論文 - 松崎　吾朗

TAK1-binding protein 2 (TAB2) and TAB3 are redundantly required for TLR-induced cytokine production in macrophages

Ali, T; Nguyen, HM; Abbas, N; Takeuchi, O; Akira, S; Suzuki, T; Matsuzaki, G; Takaesu, G (担当範囲: 研究の企画、実験手技の指導。)

INTERNATIONAL IMMUNOLOGY     2024年04月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

　概要を見る

TGF-β-activated kinase 1 (TAK1) plays a pivotal role in innate and adaptive immunity. TAK1 is essential for activating MAPK and NF-κB pathways downstream of the diverse immune receptors, including TLRs, cytokine receptors, TCR, and BCR. Upon stimulation, TAK1 is recruited to the lysine 63-linked poly-ubiquitin chain via TAK1-binding proteins (TAB)2 and TAB3. However, the physiological roles of TAB2 and TAB3 in the macrophages remain unclear. Ori et al. reported minor effects of TAB2/TAB3 double deficiency on TLR signaling in bone marrow-derived macrophages (BMDMs). However, the TAB2 conditional knockout (KO) mice used in their experimental system showed the residual TAB2 expression in BMDMs. In this study, we examined the roles of TAB2 and TAB3 in an improved KO mouse model. We observed a significant impairment in pro-inflammatory cytokine production in TAB2/TAB3 double KO (DKO) BMDMs but not in single KO BMDMs of either TAB2 or TAB3. Notably, upon TLR stimulation, IL-6 production was inhibited, whereas TNF-α production was partially reduced in the DKO BMDMs. Notably, TAB2 and TAB3 were nonessential in the TLR-induced TAK1 activation and exerted negligible effects on MAPK and NF-κB pathways. We observed that the TLR-mediated expression of IκBζ protein was severely compromised in the DKO BMDMs, which hindered IL-6 production. In contrast, the induction and the stability of IκBζ mRNA were comparable between the wild-type and DKO BMDMs. These results suggest that TAB2 and TAB3 play redundant and essential roles in regulating certain genes through TAK1-independent mechanisms in the TLR signaling pathway that are not yet known.

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GRIM-19 is a target of mycobacterial Zn2+ metalloprotease 1 and indispensable for NLRP3 inflammasome activation.

Kurane T, Matsunaga T, Ida T, Sawada K, Nishimura A, , Fukui M, Umemura1 M, Nakayama M, Ohara N, Matsumoto S, Akaike T, Matsuzaki G, Takaesu G

FASEB Journal ( Wiley )  36 ( 1 ) e22096   2022年10月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

関連する研究費コード: 20H03487

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Heat-killed Lactobacillus plantarum L-137 attenuates obesity and associated metabolic abnormalities in C57BL/6 J mice on a high-fat diet.

Yoshitake R, Hirose Y, Murosaki S, Matsuzaki G.

Bioscience of Microbiota, Food and Health   40 ( 2 ) 84 - 91   2021年04月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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TREM2 is a receptor for non-glycosylated mycolic acids of mycobacteria that limits anti-mycobacterial macrophage activation.

Iizasa E, Chuma Y, Uematsu T, Kubota M, Kawaguchi H, Umemura M, Toyonaga K, Kiyohara H, Yano I, Colonna M, Sugita M, Matsuzaki G, Yamasaki S, Yoshida H, Hara H.

Nature Communications ( Nature Communications )  12 ( 1 ) 2299 - 2299   2021年04月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Mycobacterial cell-wall glycolipids elicit an anti-mycobacterial immune response via FcRγ-associated C-type lectin receptors, including Mincle, and caspase-recruitment domain family member 9 (CARD9). Additionally, mycobacteria harbor immuno-evasive cell-wall lipids associated with virulence and latency; however, a mechanism of action is unclear. Here, we show that the DAP12-associated triggering receptor expressed on myeloid cells 2 (TREM2) recognizes mycobacterial cell-wall mycolic acid (MA)-containing lipids and suggest a mechanism by which mycobacteria control host immunity via TREM2. Macrophages respond to glycosylated MA-containing lipids in a Mincle/FcRγ/CARD9-dependent manner to produce inflammatory cytokines and recruit inducible nitric oxide synthase (iNOS)-positive mycobactericidal macrophages. Conversely, macrophages respond to non-glycosylated MAs in a TREM2/DAP12-dependent but CARD9-independent manner to recruit iNOS-negative mycobacterium-permissive macrophages. Furthermore, TREM2 deletion enhances Mincle-induced macrophage activation in vitro and inflammation in vivo and accelerates the elimination of mycobacterial infection, suggesting that TREM2-DAP12 signaling counteracts Mincle-FcRγ-CARD9-mediated anti-mycobacterial immunity. Mycobacteria, therefore, harness TREM2 for immune evasion.

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Mycobacterium bovis BCG-mediated suppression of Th17 response in mouse experimental autoimmune encephalomyelitis.

Matsuzaki G, Teruya N, Kiyohara Kohama H, Arai K, Shibuya Y, Chuma Y, Matsuo K.

Immunopharmacology and Immunotoxicology ( Informa UK Limited )  42 ( 2 ) 203 - 211   2021年 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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INTRODUCTION: Multiple sclerosis (MS) is an autoimmune disease mediated by a pro-inflammatory immune response. Experimental autoimmune encephalomyelitis (EAE) induced by immunization of mice with a myelin oligodendrocyte glycoprotein (MOG) peptide emulsified in killed Mycobacterium tuberculosis-containing complete Freund's adjuvant (CFA-EAE) is used as a model of MS. Mycobacterium bovis BCG has been reported to ameliorate clinical symptoms of CFA-EAE, although the precise mechanism has not yet been documented. Since CFA-EAE uses adjuvant with mycobacterial antigens, mycobacterial antigen-specific T cells induced by CFA may cross-react with BCG and modulate EAE. METHODS: To exclude the influence of cross-reactivity, a modified murine EAE model (cell wall skeleton (CWS)-EAE) that does not induce mycobacterial antigen-specific T cells was established and used to reevaluate the therapeutic effects of BCG on EAE. RESULTS: Inoculation with BCG 6 d after CWS-EAE induction successfully ameliorated EAE symptoms, suggesting that the therapeutic effects of BCG are independent of the mycobacterial antigen-specific T cells induced by the CFA-EAE protocol. BCG inoculation into the CWS-EAE mice resulted in reduced levels of MOG-specific Th17 in the central nervous system (CNS) with reduced demyelinated lesions of the spinal cord. In the draining lymph nodes of the MOG-immunized sites, BCG inoculation resulted in an increase in MOG-specific Th17 and Th1 cells at an early stage of immune response. CONCLUSION: The results suggest that BCG inoculation suppresses the Th17 response in the CNS of EAE mice via a mechanism that may involve the suppression of egress of encephalitogenic T cells from lymphoid organs.

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miR-935 inhibits oral squamous cell carcinoma and targets inositol polyphosphate-4-phophatase type IA (INPP4A).

Maruyama N, Umikawa M, Matsumoto H, Maruyma T, Nishihara K, Nakasone T, Matayoshi A, Goto T, Hirano F, Arasaki A, Nakamura H, Matsuzaki G, Takaesu G.

Anticancer Research ( Anticancer Research )  40 ( 11 ) 6101 - 6113   2020年 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Dispensable role of chemokine receptors in migration of mycobacterial antigen-specific CD4⁺ T cells into Mycobacterium-infected lung.

Matsuzaki G, Yamasaki M, Tamura T, Umemura M

Immunobiology ( Immunobiology )  224 ( 3 ) 440 - 448   2019年05月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Interleukin-17 family cytokines in protective immunity against infections: role of hematopoietic cell-derived and non-hematopoietic cell-derived interleukin-17s.

Matsuzaki G, Umemura M

Microbiology and immunology ( Microbiology and Immunology )  62 ( 1 ) 1 - 13   2018年01月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Two distinct ITAM-coupled receptors recognize mycobacterial mycolic acid-containing lipids and differently regulate immune responses

Ei'ichi Iizasa, Takayuki Uematsu, Yasushi Chuma, Hideyasu Kiyohara, Mio Kutobta, Masayuki Umemura, Goro Matsuzaki, Sho Yamasaki, Hiromitsu Hara

CYTOKINE ( ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD )  100   26 - 27   2017年12月 [ 査読有り ]

掲載種別: 研究論文（その他学術会議資料等）

Involvement of IL-17A-producing TCR y delta T cells in late protective immunity against pulmonary Mycobacterium tuberculosis infection

Masayuki Umemura, Yuko Okamoto-Yoshida, Ayano Yahagi, Susumu Nakae, Yoichiro Iwakura, Giichi Takaesu, Goro Matsuzaki

JOURNAL OF IMMUNOLOGY ( AMER ASSOC IMMUNOLOGISTS )  198 ( 1 )   2017年05月 [ 査読有り ]

掲載種別: 研究論文（その他学術会議資料等）

C-Type Lectin Receptor DCAR Recognizes Mycobacterial Phosphatidyl-Inositol Mannosides to Promote a Th1 Response during Infection.

Toyonaga K, Torigoe S, Motomura Y, Kamichi T, Hayashi JM, Morita YS, Noguchi N, Chuma Y, Kiyohara H, Matsuo K, Tanaka H, Nakagawa Y, Sakuma T, Ohmuraya M, Yamamoto T, Umemura M, Matsuzaki G, Yoshikai Y, Yano I, Miyamoto T, Yamasaki S

Immunity ( Immunity )  45 ( 6 ) 1245 - 1257   2016年12月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Involvement of IL-17A-producing TCR γδ T cells in late protective immunity against pulmonary <i>Mycobacterium tuberculosis</i> infection.

Umemura M, Okamoto-Yoshida Y, Yahagi A, Touyama S, Nakae S, Iwakura Y, Matsuzaki G

Immunity, inflammation and disease ( Immunity Inflammation and Disease )  4 ( 4 ) 401 - 412   2016年12月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Recombinant Mycobacterium bovis bacillus Calmette-Guérin expressing Ag85B-IL-7 fusion protein enhances IL-17A-producing innate γδ T cells.

Hatano S, Tamura T, Umemura M, Matsuzaki G, Ohara N, Yoshikai Y

Vaccine ( Vaccine )  34 ( 22 ) 2490 - 5   2016年05月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Interleukin-22-Induced Antimicrobial Phospholipase A2 Group IIA Mediates Protective Innate Immunity of Nonhematopoietic Cells against Listeria monocytogenes.

Okita Y, Shiono T, Yahagi A, Hamada S, Umemura M, Matsuzaki G

Infection and immunity ( Infection and Immunity )  84 ( 2 ) 573 - 9   2016年02月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Regulation of innate immune response to mycobacteria through DAP12 versus FcR gamma-coupled myeloid receptors that recognize different mycolic acid-containing lipids

Iizasa E, Uematsu T, Kubota M, Kiyohara H, Chuma Y, Matsuzaki G, Yamasaki S, Yoshida H

European Journal of Immunology   46   1085 - 1086   2016年 [ 査読有り ]

掲載種別: 研究論文（その他学術会議資料等）

Enhanced effect of BCG vaccine against pulmonary Mycobacterium tuberculosis infection in mice with lung Th17 response to mycobacterial heparin-binding hemagglutinin adhesin antigen.

Fukui M, Shinjo K, Umemura M, Shigeno S, Harakuni T, Arakawa T, Matsuzaki G

Microbiology and immunology ( Microbiology and Immunology )  59 ( 12 ) 735 - 43   2015年12月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Angiopoietin-like protein 2 induces proinflammatory responses in peritoneal cells.

Umikawa M, Umikawa A, Asato T, Takei K, Matsuzaki G, Kariya K, Zhang CC

Biochemical and biophysical research communications ( Biochemical and Biophysical Research Communications )  467 ( 2 ) 235 - 41   2015年11月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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IL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2(+)Vγ6(+)γδ T cells.

Akitsu A, Ishigame H, Kakuta S, Chung SH, Ikeda S, Shimizu K, Kubo S, Liu Y, Umemura M, Matsuzaki G, Yoshikai Y, Saijo S, Iwakura Y

Nature communications ( Nature Communications )  6   7464   2015年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Intravenous Mycobacterium Bovis Bacillus Calmette-Guérin Ameliorates Nonalcoholic Fatty Liver Disease in Obese, Diabetic ob/ob Mice.

Inafuku M, Matsuzaki G, Oku H

PloS one ( PLoS ONE )  10 ( 6 ) e0128676   2015年 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Enhancement of leptin receptor signaling by SOCS3 deficiency induces development of gastric tumors in mice.

Inagaki-Ohara K, Mayuzumi H, Kato S, Minokoshi Y, Otsubo T, Kawamura YI, Dohi T, Matsuzaki G, Yoshimura A

Oncogene ( Oncogene )  33 ( 1 ) 74 - 84   2014年01月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Leptin acts on its receptor (ObR) in the hypothalamus to inhibit food intake and energy expenditure. Leptin and ObR are also expressed in the gastrointestinal tract; however, the physiological significance of leptin signaling in the gut remains uncertain. Suppressor of cytokine signaling 3 (SOCS3) is a key negative feedback regulator of ObR-mediated signaling in the hypothalamus. We now show that gastrointestinal epithelial cell-specific SOCS3 conditional knockout (T3b-SOCS3 cKO) mice developed gastric tumors by enhancing leptin production and the ObRb/signal transducer and activator of transcription 3 (STAT3) signaling pathway. All T3b-SOCS3 cKO mice developed tumors in the stomach but not in the bowels by 2 months of age, even though the SOCS3 deletion occurred in both the epithelium of stomach and bowels. The tumors developed in the absence of the inflammatory response and all cKO mice died within 6 months. These tumors displayed pathology and molecular alterations, such as an increase in MUC2 (Mucin 2, oligomeric mucus/gel-forming) and TFF3 (trefoil factor 3), resembling human intestinal-type gastric tumors. Administration of antileptin antibody to T3b-SOCS3 cKO mice reduced hyperplasia of gastric mucosa, which is the step of the initiation of gastric tumor. These data suggest that SOCS3 is an antigastric tumor gene that suppresses leptin overexpression and ObRb/STAT3 hyperactivation, supporting the hypothesis that the leptin/ObRb/STAT3 axis accelerates tumorigenesis and that it may represent a new therapeutic target for the treatment of gastric cancer.

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