promising strategy for treatment of AMI. However, conventional IL-1β blockers lack targeting specificity. This increases the risk of serious side effects. To address this problem herein, we fabricated platelet microparticles (PMs) armed with anti–IL-1β antibodies to neutralize IL-1β after AMI and to prevent adverse cardiac remodeling. Our results indicate that the infarct-targeting PMs could bind to the injured heart, increasing the number of anti–IL-1β antibodies therein. The anti–IL-1β platelet PMs (IL1-PMs) protect the cardiomyocytes from apoptosis by neutralizing IL-1β and decreasing IL-1β–driven caspase-3 activity. Our findings indicate that IL1-PM is a promising cardiac detoxification agent that removes cytotoxic IL-1β during AMI and induces therapeutic cardiac repair.

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          Converging roles of caspases in inflammasome activation, cell death and innate immunity.

          Inflammatory and apoptotic caspases are central players in inflammation and apoptosis, respectively. However, recent studies have revealed that these caspases have functions beyond their established roles. In addition to mediating cleavage of the inflammasome-associated cytokines interleukin-1β (IL-1β) and IL-18, inflammatory caspases modulate distinct forms of programmed cell death and coordinate cell-autonomous immunity and other fundamental cellular processes. Certain apoptotic caspases assemble structurally diverse and dynamic complexes that direct inflammasome and interferon responses to fine-tune inflammation. In this Review, we discuss the expanding and interconnected roles of caspases that highlight new aspects of this family of cysteine proteases in innate immunity.
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            The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse.

            Acute myocardial infarction (AMI) initiates an intense inflammatory response that promotes cardiac dysfunction, cell death, and ventricular remodeling. The molecular events underlying this inflammatory response, however, are incompletely understood. In experimental models of sterile inflammation, ATP released from dying cells triggers, through activation of the purinergic P2X7 receptor, the formation of the inflammasome, a multiprotein complex necessary for caspase-1 activation and amplification of the inflammatory response. Here we describe the presence of the inflammasome in the heart in an experimental mouse model of AMI as evidenced by increased caspase-1 activity and cytoplasmic aggregates of the three components of the inflammasome--apoptosis speck-like protein containing a caspase-recruitment domain (ASC), cryopyrin, and caspase-1, localized to the granulation tissue and cardiomyocytes bordering the infarct. Cultured adult murine cardiomyocytes also showed the inducible formation of the inflammasome associated with increased cell death. P2X7 and cryopyrin inhibition (using silencing RNA or a pharmacologic inhibitor) prevented the formation of the inflammasome and limited infarct size and cardiac enlargement after AMI. The formation of the inflammasome in the mouse heart during AMI causes additional loss of functional myocardium, leading to heart failure. Modulation of the inflammasome may therefore represent a unique therapeutic strategy to limit cell death and prevent heart failure after AMI.
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              Cardiac cell–integrated microneedle patch for treating myocardial infarction

              A microneedle cardiac stromal cell patch has been developed for therapeutic heart regeneration after myocardial infarction.
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                Author and article information

                Journal
                Sci Adv
                Sci Adv
                SciAdv
                advances
                Science Advances
                American Association for the Advancement of Science
                2375-2548
                February 2020
                05 February 2020
                : 6
                : 6
                : eaay0589
                Affiliations
                [1 ]Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27607, USA.
                [2 ]Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27695, USA.
                Author notes
                [*]

                These authors contributed equally to this work.

                []Corresponding author. Email: kcheng3@ 123456ncsu.edu
                Author information
                http://orcid.org/0000-0001-9751-0864
                http://orcid.org/0000-0002-8570-3439
                http://orcid.org/0000-0002-9355-7224
                http://orcid.org/0000-0001-7888-0763
                http://orcid.org/0000-0001-8053-7059
                Article
                aay0589
                10.1126/sciadv.aay0589
                7002120
                32076644
                933264cf-241e-4334-87a7-0ea894fe027a
                Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                : 16 May 2019
                : 22 November 2019
                Funding
                Funded by: doi http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: HL123920
                Funded by: doi http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: HL137093
                Funded by: doi http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: HL144002
                Funded by: doi http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: HL146153
                Funded by: doi http://dx.doi.org/10.13039/100000968, American Heart Association;
                Award ID: 18TPA34230092
                Funded by: doi http://dx.doi.org/10.13039/100000968, American Heart Association;
                Award ID: 19EIA34660286
                Categories
                Research Article
                Research Articles
                SciAdv r-articles
                Health and Medicine
                Materials Science
                Health and Medicine
                Custom metadata
                Jeanelle Ebreo

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