琉球大学 · 医学部 · 教授

研究キーワードmycobacterial immunity・macrophage activation・TLR signaling・NLRP3 inflammasome・TREM2 receptors・innate immune regulation

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• TAK1-binding protein 2 (TAB2) and TAB3 are redundantly required for TLR-induced cytokine production in macrophages2024 · 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.
• TREM2 is a receptor for non-glycosylated mycolic acids of mycobacteria that limits anti-mycobacterial macrophage activation.2021 · 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.
• Mycobacterium bovis BCG-mediated suppression of Th17 response in mouse experimental autoimmune encephalomyelitis.2021 · 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.
• Heat-killed Lactobacillus plantarum L-137 attenuates obesity and associated metabolic abnormalities in C57BL/6 J mice on a high-fat diet.2021 · Yoshitake R, Hirose Y, Murosaki S, Matsuzaki G.

• 結核菌感染における3型免疫応答の機能解析ならびにブーストワクチンへの応用2021 · 基盤研究(C)
• 結核菌によるミトコンドリア障害と免疫抑制の分子基盤と治療への応用2020 · 本研究では、Mycobacterium tuberculosis（結核菌）の産生するinterleukin (IL)-1β産生を抑制する病原因子、Zinc metalloprotease-1 (Zmp1)の病原性の分子機構解明を目指している。申請者らは、Zmp1がミトコンドリアの電子伝達系複合体Iの構成分子であるNdufa13に結合することを見出しており、この所見を手掛かりとして、Zmp1のミトコンドリアに対する影響を検討した。その結果、①M. tuberculosis var. BCGのZmp1欠損株（⊿Zmp1 BCG）をマクロファージに感染させると、野生株では抑制されていたNLRP3依存性IL-1β産生が回復した。②⊿Zmp1 BCGをFlag標識Zmp1で相補したZmp1-Flag BCGをマクロファージに感染させると、ミトコンドリア内に抗Flag抗体で染色されるZmp1が検出された。③CRISPR-Cas9システムで作成したNdufa13欠損マウスマクロファージ細胞株J774（⊿Ndufa13 J774）に⊿Zmp1 BCG、ATP+LPSなどのNLRP3インフラマソーム活性化刺激を与えると、IL-1β産生が消失していた。④前記のIL-1β産生消失がNLRP3インフラマソーム活性化の抑制によるものであることが生化学的に示された。⑤⊿Ndufa13 J774あるいはZmp1遺伝子発現プラスミド導入細胞では、ミトコンドリア膜電位の低下が認められ、これがNLRP3インフラマソーム活性化の阻害を引き起こすと考えられた。 以上の結果から、Zmp1のIL-1β産生抑制機構は、ミトコンドリア複合体Iの構成分子Ndufa13への結合とミトコンドリアの膜電位形成阻害に関連すると考えられた。

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