論文 - 長谷　耕二

Macrophages switch their phenotype by regulating maf expression during different phases of inflammation

Kikuchi K., Iida M., Ikeda N., Moriyama S., Hamada M., Takahashi S., Kitamura H., Watanabe T., Hasegawa Y., Hase K., Fukuhara T., Sato H., Kobayashi E., Suzuki T., Yamamoto M., Tanaka M., Asano K.

Journal of Immunology （Journal of Immunology）  201 （ 2 ） 635 - 651 2018年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00221767

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Copyright © 2018 by The American Association of Immunologists, Inc Macrophages manifest distinct phenotype according to the organs in which they reside. In addition, they flexibly switch their character in adaptation to the changing environment. However, the molecular basis that explains the conversion of the macrophage phenotype has so far been unexplored. We find that CD169+ macrophages change their phenotype by regulating the level of a transcription factor Maf both in vitro and in vivo in C57BL/6J mice. When CD169+ macrophages were exposed to bacterial components, they expressed an array of acute inflammatory response genes in Maf-dependent manner and simultaneously start to downregulate Maf. This Maf suppression is dependent on accelerated degradation through proteasome pathway and microRNA-mediated silencing. The downregulation of Maf unlocks the NF-E2–related factor 2–dominant, cytoprotective/ antioxidative program in the same macrophages. The present study provides new insights into the previously unanswered question of how macrophages initiate proinflammatory responses while retaining their capacity to repair injured tissues during inflammation. The Journal of Immunology, 2018, 201: 635–651.

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Regulation of inflammatory response of macrophages and induction of regulatory T cells by using retinoic acid-loaded nanostructured lipid carrier

Zai K., Ishihara N., Oguchi H., Hirota M., Kishimura A., Mori T., Hase K., Katayama Y.

Journal of Biomaterials Science, Polymer Edition （Journal of Biomaterials Science, Polymer Edition）  in press （ 1 ） 1 - 11 2018年06月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  09205063

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© 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group. Immunomodulatory function of all-trans retinoic acid (ATRA) has been gathering much attention for the therapy of autoimmune diseases. ATRA is a chemically unstable molecule which requires proper formulation for targeted delivery. Here we examined nanostructured lipid carrier (NLC) for the formulation of ATRA. NLC is a representative nanoparticle formulation especially suited for oral delivery. We established the preparation procedures of ATRA-containing NLC (NLC-RA) which minimizes the degradation of ATRA during the preparation process. NLC-RA thus obtained was taken up by macrophages and induced anti-inflammatory response via suppressing NF-κB signaling as well as via enhancing the production of anti-inflammatory cytokines. Moreover, NLC-RA enhanced differentiation of naïve T cells to regulatory T cells in the co-culture system with dendritic cells. These results suggest that NLC-RA is a promising alternative therapy for the autoimmune diseases especially intestinal bowel disease. (Figure presented.).

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Intestinal epithelial cell-specific deletion of α-mannosidase II ameliorates experimental colitis

Suzuki K., Yamada T., Yamazaki K., Hirota M., Ishihara N., Sakamoto M., Takahashi D., Iijima H., Hase K.

Cell Structure and Function （Cell Structure and Function）  43 （ 1 ） 25 - 39 2018年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  03867196

　概要を見る

© 2018 The Author(s). Inflammatory bowel disease (IBD) is a refractory disease of the gastrointestinal tract that is believed to develop in genetically susceptible individuals. Glycosylation, a type of post-translational modification, is involved in the development of a wide range of diseases, including IBD, by modulating the function of various glycoproteins. To identify novel genes contributing to the development of IBD, we analyzed single nucleotide polymorphisms (SNPs) of glycosylation-related genes in IBD patients and identified MAN2A1, encoding alphamannosidase II (α-MII), as a candidate gene. α-MII plays a crucial, but not exclusive, role in the maturation of Nglycans. We also observed that intestinal epithelial cells (IECs), which establish the first-line barrier and regulate gut immunity, selectively expressed α-MII with minimal expression of its isozyme, alpha-mannosidase IIx (α-MIIx). This led us to hypothesize that IEC-intrinsic α-MII is implicated in the pathogenesis of IBD. To test this hypothesis, we generated IEC-specific α-MII-deficient (α-MIIΔIEC) mice. Although α-MII deficiency has been shown to have a minimal effect on N-glycan maturation in most cell types due to the compensation by α-MIIx, ablation of α-MII impaired the maturation of N-glycans in IECs. α-MIIΔIEC mice were less susceptible to dextran sulfate sodium-induced colitis compared with control littermates. In accordance with this, neutrophil infiltration in the colonic mucosa was attenuated in α-MIIΔIEC mice. Furthermore, gene expression levels of neutrophilattracting chemokines were downregulated in the colonic tissue. These results suggest that IEC-intrinsic α-MII promotes intestinal inflammation by facilitating chemokine expression. We propose SNPs in MAN2A1 as a novel genetic factor for IBD.

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Macrophage extracellular trap formation promoted by platelet activation is a key mediator of rhabdomyolysis-induced acute kidney injury

Okubo K., Kurosawa M., Kamiya M., Urano Y., Suzuki A., Yamamoto K., Hase K., Homma K., Sasaki J., Miyauchi H., Hoshino T., Hayashi M., Mayadas T., Hirahashi J.

Nature Medicine （Nature Medicine）  24 （ 2 ） 232 - 238 2018年02月

ISSN  10788956

　概要を見る

Rhabdomyolysis is a serious syndrome caused by skeletal muscle injury and the subsequent release of breakdown products from damaged muscle cells into systemic circulation. The muscle damage most often results from strenuous exercise, muscle hypoxia, medications, or drug abuse and can lead to life-threatening complications, such as acute kidney injury (AKI). Rhabdomyolysis and the AKI complication can also occur during crush syndrome, an emergency condition that commonly occurs in victims of natural disasters, such as earthquakes, and man-made disasters, such as wars and terrorism. Myoglobin released from damaged muscle is believed to trigger renal dysfunction in this form of AKI. Recently, macrophages were implicated in the disease pathogenesis of rhabdomyolysis-induced AKI, but the precise molecular mechanism remains unclear. In the present study, we show that macrophages released extracellular traps (ETs) comprising DNA fibers and granule proteins in a mouse model of rhabdomyolysis. Heme-activated platelets released from necrotic muscle cells during rhabdomyolysis enhanced the production of macrophage extracellular traps (METs) through increasing intracellular reactive oxygen species generation and histone citrullination. Here we report, for the first time to our knowledge, this unanticipated role for METs and platelets as a sensor of myoglobin-derived heme in rhabdomyolysis-induced AKI. This previously unknown mechanism might be targeted for treatment of the disease. Finally, we found a new therapeutic tool for prevention of AKI after rhabdomyolysis, which might rescue some sufferers of this pathology.

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Macrophage extracellular chromatin release induced by Mac-1 mediated platelet-macrophage interactions triggers acute kidney injury in rhabdomyolysis.

Okubo K, Kurosawa M, Kamiya M, Urano Y, Suzuki A, Yamamoto K, HASE K, Homma K, Sasaki J, Miyauchi H, Hoshino T, Hayashi M, Mayadas TN, Hirahashi J.

Nat. Med. 24   232 - 238 2018年01月

研究論文（学術雑誌）, 共著, 査読有り

Intestinal M cells contribute to the maintenance of mucosal barrier functions and immune homeostasis

Ishihara N., Kobayashi N., Hase K.

Japanese Journal of Allergology （Japanese Journal of Allergology）  67 （ 3 ） 171 - 178 2018年

ISSN  00214884

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NALT M cells are important for immune induction for the common mucosal immune system.

Date Y, Ebisawa M, Fukuda S, Shima H, Obata Y, Takahashi D, Kato T, Hanazato M, Nakato G, Williams IR, HASE K, Ohno H.

Int Immunol. 29   471 - 478 2017年12月

研究論文（学術雑誌）, 共著, 査読有り

Attenuation of CD4+CD25+regulatory T cells in the tumor microenvironment by metformin, a type 2 diabetes drug.

長谷 耕二

EBioMedicine, 25:154-164, 2017. 25   154 - 164 2017年11月

研究論文（学術雑誌）, 共著, 査読有り

IL-22BP dictates characteristics of Peyer's patch follicle-associated epithelium for antigen uptake.

Jinnohara T, Kanaya T, HASE K, Sakakibara S, Kato T, Tachibana N, Sasaki T, Hashimoto Y, Sato T, Watarai H, Kunisawa J, Shibata N, Williams I, Kiyono H, and Ohno H.

J. Exp. Med. 214   1607 - 1618 2017年06月

研究論文（学術雑誌）, 共著, 査読有り

Zinc Transporter SLC39A7/ZIP7 Promotes Intestinal Epithelial Self-Renewal by Resolving ER Stress.

1 Ohashi W, Kimura S, Iwanaga T, Furusawa Y, Irié T, Izumi H, Watanabe T, Hijikata A, Hara T, Ohara O, Koseki H, Sato T, Robine S, Mori H, Hattori Y, Watarai H, Mishima K, Ohno H, Hase K, Fukada T.

PLoS Genet. 12   e1006349 2016年10月

研究論文（学術雑誌）, 共著, 査読有り

Distinct Roles for the N- and C-terminal Regions of M-Sec in Plasma Membrane Deformation during Tunneling Nanotube Formation.

2 Kimura S, Yamashita M, Yamakami-Kimura M, Sato Y, Yamagata A, Kobashigawa Y, Inagaki F, Amada T, Hase K, Iwanaga T, Ohno H, Fukai S.

Sci. Rep. 6   33548 2016年09月

研究論文（学術雑誌）, 共著, 査読有り

Gut commensal Bacteroides acidifaciens prevents obesity and improves insulin sensitivity in mice.

Yang JY, Lee YS, Kim Y, Lee SH, Ryu S, Fukuda S, #HHase K<U/>, Yang CS, Lim HS, Kim MS, Kim HM, Ahn SH, Kwon BE, Ko HJ, Kweon MN

Mucosal Immunol. 10   104 - 116 2016年04月

研究論文（学術雑誌）, 共著, 査読有り

EAF2 mediates germinal centre B-cell apoptosis to suppress excessive immune responses and prevent autoimmunity.

Li Y, Takahashi Y, Fujii S, Zhou Y, Hong R, Suzuki A, Tsubata T, HASE Koji, Wang JY.

Nature Commun. 7   10836 2016年03月

研究論文（学術雑誌）, 共著, 査読有り

Epithelium-Intrinsic MicroRNAs Contribute to Mucosal Immune Homeostasis by Promoting M-Cell Maturation.

Nakato G, HASE Koji, Sato T, Kimura S, Sakakibara S, Sugiyama M, Obata Y,Hanazato M, Iwanaga T, Ohno H

PLoS One 11 （ 3 ） e0150379 2016年03月

研究論文（学術雑誌）, 共著, 査読有り

Potential Role of the Formation of Tunneling Nanotubes in HIV-1 Spread in Macrophages

<5 Hashimoto M, Bhuyan F, Hiyoshi M, Noyori O, Nasser H, Miyazaki M, Saito T,Kondoh Y, Osada H, Kimura S, HASE Koji, Ohno H, Suzu S.

J. Immunol. 196   18321 - 1841 2016年02月

研究論文（学術雑誌）, 共著, 査読有り

Distinct microRNA expression profiles in follicle-associated epithelium and villous epithelium.

Genom Data 5   388 - 390 2015年07月

研究論文（学術雑誌）, 共著, 査読有り

The microbiota regulates type 2 immunity through RORγt+ T cells.

Ohnmacht C, Park JH, Cording S, Wing JB, Atarashi K, Obata Y, Gaboriau-Routhiau V, Marques R, Dulauroy S, Fedoseeva M, Busslinger M, Cerf-Bensussan N, Boneca IG, Voehringer D, Hase K, Honda K, Sakaguchi S, Eberl G.

Science 349   989 - 993 2015年07月

研究論文（学術雑誌）, 査読有り

Botulinum toxin A complex exploits intestinal M cells to enter the host and exert neurotoxicity.

Matsumura T, Sugawara Y, Yutani M, Amatsu S, Yagita H，Kohda T, Fukuoka S-I, Nakamura Y, Hase K, Ohno H and Fujinaga Y.

Nat. Commun. 6   6255 2015年02月

研究論文（学術雑誌）, 共著

Epithelial-stromal interaction via Notch signaling is essential for the full maturation of gut-associated lymphoid tissues.

10 Obata Y, Kimura S, Nakato G, Iizuka K, Miyagawa Y, Nakamura Y, Furusawa Y, Sugiyama M, Suzuki K, Ebisawa M, Fujimura Y, Yoshida H, Iwanaga T, Hase K, Ohno H

EMBO Rep. 15   1297 - 1304 2014年11月

研究論文（学術雑誌）, 共著, 査読有り

The Role of the Clathrin Adaptor AP-1: Polarized Sorting and Beyond.

Nakatsu F, Hase K and Ohno H

Membranes 4   747 - 763 2014年11月

研究論文（学術雑誌）, 共著, 査読有り