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      Interleukin-17A/F1 Deficiency Reduces Antimicrobial Gene Expression and Contributes to Microbiome Alterations in Intestines of Japanese medaka ( Oryzias latipes)

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          Abstract

          In mammals, interleukin (IL)-17A and F are hallmark inflammatory cytokines that play key roles in protection against infection and intestinal mucosal immunity. In the gastrointestinal tract (GI), the induction of antimicrobial peptide (AMP) production via Paneth cells is a fundamental role of IL-17A and F in maintaining homeostasis of the GI microbiome and health. Although mammalian IL-17A and F homologs (referred to as IL-17A/F1-3) have been identified in several fish species, their function in the intestine is poorly understood. Additionally, the fish intestine lacks Paneth cells, and its GI structure is very different from that of mammals. Therefore, the GI microbiome modulatory mechanism via IL-17A/F genes has not been fully elucidated. In this study, Japanese medaka ( Oryzias latipes) were used as a teleost model, and IL-17A/F1-knockout (IL-17A/F1-KO) medaka were established using the CRISPR/Cas9 genome editing technique. Furthermore, two IL-17A/F1-deficient medaka strains were generated, including one strain containing a 7-bp deletion (-7) and another with an 11-bp addition (+11). After establishing F2 homozygous KO medaka, transcriptome analysis (RNA-seq) was conducted to elucidate IL-17A/F1-dependent gene induction in the intestine. Results of RNA-seq and real-time PCR (qPCR) demonstrated down-regulation of immune-related genes, including interleukin-1β ( IL-1β), complement 1q subunit C ( C1qc), transferrin a ( Tfa), and G-type lysozyme ( LyzG), in IL-17A/F1-KO medaka. Interestingly, protein and lipid digestive enzyme genes, including phospholipase A2, group IB ( pla2g1b), and elastase-1-like ( CELA1), were also downregulated in the intestines of IL-17A/F1-KO medaka. Furthermore, to reveal the influence of these downregulated genes on the gut microbiome in IL-17A/F1-KO, 16S rRNA-based metagenomic sequencing analysis was conducted to analyze the microbiome constitution. Under a non-exposed state, the intestinal microbiome of IL-17A/F1-KO medaka differed at the phylum level from wild-type, with significantly higher levels of Verrucomicrobia and Planctomycetes. Additionally, at the operational taxonomic unit (OTU) level of the human and fish pathogens, the Enterobacteriaceae Plesiomonas shigelloides was the dominant species in IL-17A/F1-KO medaka. These findings suggest that IL-17A/F1 is involved in the maintenance of a healthy gut microbiome.

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          Most cited references38

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          Bacterial iron homeostasis.

          Iron is essential to virtually all organisms, but poses problems of toxicity and poor solubility. Bacteria have evolved various mechanisms to counter the problems imposed by their iron dependence, allowing them to achieve effective iron homeostasis under a range of iron regimes. Highly efficient iron acquisition systems are used to scavenge iron from the environment under iron-restricted conditions. In many cases, this involves the secretion and internalisation of extracellular ferric chelators called siderophores. Ferrous iron can also be directly imported by the G protein-like transporter, FeoB. For pathogens, host-iron complexes (transferrin, lactoferrin, haem, haemoglobin) are directly used as iron sources. Bacterial iron storage proteins (ferritin, bacterioferritin) provide intracellular iron reserves for use when external supplies are restricted, and iron detoxification proteins (Dps) are employed to protect the chromosome from iron-induced free radical damage. There is evidence that bacteria control their iron requirements in response to iron availability by down-regulating the expression of iron proteins during iron-restricted growth. And finally, the expression of the iron homeostatic machinery is subject to iron-dependent global control ensuring that iron acquisition, storage and consumption are geared to iron availability and that intracellular levels of free iron do not reach toxic levels.
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            Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis.

            Building and maintaining a homeostatic relationship between a host and its colonizing microbiota entails ongoing complex interactions between the host and the microorganisms. The mucosal immune system, including epithelial cells, plays an essential part in negotiating this equilibrium. Paneth cells (specialized cells in the epithelium of the small intestine) are an important source of antimicrobial peptides in the intestine. These cells have become the focus of investigations that explore the mechanisms of host-microorganism homeostasis in the small intestine and its collapse in the processes of infection and chronic inflammation. In this Review, we provide an overview of the intestinal microbiota and describe the cell biology of Paneth cells, emphasizing the composition of their secretions and the roles of these cells in intestinal host defence and homeostasis. We also highlight the implications of Paneth cell dysfunction in susceptibility to chronic inflammatory bowel disease.
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              Interleukin-17 family and IL-17 receptors.

              Interleukin-17 (IL-17) is a pro-inflammatory cytokine secreted by activated T-cells. Recently discovered related molecules are forming a family of cytokines, the IL-17 family. The prototype member of the family has been designated IL-17A. Due to recent advances in the human genome sequencing and proteomics five additional members have been identified and cloned: IL-17B, IL-17C, IL-17D, IL-17E and IL-17F. The cognate receptors for the IL-17 family identified thus far are: IL-17R, IL-17RH1, IL-17RL (receptor like), IL-17RD and IL-17RE. However, the ligand specificities of many of these receptors have not been established. The IL-17 signaling system is operative in disparate tissues such as articular cartilage, bone, meniscus, brain, hematopoietic tissue, kidney, lung, skin and intestine. Thus, the evolving IL-17 family of ligands and receptors may play an important role in the homeostasis of tissues in health and disease beyond the immune system. This survey reviews the biological actions of IL-17 signaling in cancers, musculoskeletal tissues, the immune system and other tissues.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                17 March 2020
                2020
                : 11
                : 425
                Affiliations
                [1] 1Interdisciplinary Graduate School of Agriculture and Engineering, University of Miyazaki , Miyazaki, Japan
                [2] 2School of Marine Biosciences, Kitasato University , Sagamihara, Japan
                [3] 3Department of Marine Biology and Environmental Science, Faculty of Agriculture, University of Miyazaki , Miyazaki, Japan
                [4] 4Department of Biochemistry and Applied Bioscience, Faculty of Agriculture, University of Miyazaki , Miyazaki, Japan
                [5] 5Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University , Tokyo, Japan
                [6] 6Integrated Institute for Regulatory Science, Research Organization for Nao and Life Innovation, Waseda University , Tokyo, Japan
                [7] 7Division of Applied Bioscience, Graduate School of Agriculture, Kyoto University , Kyoto, Japan
                Author notes

                Edited by: Jonathan P. Rast, Emory University, United States

                Reviewed by: Katherine Buckley, Auburn University, United States; Larry J. Dishaw, University of South Florida St. Petersburg, United States

                *Correspondence: Jun-ichi Hikima jhikima@ 123456cc.miyazaki-u.ac.jp

                This article was submitted to Comparative Immunology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2020.00425
                7092794
                32256492
                a5aac02c-a494-4a02-9dc5-c0dd7f9d6852
                Copyright © 2020 Okamura, Morimoto, Ikeda, Mizusawa, Watabe, Miyanishi, Saeki, Takeyama, Aoki, Kinoshita, Kono, Sakai and Hikima.

                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
                : 18 November 2019
                : 25 February 2020
                Page count
                Figures: 8, Tables: 3, Equations: 0, References: 55, Pages: 17, Words: 9914
                Funding
                Funded by: Japan Society for the Promotion of Science 10.13039/501100001691
                Award ID: 17H03863
                Award ID: 17H01486
                Categories
                Immunology
                Original Research

                Immunology
                genome editing,interleukin-17a/f1,japanese medaka,oryzias latipes,transcriptome analysis,metagenomics,teleosts

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