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MMCB 2014 The 22 nd International Symposium on Molecular Cell Biology of Macrophages June 2 ( Mon ) –3 ( Tue ) , 2014 The Kobe Chamber of Commerce and Industry ( Kobe CCI ) , Kobe, Japan Macrophage in Maintenance of Tissue Homeostasis and Disease Date Venue T T T T T T T T Th h h h h h h h h he e e e e e e e e 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 n n n n n n n n d d d d d d d d d I I I I I I I I I In n n n n n n n n n nt t t t t t t t te e e e e e er r r r r r r rn n n n n n n n na a a a a a at t t t t t t t ti i i i i i i i io o o o o o o o on n n n n n n n n na a a a a a a a al l l l l l l l S S S S S S S S Sy y y y y y y y ym m m m m m m m mp p p p p p p p po o o o o o os s s s s s s si i i i i i i i iu u u u u u u u um m m m m m m m o o o o o o o o on n n n n n n n n M M M M M M M M Mo o o o o o o o ol l l l l l l l le e e e e e e ec c c c c c c c c cu u u u u u u u ul l l l l l l l l la a a a a a a a a a ar r r r r r r r r r C C C C C C C Ce e e e e e e e e el l l l l l l l l ll l l l l l l l B B B B B B B B Bi i i i i i i i io o o o o o o o ol l l l l l l l l lo o o o o o o o og g g g g g g g g gy y y y y y y y y y o o o o o o o o of f f f f f f f f M M M M M M M M M Ma a a a a a ac c c c c c cr r r r r r ro o o o o o op p p p p p p h h h h h h h h h ha a a a a a a a a a g g g g g g g g g ge e e e e e e e e es s s s s s s s s s s J J J J J J J J J Ju u u u u u u u u un n n n n n n n ne e e e e e 2 2 2 2 2 2 2 2 2 ( ( ( ( ( ( ( ( ( M M M M M M M M Mo o o o o o o o on n n n n n n n n n ) ) ) ) ) ) ) ) ) 3 3 3 3 3 3 3 3 3 ( ( ( ( ( ( ( ( T T T T T T T T Tu u u u u u ue e e e e e e ) ) ) ) ) ) ) , , , , , 2 2 2 2 2 2 2 2 20 0 0 0 0 0 0 0 0 0 01 1 1 1 1 1 1 1 14 4 4 4 4 4 4 4 4 T T T T T T T T T Th h h h h h h h he e e e e e e e e K K K K K Ko o o o o o o ob b b b b b b b b be e e e e e e e e e e C C C C C C Ch h h h h h h ha a a a a am m m m m m m m m m mb b b b b b b b be e e e e e e e er r r r r r r r r r o o o o o o o of f f f f f f f f C C C C C C C C C Co o o o o o o o om m m m m m m m m mm m m m m m m me e e e e e e e er r r r r r r r r rc c c c c c c c c c ce e e e e e e e e a a a a a a a a an n n n n n n n n nd d d d d d d d d I I I I I I In n n n n n n n n nd d d d d d d d du u u u u u u u us s s s s s s s st t t t t t t tr r r r r r ry y y y y y y y y y ( ( ( ( ( ( ( ( ( ( K K K K K K Ko o o o o ob b b b b b be e e e e e e e e C C C C C C C C CC C C C C C C CI I I I I I ) ) ) ) ) ) ) ) , , , , , , K K K K K K K Ko o o o o o o ob b b b b b b be e e e e e e e e, , , , , , J J J J J J J J Ja a a a a a ap p p p p p p p p a a a a a a a a an n n n n n n n n n Da Da Da Da Da Da Da Date te te te te te te te t t V V V V V V V V en en en en en en en en e ue ue ue ue ue ue ue V V V V V V V V V V V V

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Page 1: MMCB 2014 - secand.jp

MMCB 2014The 22nd International Symposium onMolecular Cell Biology of Macrophages

June 2(Mon) – 3(Tue), 2014

The Kobe Chamber of

Commerce and Industry (Kobe CCI), Kobe, Japan

Macrophage in Maintenance of

Tissue Homeostasis and Disease

Date

Venue

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Page 2: MMCB 2014 - secand.jp

MMCB 2014The 22nd International Symposium on

Molecular Cell Biology of Macrophages

Macrophage in Maintenance of

Tissue Homeostasis and Disease

SECRETARIAT

MMCB2014 Office

Toshiyuki Tanaka, Ph.D.(Conference Chairperson)

Laboratory of ImmunobiologySchool of Pharmacy,

Hyogo University of Health Sciences1-3-6, Minato-jima, Chuo-ku, Kobe 650-8530, Japan

Phone:+81-78-304-3065, Fax:+81-78-304-2765E-mail: [email protected]

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1The 22nd International Symposium on Molecular Cell Biology of Macrophages 2014(June 2-3, 2014, Kobe)

Welcome to MMCB2014 in Kobe

Dear Colleagues and Friends,

Welcome to 22nd International Symposium on Molecular Cell Biology of Macrophages (MMCB2014). This symposium is sponsored by The Japanese Society for Molecular Cell Biology of Macrophages, which was founded in 1991 by Professor Kouji Matsushima to promote basic and clinical research in the fi eld of macrophage and dendritic cell biology. Since then, this symposium has been held each year, and made a signifi cant contribution in creating attractive and interactive platform for both young and experienced scientists in this research fi eld.

This year's symposium provides a 2-day scientifi c program with 22 invited lectures, including those by speakers from abroad, and poster presentations by the members of our society. The theme of the symposium is "Macrophages in Maintenance of Tissue Homeostasis and Disease", and the program puts a strong emphasis on the topics of "Development and Functions", "Innate Recognition and Metabolism", "Infl ammation, Immunity and Disease" as well as "Tumor Microenvironment". I sincerely hope that all the participants from both abroad and Japan actively participate in the discussion, leading to develop international and interdisciplinary interactions as well as friendship.

Please enjoy MMCB2014 and have a wonderful time during your stay in Kobe.

June 2, 2014

Toshiyuki TanakaConference Chairperson

Conference Chairperson:

Toshiyuki TanakaLaboratory of Immunobiology, School of Pharmacy, Hyogo University of Health Sciences, 1-3-6, Minato-jima, Chuo-ku, Kobe 650-8530, Japan.Phone: +81-78-304-3065, Fax: +81-78-304-2765E-mail: [email protected]://www2.huhs.ac.jp/~h070015t/index.html

Organizing Committee:

Kouji Matsushima President, Japanese Society for Molecular Cell Biology of Macrophages The University of TokyoTel: +81-3-5841-3434, Fax: +81-3-5841-3393 E-mail: [email protected]

Manabu Ato (National Institute of Infectious Diseases) Kazuyoshi Takeda (Juntendo University) Toshiaki Ohteki (Tokyo Medical and Dental University) Norimitsu Kadowaki (Kyoto University) Akihiro Matsukawa (Okayama University)

Kensuke Miyake (The University of Tokyo) Shigeo Koyasu ( RIKEN Center for Integrative

Medical Sciences) Motohiro Takeya (Kumamoto University) Kenjiro Matsuno (Dokkyo Medical University)

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2 The 22nd International Symposium on Molecular Cell Biology of Macrophages 2014(June 2-3, 2014, Kobe)

General Information

Date: June 2 (Mon) - 3 (Tue), 2014

Venue: The Kobe Chamber of Commerce and Industry (Kobe CCI)(神戸商工会議所・神商ホール)

Offi cial Language: English

Home Page: http://www.huhs.ac.jp/studygroup/mmcb2014/

General Meeting: June 2 (Mon) 16:30 - 17:00 (神戸商工会議所・神商ホール) Poster Viewing: June 2 (Mon) 16:30 - 18:30 (神戸商工会議所・第二会議室)

Get-together Party: June 2 (Mon) 18:30 - 20:30 (クオリティホテル神戸・2階バレンシア)Fee ¥3,000 (Student Fee ¥2,000)

Registration: June 2 (Mon): 8:30 - 18:30, June 3 (Tue): 8:30 - 16:30

Registration fee:

Member (before May 2) ¥5,000Non-Member (before May 2) ¥7,000Member (on-site) ¥7,000Non-Member (on-site) ¥10,000Student ¥3,000

来年度の開催予告

International Conference of Cancer Immunotherapy and Macrophages 2015

第23回マクロファージ分子細胞生物学国際シンポジウム (MMCB2015)

(第19回日本がん免疫学会(JACI)学術集会との合同開催)

日  時:2015年7月9日(木)~11日(土)

会  場: 伊藤国際学術研究センター 伊藤謝恩ホール〒113 ー0033 東京都文京区本郷7ー3ー1

TEL:03ー5841 ー0779 FAX:03ー5841 ー0932

http://www.u-tokyo.ac.jp/ext01/iirc/index.html

当番幹事:順天堂大学 竹田 和由

Page 5: MMCB 2014 - secand.jp

3The 22nd International Symposium on Molecular Cell Biology of Macrophages 2014(June 2-3, 2014, Kobe)

Instructions for the Presentation

Oral Session (Invited Speakers)An LCD projector will be provided. Please bring your own PC to make your presentation. The secretariat will prepare a Mini D-sub 15 pin PC cable connector. If your PC is not compatible with this cable connector, please bring an adaptor to connect your PC to the Mini D-sub 15 pin PC cable connector. In order to avoid technical problems, we ask you to kindly bring your PC to PC center at least 30 min prior to the session.

Poster PresentationPoster will be presented in the poster room throughout the conference. The size of poster board is 90-cm in width and 210-cm in height. We will provide the poster numbers only. Please prepare the title of your poster yourself.

Poster set up: June 2, 2014 8:40 - 11:45

Poster removal: June 3, 2014 16:40 - 17:00

Each presenter should mount the poster on the designated board. Please use pushpin to affix your poster presentation on the board firmly. The secretariat will provide equipment and items required for affixing the posters. Any poster left after the scheduled removal time will be discarded by the secretariat.

Young Investigator AwardYoung Investigator Award was established to encourage young investigators who have made signifi cant contributions to this symposium. Candidates of this award are marked as “*“ after each poster number. The committee will select three awardees from the fi rst authors of the posters, who are graduate and undergraduate students or were awarded Ph.D. degree within fi ve years. There will be voting by the invited speakers and members of the organizing committee, and posters getting the top three places will be selected.

Titlename, affiliation

Posters space

PosterNo.

70㎝90㎝

20㎝

210㎝190㎝

20㎝

Page 6: MMCB 2014 - secand.jp

4 The 22nd International Symposium on Molecular Cell Biology of Macrophages 2014(June 2-3, 2014, Kobe)

Acknowledgement for Sponsorship (平成26年5月22日現在)

The organizing committee of MMCB2014 gratefully acknowledges the generous fi nancial support of the following organizations.

GRANTS (助成金)The Nakatomi Foundation (公益財団法人 中冨健康科学振興財団)

The Novartis Foundation (Japan) for Promotion of Science(公益財団法人 ノバルティス科学振興財団)

The Tokyo Biochemical Research Foundation (公益財団法人 東京生化学研究会)

Inoue Foundation for Science (公益財団法人 井上科学振興財団)

Yakult Bio-Science Foundation (公益財団法人 ヤクルト・バイオサイエンス研究財団)

Kobe Convention & Visitors Association (一般財団法人 神戸国際観光コンベンション協会)

Tsutomu Nakauchi Foundation (公益財団法人 中内力コンベンション振興財団)

Life Science Foundation of Japan (公益財団法人 ライフサイエンス振興財団)

DONATION (賛助寄付)SEIKAGAKU CORPORATION (生化学工業株式会社)Miyano Medical Instruments Co., Ltd (宮野医療器株式会社)Logic Bio INC (株式会社ロジックバイオ)

Kaken Pharmaceutical Co., Ltd (科研製薬株式会社)TEIJIN PHARMA LIMITED (帝人ファーマ株式会社)

Institute of Immunology Co., Ltd (株式会社特殊免疫研究所)TSUMURA & CO. (株式会社ツムラ)Senju Pharmaceutical Co., Ltd. (千寿製薬株式会社)Kyowa Hakko Kirin Co., Ltd. (協和発酵キリン株式会社)Kan Research Institute, Inc. (株式会社 カン研究所)

ADVERTISEMENTS (広告)Miltenyi Biotec K.K. (ミルテニーバイオテク株式会社)Beckman Coulter, Inc. (ベックマン・コールター株式会社)Merck KGaA (メルク株式会社)TOMY DIGITAL BIOLOGY CO., LTD (トミーデジタルバイオロジー株式会社)Bay bioscience Inc. (ベイ バイオサイエンス株式会社)

Becton, Dickinson and Company. (日本ベクトン・ディッキンソン株式会社)Logic Bio INC (株式会社ロジックバイオ)CLEA Japan, Inc. (日本クレア株式会社)Sony Corporation (ソニー株式会社)

YOUNG INVESTIGATOR AWARDS (若手研究奨励賞)BioLegend, Inc. (BioLegend Japan 株式会社)

Page 7: MMCB 2014 - secand.jp

5The 22nd International Symposium on Molecular Cell Biology of Macrophages 2014(June 2-3, 2014, Kobe)

理化学研究所京速コンピュータ「京」

神戸学院大学

兵庫医療大学

神戸国際展示場●

先端医療センター

甲南大学●

神戸空港

神戸夙川学院大学

●神戸女子大学・短大

南 公 園

●ポートピアホテル

●神戸大学

●IKEA神戸

●神戸国際交流会館

神戸大橋

神戸市役所

神戸港港島トンネル

神 戸 港

山 陽 新 幹 線

地下鉄海岸線

神戸市営地下鉄

至大阪・堺・和歌山

至大阪・京都

至名古屋・東京

至九州・四国

至姫路・明石

至博多・広島

阪 急 神 戸 線

JR東海道本線国 道 2 号 線

ハーバーハイウェイ

阪 神 高 速

三宮駅

新神戸駅

N

至西神・名谷 至有馬・三田

●神戸花鳥園

先端医療センター前駅

京コンピュータ前駅

市民広場駅

貿易センター駅

ポートターミナル駅

中公園駅

南公園駅

神戸空港駅

みなとじま(キャンパス前)駅

北埠頭駅

中埠頭駅

2

ポートライナー

ポートライナー

神戸商工会議所会館

会場への交通■ 三宮駅からポートライナーで 「みなとじま・キャンパス前駅」下車(約11分)、徒歩約5分

■ 新神戸駅から車で約15分

■ 神戸空港からポートライナーで 「みなとじま・キャンパス前駅」下車(約13分)、徒歩約5分

神戸商工会議所 〒650-8543 神戸市中央区港島中町6-1The Kobe Chamber of Commerce and Industry (KOBE CCI)  6-1 Minatojima-nakamachi, Chuo-ku Kobe 650-8543, Japan

Access Map

Page 8: MMCB 2014 - secand.jp

6 The 22nd International Symposium on Molecular Cell Biology of Macrophages 2014(June 2-3, 2014, Kobe)

EV EV EV EVEV EV

3F

2F

会 場

事務局

ポスター会場

懇親会会場

アトリウム

EV EV EV EVEV EV

1F正面出入口

2F出入口

EVホール

EVホール

EVホール

EVホール

バレンシアホール

クオリティホテル神戸

神戸商工会議所事務所

神商ホール

イベントホール

役員会議室

第一会議室

第三会議室

第二会議室特別会議室A

特別会議室B

特別会議室C

受 付

Venue Map

Page 9: MMCB 2014 - secand.jp

7The 22nd International Symposium on Molecular Cell Biology of Macrophages 2014(June 2-3, 2014, Kobe)

Program

June 2(Monday)

8:30- Registration

8:55-9:00 Opening: Toshiyuki Tanaka (Hyogo University of Health Sciences, Japan)

Session 1: Development and Functions (9:00-11:45)

Chairpersons: Kenjiro Matsuno (Dokkyo Medical University, Japan)Katsuaki Sato (Miyazaki University, Japan)

9:00-9:30 Tissue resident macrophages self-maintain locally throughout adult life with minimal

contribution from circulating monocytes

Daigo Hashimoto (Hokkaido University, Japan)

9:30-10:00 Ontogeny of tissue-resident macrophages

Florent Ginhoux (Singapore Immunology Network, Singapore)

10:00-10:30 Plasmacytoid dendritic cell development

Nobuyuki Onai (Tokyo Medical and Dental University, Japan)

10:30-10:45 Coffee Break

10:45-11:15 Two sides of a coin: Intestinal macrophages and brain microglia

Alexander Mildner (Weizmann Institute of Science, Israel)

11:15-11:45 Macrophage self-renewal and lineage identity

Michael Sieweke (Centre d'Immunologie de Marseille-Luminy, France)

Lunch Time Special Lecture 1 (12:00-13:00)

Chairperson: Toshiyuki Tanaka (Hyogo University of Health Sciences, Japan)

12:00-13:00 Adjuvant recognition through C-type lectin receptors

Sho Yamasaki (Kyushu University, Japan)

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8 The 22nd International Symposium on Molecular Cell Biology of Macrophages 2014(June 2-3, 2014, Kobe)

Session 2: Innate Recognition and Metabolism (13:30-16:15)

Chairpersons: Osamu Takeuchi (Kyoto University, Japan)Satoshi Uematsu (Chiba University/ The University of Tokyo, Japan)

13:30-14:00 Immunological functions of semaphorins and pathological implications of

mitochondrial DNA

Atsushi Kumanogoh (Osaka University, Japan)

14:00-14:30 Understanding and manipulation of NLRP3-inflammasome

Tatsuya Saitoh (Osaka University, Japan)

14:30-15:00 Interplay between innate and adaptive immune system controls age-related

inflammation

Vishwa Deep Dixit (Yale School of Medicine, USA)

15:00-15:15 Coffee Break

15:15-15:45 A novel scavenging system for biological garbage promoted by circulating AIM

protein and its therapeutic application

Toru Miyazaki (The University of Tokyo, Japan)

15:45-16:15 Immune regulation of adipose tissue

Anthony W. Ferrante Jr. (Columbia University, USA)

16:30- General Meeting (MMCB)Poster Presentation & Poster Viewing

18:30- Get-together Party (Quality Hotel Kobe, Room: Valencia/2F)

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9The 22nd International Symposium on Molecular Cell Biology of Macrophages 2014(June 2-3, 2014, Kobe)

June 3(Tuesday)

8:30- Registration

Session 3: Inflammation, Immunity and Disease (9:00-11:45)

Chairpersons: Toshiaki Ohteki (Tokyo Medical and Dental University, Japan)Akihiro Matsukawa (Okayama University, Japan)

9:00-9:30 Activation of spinal microglia causing neuropathic pain

Kazuhide Inoue (Kyushu University, Japan)

9:30-10:00 Hematopoiesis and programmed cell removal

- Self-Recognition system mediated through CD47-SIRPA interaction -

Katsuto Takenaka (Kyushu University, Japan)

10:00-10:30 Perivascular leukocyte cluster formation via perivascular macrophages is required for

optimal elicitation of contact hypersensitivity

Kenji Kabashima (Kyoto University, Japan)

10:30-10:45 Coffee Break

10:45-11:15 Intravital imaging analysis of different macrophages, bone-destroying osteoclasts and

inflammatory macrophages in obese adipose tissues

Masaru Ishii (Osaka University, Japan)

11:15-11:45 Studying monocytes and Kupffer cells in infection and sterile injury

Paul Kubes (University of Calgary, Canada)

Lunch Time Special Lecture 2 (12:00-13:00)

Chairperson: Kazuyoshi Takeda (Juntendo University, Japan)

12:00-13:00 Immune modulation by the gut microbiota

Kenya Honda (RIKEN IMS, Japan)

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10 The 22nd International Symposium on Molecular Cell Biology of Macrophages 2014(June 2-3, 2014, Kobe)

Session 4: Tumor Microenvironment (13:30-16:15)

Chairpersons: Naofumi Mukaida (Kanazawa University, Japan)Norimitsu Kadowaki (Kyoto University, Japan)

13:30-14:00 Chronic inflammatory responses in gastrointestinal cancer development

Masanobu Oshima (Kanazawa University, Japan)

14:00-14:30 Distinct macrophage subsets in the tumor microenvironment and in non-cancerous

tissues

Jo A. Van Ginderachter (VIB-Vrije Universiteit Brussels, Belgium)

14:30-15:00 Significance of macrophage infiltration in human malignancies

Motohiro Takeya (Kumamoto University, Japan)

15:00-15:15 Coffee Break

15:15-15:45 Gut microbiota control responses of innate immune cells to anti-cancer therapies

Noriho Iida (Kanazawa University, Japan)

15:45-16:15 Development of a novel type of cancer vaccine linking innate and adaptive immunity

Shin-ichiro Fujii (RIKEN IMS, Japan)

16:15- Award Ceremony

Closing: Kouji Matsushima (The University of Tokyo, Japan)

Page 13: MMCB 2014 - secand.jp

Session 1: Development and Functions

Chairpersons: Kenjiro Matsuno (Dokkyo Medical University, Japan)

Katsuaki Sato (Miyazaki University, Japan)

Speakers: Daigo Hashimoto (Hokkaido University, Japan)

Florent Ginhoux (Singapore Immunology Network, Singapore)

Nobuyuki Onai (Tokyo Medical and Dental University, Japan)

Alexander Mildner (Weizmann Institute of Science, Israel)

Michael Sieweke (Centre d'Immunologie de Marseille-Luminy, France)

Page 14: MMCB 2014 - secand.jp

18 The 22nd International Symposium on Molecular Cell Biology of Macrophages 2014(June 2-3, 2014, Kobe)

Tissue resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes

Daigo HashimotoDepartment of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Recently, accumulating evidences suggest local self-maintenance of tissue macro-phages in the steady state. Using hematopoietic stem cell fate mapping system, we found that tissue resident macrophages in the lung, spleen, peritoneal lavage, brain, and bone marrow differentiated, at least, partially independently of bone marrow he-matopoietic stem cells. Next we examined if these tissue resident macrophages self-maintain locally independently of circulating monocytes. In parabiosis experiments, B6-Ccr2-/- mouse and B6-CD45.1+ mouse were sutured side by side to form a shared circulatory system. Although 75~90% of circulating monocytes in the Ccr2-/- parabiont derived from the WT parabiont, tissue resident macrophages remained of host origin for more than a year. Similarly, we found that after depletion of macrophages, the majority of repopulation occurs by enhanced local proliferation. This repopulation from a non-circulating population was observed after cytoablation and infection-in-duced cell death of local macrophages. We also found that after bone marrow trans-plantation, host tissue macrophages retain the capacity to expand without any contri-bution from donor circulating cells. The rate of host macrophage-expansion was slow, but these cells were functional and prevented the development of alveolar proteinosis in mice transplanted with Csf-2 receptor-deficient bone marrow cells. Collectively, these results indicate that tissue resident macrophages and circulating monocytes should be classified as independent mononuclear phagocyte lineages. Next, we focused on macrophages in the gut. Unlike other tissue resident mac-rophages, gut macrophages are quickly replaced by circulating precursors in parabi-otic mice. Interestingly, these macrophages produce IL-1β in the response to MyD88-dependent sensing of gut microflora. IL-1β from macrophages stimulates CSF-2 production from innate lymphoid cells. CSF-2 from innate lymphoid cells, in turn, stimulates gut dendritic cells and macrophages to produce IL-10 and retinoic acid, maintaining the regulatory T cells in the gut. In conclusion, tissue resident macrophages self maintained locally independently of circulating precursors with the exception of gut macrophages. Tissue resident mac-rophages play critical roles in the maintenance of tissue homeostasis. In particular, the reciprocal interaction between gut macrophages and innate lymphoid cells is critical to maintain regulatory T cells in the gut and induce oral tolerance.

S1-1

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103The 22nd International Symposium on Molecular Cell Biology of Macrophages 2014(June 2-3, 2014, Kobe)

MafB promotes atherosclerosis by inhibiting foam-cell apoptosis

Michito Hamada1), Megumi Nakamura1), Mai Thi Nhu Tran1), Satoko Arai2), Takashi Kudo1), Hitoshi Shimano3), Toru Miyazaki2), Peter Tontonoz4) and Satoru Takahashi1)

1) Anatomy and Embryology, Faculty of Medicine, University of Tsukuba2) Division of Molecular Biomedicine for Pathogenesis, Faculty of Medicine, University of Tokyo

3) Department of Internal Medicine (Endocrinology and Metabolism), University of Tsukuba4) Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California

MafB is a transcription factor that induces myelomonocytic differentiation. However, the precise role of MafB in the pathogenic function of macrophages has never been clarified. Here we demonstrate that MafB promotes hyperlipidemic atherosclerosis by suppressing foam-cell apoptosis. Our data show that MafB is predominantly expressed in foam cells found within atherosclerotic lesions, where MafB mediates the oxidized LDL-activated LXR/RXR-induced expression of apoptosis inhibitor of macrophages (AIM). In the absence of MafB, activated LXR/RXR fails to induce the expression of AIM, a protein that is normally responsible for protecting macro-phages from apoptosis; thus, Mafb-deficient macrophages are prone to apoptosis. Haematopoietic reconstitution with Mafb-deficient fetal liver cells in recipient LDL receptor-deficient hyperlipidemic mice revealed accelerated foam-cell apoptosis, which subsequently led to the attenuation of the early atherogenic lesion. These findings represent the first evidence that the macrophage-affiliated MafB transcrip-tion factor participates in the acceleration of atherogenesis.

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104 The 22nd International Symposium on Molecular Cell Biology of Macrophages 2014(June 2-3, 2014, Kobe)

Lysosomal oligopeptide transporter SLC15A4 is critical for TLR7/9-mediated infl ammatory responses

Toshihiko Kobayashi1), Tadashi Okamura2) and Noriko Toyama-Sorimachi1)

1) Department of Molecular Immunology and Infl ammation, Research Institute, National Center for Global Health and Medicine

2) Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine

The endolysosome plays pivotal roles as signaling platforms in ligand recognition and the subsequent signaling of TLR7, or TLR9. However, the precise molecular mechanism by which signaling events at the endosomal/lysosomal compartments are regulated in the course of inflammatory responses is not fully understood. Solute Carrier family (SLC) 15A4 is a lysosomal resident proton-coupled oli-gopeptide transporter highly expressed in plamacytoid dendritic cells, macrophages and B cells, and carries histidine and oligopeptides from inside the lysosome to the cytosol. We have previously reported that SLC15A4 is necessary for TLR7- and TLR9-dependent cytokine productions and responsible for Tri-DAP transfer to the cytosolic NOD1. Importantly, SLC15A4 is involved in the pathogenesis of diseases of colitis, viral infection, and lupus-like autoimmunity. How SLC15A4 contributes to diseases or molecular bases of SLC15A4-dependent TLR7/9 signaling is however largely unknown. We investigated SLC15A4's function at the lysosomes using SLC15A4 deficient mice. SLC15A4 deficiency cased a change of amino acid components in the lys-osome-rich vesicular fraction. In addition, SLC15A4-/- dendritic cells showed disturbance of lysosomal pH regulation upon TLR7 stimulation. These results suggest that SLC15A4-dependent movement of amino acids/protons is crucial for regulating lysosomal functions. To investigate whether the transporter activity of SLC15A4 is actually required for TLR7/9 functions, we established a SLC15A4 mutant lacking the transporter activity, and showed that the transporter activity is required for TLR7/9-dependent cytokine productions including IFNβ, IL-12, IL-6 and TNFα. Furthermore, we found that SLC15A4's function is also important for signaling downstream of IFNAR which is essential for the establishment of the IFN-I-IRF7 circuit. Our finding suggested that SLC15A4 plays a crucial role for conditioning the endolysosomal environments to efficiently transmit TLRs- or IFNAR-triggered signals at the lysosomes.

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105The 22nd International Symposium on Molecular Cell Biology of Macrophages 2014(June 2-3, 2014, Kobe)

A crucial role for chemokine receptor-interacting molecule, FROUNT, in macrophage migration and tumor metastasis

Yuya Terashima, Etsuko Toda and Kouji MatsushimaDepartment of Molecular Preventive Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.Japan Science and Technology Agency, Project for Development of Innovative Research on Cancer Therapeutics (P-Direct), Tokyo, Japan.

Chemokine receptors CCR2 and CCR5-mediated migration of monocytes/macro-phages into the tumor site enhances tumor growth and metastasis. However, the intracellular signaling mechanisms of monocytes/macrophages migration remain largely unexplored. We identified an intracellular modulator, named FROUNT, which interacts with chemokine receptor CCR2 (Nature Immunology 2005). FROUNT functions as a protein hub which regulates cell migration signals via CCR2 and another chemokine receptor CCR5 (Journal of Immunology 2009 & Biochemical Journal 2014). To assess the role of FROUNT in the tumor microenvironment, we generated FROUNT conditional knockout mouse (FROUNT-cKO). FROUNT deficient monocytes/macrophages poorly migrated in vitro. FROUNT deficiency impaired the formation of metastatic foci in experimental metastasis models. Although the number of major leukocyte subsets was not altered in control and FROUNT-cKO, the number of macrophages accumulated in the metastatic foci was decreased in FROUNT-cKO. These results indicate the potent role of FROUNT in macrophage migration and tumor metastasis.

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MMCB2014

Secretariat: MMCB2014 Offi ce Toshiyuki Tanaka, Ph.D. (Conference Chairperson) Laboratory of Immunobiology

School of Pharmacy, Hyogo University of Health Sciences 1-3-6, Minato-jima, Chuo-ku, Kobe 650-8530, Japan

Phone: +81-78-304-3065, Fax: +81-78-304-2765E-mail: [email protected]

Printer: SECAND., 4-39-11 Suizenji, Chuo-ku, Kumamoto 862-0950, Japan

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pg

SECRETARIAT

MMCB2014 Office

Toshiyuki Tanaka, Ph.D.(Conference Chairperson)

Laboratory of Immunobiology

School of Pharmacy,

Hyogo University of Health Sciences

1-3-6, Minato-jima, Chuo-ku, Kobe 650-8530, Japan

Phone:+81-78-304-3065, Fax:+81-78-304-2765

E-mail: [email protected]

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