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      Editorial: Antimicrobial Peptides and Complement – Maximising the Inflammatory Response

      editorial
      1 , *
      Frontiers in Immunology
      Frontiers Media S.A.
      inflammation, complement, antimicrobial peptides, immune response, inflammatory response

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          Abstract

          Striking commonalities in the roles of complement and antimicrobial peptides have recently been reported; their abilities to apply selection pressures on a bacterial population in the bloodstream (1), to contribute to enhanced phagocytosis of opsonized bacteria (2), and to interactively determine skin microbiome (3). Evolutionary roots for complement proteins and antimicrobial peptides are ancient (4). Predating the avenue of somatic recombination, antimicrobial peptides and complement have further emerged as modulators of cell activities that are part of the adaptive immune response. Therefore, antimicrobial peptides and complement were logical contenders for a focused analysis to distil from a wide complexity a range of overlapping and distinct activities that could serve to maximize local and systemic inflammatory responses. The task was ambitious. Aiming to draw together experts and junior scientists in two distinct areas of inflammatory responses, an e-book series was produced which in its entirety challenges oligofactorial analyses in health and disease and points to a gain in embracing more fully the interconnection of inflammatory reactions and their components using, as examples, complement and antimicrobial peptides. Functional analytical approaches may be derived from genomic analyses using cross species comparisons for antimicrobial peptides and is demonstrated in Machado and Ottolini’s article (5). Significant copy number variations for defensin genes in and between populations make these exciting modulators of inflammation, mucosal immunity, and infection responses. In the complement system, gene duplication leading to C4A and C4B and functional polymorphisms in the MBL gene (in humans) provide variability in the fluid phase of complement activation. In two parts, Roumenina’s team provide a delicately researched state-of-the-art evaluation of complement activation and its regulation as well as a summary of current understanding of the mutlifaceted roles of complement anaphylatoxins in inflammation (6, 7). Bevington’s group put forward a case in support of further avenues of research to identify pH sensing molecules and understand pH-dependent contact and complement system activation and their interactions (8). The activity of antimicrobial peptides is also influenced by pH conditions (9). It appears therefore that more rigorous measurements of pH in in vivo models may help to discern a level of regulation that is currently still underappreciated. Day and Clark’s group remind that sialic acids or glycosaminoglycan structures on the cell surface or in the extracellular compartment provide interfaces, which can determine propagation or inhibition of complement activation and be the basis for tissue-specific susceptibilities to targeting binding of complement proteins (10). Interestingly, in Drosophila, engagement of the sulfated polysaccharide chains of heparin sulfate proteoglycans leads to expression of antimicrobial peptides (11). Stadnyk’s group presents a program of work to test hypotheses or inferred models of interaction, which are relevant in understanding pathomechanisms of colitis, but also contribute to our understanding of mucosal tolerance (12). Much has yet to be gained from studying the luminal role of antimicrobial peptides vs. the mucosal role of complement to maintain the mucosal barrier (13). In the periodontal pocket, Porphyromonas gingivalis, its reciprocal interaction with complement and antimicrobial peptides during periodontitis is associated with altered local microbiota, bone loss, and evasion to atherosclerotic plaque (14). Chemokines, for which direct antimicrobial activities have been shown, are the focus in Sahingur and Yeudall’s treatise on molecular determinants in the development and progression of oral cavity cancers. Produced in response to a polymicrobial insult, locally produced chemokines are relevant to epithelial dysplasia and osteoclast activity and, furthermore, shape the tumor microenvironment (15). Al-Rayahi and Sanyi juxtapose complex activities of antimicrobial peptides and complement components in a wide range of cancers and remind us of early tumoricidal work using bacterial extracts (16). Rocha-Ferreira and Hristova discuss for the neonatal brain the role of complement and antimicrobial peptides in the dynamics and extent of inflammation and their potential as targetable mediators of hypoxia-induced brain damage (17). A cautionary tale is told by Schuerholz et al. and Thompson et al., who deal with antimicrobial peptides and complement, respectively, in human sepsis (18, 19). Interactions of host to pathogen are multimodal and immune markers alter over the duration of disease. It seems reasonable to propose that parallel measurement of humorally accessible complement and antimicrobial peptides, players of the innate immunity bridging the adaptive immunity, will yield greater understanding of the dynamic host response during sepsis. Finally, Zimmer et al. systematically present activity signatures of complement and antimicrobial peptides in homeostasis and disease (20) and point to a need to distinguish other activities, which relate to routine design of recombinant protein expression (21). In their entirety, the contributions, by providing succinct and critical summaries, primary data and viewpoints, achieve to deepen insight in and understanding of complex matters involving and surrounding antimicrobial peptides and complement. The mind may become more prepared to consider a multipronged approach to health and disease, impacting on both, experimental and therapeutic designs. Conflict of Interest Statement The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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          Complement System Part II: Role in Immunity

          The complement system has been considered for a long time as a simple lytic cascade, aimed to kill bacteria infecting the host organism. Nowadays, this vision has changed and it is well accepted that complement is a complex innate immune surveillance system, playing a key role in host homeostasis, inflammation, and in the defense against pathogens. This review discusses recent advances in the understanding of the role of complement in physiology and pathology. It starts with a description of complement contribution to the normal physiology (homeostasis) of a healthy organism, including the silent clearance of apoptotic cells and maintenance of cell survival. In pathology, complement can be a friend or a foe. It acts as a friend in the defense against pathogens, by inducing opsonization and a direct killing by C5b–9 membrane attack complex and by triggering inflammatory responses with the anaphylatoxins C3a and C5a. Opsonization plays also a major role in the mounting of an adaptive immune response, involving antigen presenting cells, T-, and B-lymphocytes. Nevertheless, it can be also an enemy, when pathogens hijack complement regulators to protect themselves from the immune system. Inadequate complement activation becomes a disease cause, as in atypical hemolytic uremic syndrome, C3 glomerulopathies, and systemic lupus erythematosus. Age-related macular degeneration and cancer will be described as examples showing that complement contributes to a large variety of conditions, far exceeding the classical examples of diseases associated with complement deficiencies. Finally, we discuss complement as a therapeutic target.
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            Complement modulates the cutaneous microbiome and inflammatory milieu.

            The skin is colonized by a plethora of microbes that include commensals and potential pathogens, but it is currently unknown how cutaneous host immune mechanisms influence the composition, diversity, and quantity of the skin microbiota. Here we reveal an interactive role for complement in cutaneous host-microbiome interactions. Inhibiting signaling of the complement component C5a receptor (C5aR) altered the composition and diversity of the skin microbiota as revealed by deep sequencing of the bacterial 16S rRNA gene. In parallel, we demonstrate that C5aR inhibition results in down-regulation of genes encoding cutaneous antimicrobial peptides, pattern recognition receptors, and proinflammatory mediators. Immunohistochemistry of inflammatory cell infiltrates in the skin showed reduced numbers of macrophages and lymphocytes with C5aR inhibition. Further, comparing cutaneous gene expression in germ-free mice vs. conventionally raised mice suggests that the commensal microbiota regulates expression of complement genes in the skin. These findings demonstrate a component of host immunity that impacts colonization of the skin by the commensal microbiota and vice versa, a critical step toward understanding host-microbe immune mutualism of the skin and its implications for health and disease. Additionally, we reveal a role for complement in homeostatic host-microbiome interactions of the skin.
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              Chemokine Function in Periodontal Disease and Oral Cavity Cancer

              The chemotactic cytokines, or chemokines, comprise a superfamily of polypeptides with a wide range of activities that include recruitment of immune cells to sites of infection and inflammation, as well as stimulation of cell proliferation. As such, they function as antimicrobial molecules and play a central role in host defenses against pathogen challenge. However, their ability to recruit leukocytes and potentiate or prolong the inflammatory response may have profound implications for the progression of oral diseases such as chronic periodontitis, where tissue destruction may be widespread. Moreover, it is increasingly recognized that chronic inflammation is a key component of tumor progression. Interaction between cancer cells and their microenvironment is mediated in large part by secreted factors such as chemokines, and serves to enhance the malignant phenotype in oral and other cancers. In this article, we will outline the biological and biochemical mechanisms of chemokine action in host–microbiome interactions in periodontal disease and in oral cancer, and how these may overlap and contribute to pathogenesis.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/41389
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                24 September 2015
                2015
                : 6
                : 491
                Affiliations
                [1] 1Department of Infection, Immunity and Inflammation, College of Medicine, Biological Sciences and Psychology, University of Leicester , Leicester, UK
                Author notes

                Edited and reviewed by: Johan Van Der Vlag, Radboud University Medical Center, Netherlands

                *Correspondence: Cordula M. Stover, cms13@ 123456le.ac.uk

                Specialty section: This article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2015.00491
                4585229
                44cfffc1-ea9f-40e7-8c27-c6df416dbb08
                Copyright © 2015 Stover.

                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) or licensor 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
                : 24 July 2015
                : 08 September 2015
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 21, Pages: 2, Words: 1518
                Categories
                Immunology
                Editorial

                Immunology
                inflammation,complement,antimicrobial peptides,immune response,inflammatory response
                Immunology
                inflammation, complement, antimicrobial peptides, immune response, inflammatory response

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