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Enteric Alpha Defensins in Norm and Pathology Nikolai a Lisitsyn1*, Yulia a Bukurova1, Inna G Nikitina1, George S Krasnov1, Yuri Sykulev2 and Sergey F Beresten1

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Enteric Alpha Defensins in Norm and Pathology Nikolai a Lisitsyn1*, Yulia a Bukurova1, Inna G Nikitina1, George S Krasnov1, Yuri Sykulev2 and Sergey F Beresten1 Lisitsyn et al. Annals of Clinical Microbiology and Antimicrobials 2012, 11:1 http://www.ann-clinmicrob.com/content/11/1/1 REVIEW Open Access Enteric alpha defensins in norm and pathology Nikolai A Lisitsyn1*, Yulia A Bukurova1, Inna G Nikitina1, George S Krasnov1, Yuri Sykulev2 and Sergey F Beresten1 Abstract Microbes living in the mammalian gut exist in constant contact with immunity system that prevents infection and maintains homeostasis. Enteric alpha defensins play an important role in regulation of bacterial colonization of the gut, as well as in activation of pro- and anti-inflammatory responses of the adaptive immune system cells in lamina propria. This review summarizes currently available data on functions of mammalian enteric alpha defensins in the immune defense and changes in their secretion in intestinal inflammatory diseases and cancer. Keywords: Enteric alpha defensins, Paneth cells, innate immunity, IBD, colon cancer Introduction hydrophobic structure with a positively charged hydro- Defensins are short, cysteine-rich, cationic peptides philic part) is essential for the insertion into the micro- found in vertebrates, invertebrates and plants, which bial membrane and the formation of a pore leading to play an important role in innate immunity against bac- membrane permeabilization and lysis of the microbe teria, fungi, protozoa, and viruses [1]. Mammalian [10]. Initial recognition of numerous microbial targets is defensins are predominantly expressed in epithelial cells a consequence of electrostatic interactions between the of skin, respiratory airways, gastrointestinal and geni- defensins arginine residues and the negatively charged tourinary tracts, which form physical barriers to external phospholipids of the microbial cytoplasmic membrane infectious agents [2,3], and also in leukocytes (mostly [2,5]. However, the precise mechanism of target recogni- neutrophils), which kill microbes that have already pene- tion and its putative effectors have not been studied in trated the body [4]. Mature defensins contain six sufficient detail for all known defensin molecules [11]. cysteine residues (Cys1-6) forming three intramolecular The most sensitive targets of enteric alpha defensins are disulphide bonds. Depending on the bonds arrangement Gram-positive and Gram-negative bacteria [12]. Though they are classified into alpha, beta and theta subfamilies. viruses usually cannot be cleared by the innate immune Alpha defensins secreted by leukocytes and intestinal system, some defensins are able to suppress replication Paneth cells of mammals [5] contain disulfide bridges of human immunodeficiency virus [13]. between 1-6, 2-4, and 3-5 cysteine residues, while beta Since their discovery in rabbit neutrophils in 1966 defensins produced by epithelial cells and leukocytes of [14], around fifty alpha defensin genes have been identi- most multicellular organisms [6] are distinguished by fied in primates, rodents, and equines, most of which pairing of cysteine residues 1-5, 2-4, and 3-6 [7]. Mem- haven’t been analyzed in sufficient detail. The genes bers of the rare theta defensin subfamily (circular mini- evolve extremely rapidly, so that their copy number in defensins) are expressed only in leukocytes and bone various organisms and even in individual genomes of marrow cells of monkeys. They are produced by the the same species significantly varies [15]. Six best char- head-to-tail ligation of two different C-terminally trun- acterized alpha defensins, which are most abundantly cated pro-alpha defensins (demidefensins), each nine expressed in the human body, include four peptides amino acids long [8]. expressed in neutrophils (DEFA1 through 4, previously The tertiary structure of mature alpha defensins con- referred to as human neutrophil peptides HNP1-4) and sists of a triple-stranded b-sheet with two b-turns [9]. two enteric defensins - DEFA5 and 6 (formerly desig- An amphipathic character of the peptide (i.e., mostly nated as HD5 and 6). DEFA5 and 6 are secreted in the mucous layer by Paneth cells of small intestine and * Correspondence: [email protected] colon and to a smaller extent by cells of female repro- 1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilova St., Moscow 119991, Russian Federation ductive tract and oropharyngeal mucosa [16,17]. Besides, Full list of author information is available at the end of the article Panethcellsproducemorethanadozenofother © 2012 Lisitsyn et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Lisitsyn et al. Annals of Clinical Microbiology and Antimicrobials 2012, 11:1 Page 2 of 6 http://www.ann-clinmicrob.com/content/11/1/1 antimicrobials, including lysozyme, IgAs, angiogenins, secretion [27,28]. Conversely, murine defensins are and secreted phospholipase A2 [16]. stored in vesicles in a mature form after propeptide pro- Twenty-four murine alpha defensin genes are listed in cessing by matrilysin (also known as matrix metallopro- the mouse genome informatics database http://www. teinase Mmp7) [29]. It has been shown that abrogation informatics.jax.org, six of which (enteric alpha defensins of murine alpha defensin processing by targeted disrup- 1 through 6, formerly referred to as cryptdins) have tion of the matrilysin gene increases susceptibility of been thoroughly investigated in recent years. Unlike Mmp7 knockout mice to oral challenges with enteric humans, rats, and rabbits genomes, mouse DNA does bacteria, whereas transgenic mice overexpressing human not contain Defa encoding genes that are expressed in DEFA5 are markedly resistant to orally administered neutrophils [18]. Recently, eleven murine alpha defensin virulent Salmonella typhimurium, due to proper proces- related genes (formerly called cryptdin related sing of human propeptide by murine matrilysin [22]. sequences) with yet unknown functions have been iden- tified. These genes encode prepro-sequences that are Structure of the intestinal epithelium nearly identical to those of alpha defensins, but their The mucosal surface of the small intestine consists of mature peptides show no homology to defensins [19]. crypts of Lieberkühn and villi. Due to the constant shed- ding of gut epithelial cells in the lumen the whole Gene expression and peptide processing epithelium renews once in four-five days, except for Human and murine enteric alpha defensin genes consist Paneth cells, which live approximately 70 days. Intestinal of two exons, whereas alpha defensin genes expressed in epithelium is derived from multipotent columnar stem human neutrophils consist of three exons, two of which cells located at the base of the crypt, which expess (second and third) are homologous to enteric defensins LGR5 receptor and other stem cell-specific protein mar- [1]. Search for orthologous sequences in promoters of kers [30]. An alternative pool of stem cells is positioned these genes revealed presence of putative binding sites higher in the crypt wall [30-32]. Columnar stem cells for transcription factors AP1, OCT1.4, and GCN4 give rise to actively proliferating transit amplifying cells [20,21]. Upstream regions of human DEFA5 and murine differentiating into four major epithelial cell lineages: 1) Defa4 genes contain highly conserved cis-acting ele- enterocytes absorbing nutrients; 2) goblet cells produ- ments as evident from the expression of functionally cing mucus; 3) enteroendocrine cells secreting hor- active human peptide in small intestinal crypts of mice mones in the capillaries of the underlying connective transgenic for human DEFA5 minigene construct [22]. tissue (lamina propria); and 4) Paneth cells secreting Analysis of postnatal changes in concentration of mur- enteric alpha defensins, as well as other antimicrobials ine enteric defensins in the small intestine of conventional in the mucous layer. Besides, stem cells generate less and germ-free mice revealed two patterns of gene expres- documented microfold cells (M-cells) responsible for the sion: gradual increase in production of defensins 1, 3 and uptake of mucosal antigens [33] and the recently 6 and rapid raise in secretion of defensins 2, 4 and 5 in the described tuft cells secreting endogenous intestinal jejunum (but not in the ileum), which is presumably opioids [34]. Paneth cells protect the adjacent stem cells induced by the presence of luminal bacteria [23]. In adult and the whole gut epithelium from microbial infection mice alpha defensins are equally expressed along the small and regulate bacterial colonization of the gut [35]. intestine except Defa4, which is more abundant in the ileum as compared to the duodenum [24]. Recently, it has Functions of enteric alpha defensins been shown, that in human tropical populations secretion Enteric alpha defensins are the most abundant products of enteric alpha defensins may decrease up to ten times, as secreted by Paneth cells [36]. The main inducers of compared to Europeans, due to down-regulation of gene their secretion are the products of degradation of Gram- expression in response to infections, inflammatory condi- positive and Gram-negative bacteria, inhabiting the gut tions, and malnutrition [25]. including: muramyl dipeptide, bacterial lipopolysacchar- Human enteric alpha defensins are synthesized in vivo ide, flagellin, lipid
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