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      Macrophage Proinflammatory Responses to Microorganisms and Transplanted Organs

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          Abstract

          Tissue-resident macrophages and those conscripted from the blood/bone marrow are professional phagocytes. They play a role in tissue homeostasis, replacement, and healing, and are the first-line responders to microbial (viral, bacterial, and fungi) infections. Intrinsic ameboid-type motility allows non-resident macrophages to move to the site of inflammation or injury, where, in response to the inflammatory milieu they perform the anti-microbial and/or tissue repair functions. Depending on the need and the signaling from the surrounding tissue and other immune cells, macrophages acquire morphologically and functionally different phenotypes, which allow them to play either pro-inflammatory or anti-inflammatory functions. As such, the macrophages are also the major players in the rejection of the transplanted organs making an excellent target for the novel anti-rejection therapies in clinical transplantation. In this review, we describe some of the less covered aspects of macrophage response to microbial infection and organ transplantation.

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          Most cited references81

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          The NLRP3 inflammasome: molecular activation and regulation to therapeutics

          NLRP3 (NACHT, LRR and PYD domains-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase-1-dependent release of the proinflammatory cytokines, IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Recent studies have revealed new regulators of the NLRP3 inflammasome, including new interacting or regulatory proteins, metabolic pathways and a regulatory mitochondrial hub. In this Review, we present the molecular, cell biological and biochemical basis of NLRP3 activation and regulation, and describe how this mechanistic understanding is leading to potential therapeutics that target the NLRP3 inflammasome.
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            Exploring the full spectrum of macrophage activation.

            Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities - host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.
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              The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.

              Generation of Interleukin (IL)-1beta via cleavage of its proform requires the activity of caspase-1 (and caspase-11 in mice), but the mechanism involved in the activation of the proinflammatory caspases remains elusive. Here we report the identification of a caspase-activating complex that we call the inflammasome. The inflammasome comprises caspase-1, caspase-5, Pycard/Asc, and NALP1, a Pyrin domain-containing protein sharing structural homology with NODs. Using a cell-free system, we show that proinflammatory caspase activation and proIL-1beta processing is lost upon prior immunodepletion of Pycard. Moreover, expression of a dominant-negative form of Pycard in differentiated THP-1 cells blocks proIL-1beta maturation and activation of inflammatory caspases induced by LPS in vivo. Thus, the inflammasome constitutes an important arm of the innate immunity.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                18 December 2020
                December 2020
                : 21
                : 24
                : 9669
                Affiliations
                [1 ]The Houston Methodist Research Institute, Houston, TX 77030, USA; Auosef@ 123456houstonmethodist.org (A.U.); RMGhobrial@ 123456houstonmethodist.org (R.M.G.)
                [2 ]Department of Surgery, The Houston Methodist Hospital, Houston, TX 77030, USA
                [3 ]MD Anderson Cancer Center, Department of Genetics Houston, The University of Texas, Austin, TX 77030, USA
                [4 ]Laboratory of Regenerative Medicine and Cell Biology, Military Institute of Hygiene and Epidemiology (WIHE), 01-163 Warsaw, Poland; jacek.kubiak@ 123456univ-rennes1.fr
                [5 ]Cell Cycle Group, Faculty of Medicine, Institute of Genetics and Development of Rennes (IGDR), University Rennes, UMR 6290, CNRS, 35043 Rennes, France
                Author notes
                Author information
                https://orcid.org/0000-0003-2772-5127
                Article
                ijms-21-09669
                10.3390/ijms21249669
                7766629
                33352942
                aa6bac10-76a0-444c-9367-01cb5609d590
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 05 November 2020
                : 16 December 2020
                Categories
                Review

                Molecular biology
                macrophage,transplantation,infection,chronic rejection
                Molecular biology
                macrophage, transplantation, infection, chronic rejection

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