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      Complement Receptors and Their Role in Leukocyte Recruitment and Phagocytosis

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          Abstract

          The complement system is deeply embedded in our physiology and immunity. Complement activation generates a multitude of molecules that converge simultaneously on the opsonization of a target for phagocytosis and activation of the immune system via soluble anaphylatoxins. This response is used to control microorganisms and to remove dead cells, but also plays a major role in stimulating the adaptive immune response and the regeneration of injured tissues. Many of these effects inherently depend on complement receptors expressed on leukocytes and parenchymal cells, which, by recognizing complement-derived molecules, promote leukocyte recruitment, phagocytosis of microorganisms and clearance of immune complexes. Here, the plethora of information on the role of complement receptors will be reviewed, including an analysis of how this functionally and structurally diverse group of molecules acts jointly to exert the full extent of complement regulation of homeostasis.

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          Most cited references292

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          Origin and physiological roles of inflammation.

          Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.
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            Complement: a key system for immune surveillance and homeostasis.

            Nearly a century after the significance of the human complement system was recognized, we have come to realize that its functions extend far beyond the elimination of microbes. Complement acts as a rapid and efficient immune surveillance system that has distinct effects on healthy and altered host cells and foreign intruders. By eliminating cellular debris and infectious microbes, orchestrating immune responses and sending 'danger' signals, complement contributes substantially to homeostasis, but it can also take action against healthy cells if not properly controlled. This review describes our updated view of the function, structure and dynamics of the complement network, highlights its interconnection with immunity at large and with other endogenous pathways, and illustrates its multiple roles in homeostasis and disease.
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              Complement System Part I – Molecular Mechanisms of Activation and Regulation

              Complement is a complex innate immune surveillance system, playing a key role in defense against pathogens and in host homeostasis. The complement system is initiated by conformational changes in recognition molecular complexes upon sensing danger signals. The subsequent cascade of enzymatic reactions is tightly regulated to assure that complement is activated only at specific locations requiring defense against pathogens, thus avoiding host tissue damage. Here, we discuss the recent advances describing the molecular and structural basis of activation and regulation of the complement pathways and their implication on physiology and pathology. This article will review the mechanisms of activation of alternative, classical, and lectin pathways, the formation of C3 and C5 convertases, the action of anaphylatoxins, and the membrane-attack-complex. We will also discuss the importance of structure–function relationships using the example of atypical hemolytic uremic syndrome. Lastly, we will discuss the development and benefits of therapies using complement inhibitors.
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                Author and article information

                Contributors
                Journal
                Front Cell Dev Biol
                Front Cell Dev Biol
                Front. Cell Dev. Biol.
                Frontiers in Cell and Developmental Biology
                Frontiers Media S.A.
                2296-634X
                11 February 2021
                2021
                : 9
                : 624025
                Affiliations
                Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven) , Leuven, Belgium
                Author notes

                Edited by: Hao Sun, University of California, San Diego, United States

                Reviewed by: James L. Stafford, University of Alberta, Canada; Maurice Bartlett Hallett, Cardiff University, United Kingdom; Michael Hickey, Monash University, Australia

                *Correspondence: Pedro E. Marques pedro.marques@ 123456kuleuven.be

                This article was submitted to Cell Adhesion and Migration, a section of the journal Frontiers in Cell and Developmental Biology

                †These authors have contributed equally to this work

                Article
                10.3389/fcell.2021.624025
                7905230
                33644062
                5b8c10c1-9981-4955-8e5e-74b4233966e6
                Copyright © 2021 Vandendriessche, Cambier, Proost and Marques.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 October 2020
                : 15 January 2021
                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 292, Pages: 25, Words: 22668
                Funding
                Funded by: Fonds Wetenschappelijk Onderzoek 10.13039/501100003130
                Award ID: 11A4220N
                Award ID: 1S56521N
                Award ID: G058421N
                Award ID: G080818N
                Funded by: H2020 Marie Skłodowska-Curie Actions 10.13039/100010665
                Award ID: MSCA-IF-2018-839632
                Funded by: Onderzoeksraad, KU Leuven 10.13039/501100004497
                Categories
                Cell and Developmental Biology
                Review

                complement,complement receptors,leukocyte,inflammation,cell migration,phagocytosis

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