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The Dichotomous Responses Driven by Β-Defensins

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The Dichotomous Responses Driven by Β-Defensins Edinburgh Research Explorer The Dichotomous Responses Driven by -Defensins Citation for published version: Shelley, JR, Davidson, DJ & Dorin, JR 2020, 'The Dichotomous Responses Driven by -Defensins', Frontiers in Immunology, vol. 11. https://doi.org/10.3389/fimmu.2020.01176 Digital Object Identifier (DOI): 10.3389/fimmu.2020.01176 Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: Frontiers in Immunology Publisher Rights Statement: This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer content complies with UK legislation. If you believe that the public display of this file breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 24. Sep. 2021 REVIEW published: 12 June 2020 doi: 10.3389/fimmu.2020.01176 The Dichotomous Responses Driven by β-Defensins Jennifer R. Shelley, Donald J. Davidson and Julia R. Dorin* Centre for Inflammation Research, The University of Edinburgh, Edinburgh BioQuarter, Edinburgh, Scotland Defensins are short, rapidly evolving, cationic antimicrobial host defence peptides with a repertoire of functions, still incompletely realised, that extends beyond direct microbial killing. They are released or secreted at epithelial surfaces, and in some cases, from immune cells in response to infection and inflammation. Defensins have been described as endogenous alarmins, alerting the body to danger and responding to inflammatory signals by promoting both local innate and adaptive systemic immune responses. However, there is now increasing evidence that they exert variable control on the response to danger; creating a dichotomous response that can suppress inflammation in some circumstances but exacerbate the response to danger and damage in others and, at higher levels, lead to a cytotoxic effect. Focussing in this review on human β-defensins, we discuss the evidence for their functions as proinflammatory, immune activators amplifying the response to infection or damage signals and/or as mediators of resolution of damage, contributing to a return to homeostasis. Finally, we consider their Edited by: involvement in the development of autoimmune diseases. Charles Lee Bevins, University of California, Davis, Keywords: beta defensin, psoriasis, atopic dermatitis, autoimmunity, immunomodulation, AMP United States Reviewed by: Gill Diamond, INTRODUCTION University of Louisville, United States Joost Joe Oppenheim, Defensins and defensin-like peptides are found throughout multicellular organisms including National Cancer Institute at Frederick, plants, insects and fungi, as well as vertebrates. They were first described as antimicrobial peptides United States (AMP), with the ability to rapidly penetrate and disrupt the outer membrane of bacteria, viruses and *Correspondence: fungi to varying degrees and subsequently disrupt metabolic processes within (1). It is appealing Julia R. Dorin to consider that this innate, protective mechanism is so fundamental that the defensin genes [email protected] have been evolutionarily conserved for this purpose. In fact, the value of the structure of these disulphide-stabilised, cysteine containing, positively charged loop peptides has resulted in two Specialty section: evolutionarily distinct defensin families that have arisen separately by convergent evolution (2). The This article was submitted to cis-defensin superfamily (present in insects, fungi and plants), has the central beta-strand stabilised Microbial Immunology, by disulphide bridges, connected to the same alpha-helix in the “cis” orientation. This is in contrast a section of the journal to the vertebrate (and some invertebrate) defensins, in which the central beta strand has disulphide Frontiers in Immunology bridges that stabilise structures in non-cis or “trans” orientations (3, 4). Both cis and trans families Received: 16 March 2020 have undergone rapid expansion and evolutionary change to reveal a repertoire of diverse functions Accepted: 13 May 2020 that are only recently becoming clear (5). Published: 12 June 2020 Here we focus on the human, trans-defensins—specifically β-defensins. We discuss their role(s) Citation: in host defence other than by direct microbial killing. We consider whether the function of these Shelley JR, Davidson DJ and Dorin JR (2020) The Dichotomous Responses molecules is purely as an acute “alarmin”-type response to danger/damage (alerting the body and Driven by β-Defensins. promoting both local innate, and also local and systemic adaptive immune responses), or if they Front. Immunol. 11:1176. are also instrumental in controlling inflammation (limiting the damage response and mediating doi: 10.3389/fimmu.2020.01176 resolution)—thus speeding a return to homeostasis. Frontiers in Immunology | www.frontiersin.org 1 June 2020 | Volume 11 | Article 1176 Shelley et al. Dichotomous Responses of β-Defensins BETA-DEFENSIN BACKGROUND modulation/damage, the human defensin HBD2 has been shown to bind to the outer pore domain of potassium channel Kv1.3 and The defensin family is a large, multigene family that is rapidly efficiently inhibit channel currents and suppress IL-2 production changing and evolving. In humans there are two functional in both human primary T cells and peripheral mononuclear subfamilies of defensins (α and β) which differ in their cysteine cells (17). connections but retain the central structure of a trans-defensin At this point, the expression pattern of β-defensins in humans cysteine knot. Both α- and β- defensins are generally encoded is worthy of mention [see useful reviews on this here (18, 19)]. All by two (sometimes three) exons, with the first exon containing the many β-defensin members are strongly expressed in various the hydrophobic, anionic leader sequence and the second exon segments of the epididymis post puberty (20, 21) and a major encoding the mature, cationic peptide. The α-defensins are function of β-defensins is in sperm maturation. A β-defensin stored in this inactive form in the granules of either neutrophils mutation in human DEFB126 was found to reduce sperm motility or intestinal Paneth cells, while β-defensins are expressed and fertility in Chinese men (22). In addition, mice deleted predominantly in epithelial cells and believed to be cleaved by for several β-defensins (in pairs or more) are infertile and this signal peptidase as they are secreted (6). demonstrates their synergistic function in sperm maturation, β-defensins are an ancient family, from which the α-defensins movement and protection against premature acrosome reaction have evolved. The amino acid sequence of human β-defensins (23, 24). Sperm are rich in β-defensin in the glycocalyx of is highly divergent, and has been subject to complex positive the head and this may protect the sperm from inappropriate and negative selection (7). During this process, other than activation. However, mice with transgenic over-expression of the cysteines, only a core glycine and aspartic acid are well- an epidydimal specific β-defensin (orthologous to human β- conserved. β-Defensins have an identifiable consensus sequence defensin SPAG11), while being resistant to E. coli infection, of X2−10CX5−7(G/A)XCX3−4CX9−13CX4−7CCXn and the three simultaneously show reduced expression of inflammatory disulphide connections following oxidation are assumed to be cytokines IL-1α and IL-1β, indicating multiple functions and the same for all β-defensins (CI—CV, CII—CIV, and CIII—CVI). implying immunomodulatory properties. The highly variable residues in the mature peptide are rich in Expression of β-defensins is not just evident in the male the positively charged amino acids lysine and arginine to varying genitourinary system, as these peptides are also widely expressed degrees (7). Some of the peptides have extended peptide tails in other tissues. In this review we are focussing primarily with clusters of lysines and residues for additional potential on HBD1–4, as these genes are the most studied in human. glycosylation sites (8). In the human genome there are five β- Their peptide sequence, gene name and charge are given in defensin clusters located over three chromosomes, with around Table 1. HBD1–3 are found in the female reproductive tract 33 genes, of which only a few have known function (9, 10) and in endometrium, vagina and cervix, while HBD1 is found seven of which (in humans) are hyper copy number variable in fallopian tubes (26). These defensins are increased in (CNV) (5). The many gene duplications in the defensin family expression at a number of sites in the body, including the result in gene “birth and death” and as the gene number and tracheal epithelium, gingival mucosa, respiratory epithelium, sequence changes, some genes become specialised for a new gastrointestinal epithelium, genitourinary tract epithelium and function; while at the species level, there are increased numbers skin (27–30). In addition, HBD1 is produced constitutively or complete loss
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