Innate immunity and non-alcoholic steatohepatitis. A study for developing new immunologic therapy.

先天免疫和非酒精性脂肪性肝炎。

• 批准号: 22590714
• 负责人: MIURA Koichi
• 金额: $ 2.83万
• 依托单位: Akita University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22590714/
• 关键词: 肝臓学; 非アルコール性脂肪性肝炎; Toll-like receptor; 炎症性サイトカイン; ケモカイン

Nonalcoholic steatohepatitis (NASH) is a hepatic manifestation of metabolic syndrome. Currently, no effective treatment for NASH is available due to its complex mechanism. We hypothesized that altered immune response by TLR ligands causes excess lipid accumulation and inflammation in the liver. Thus, we used gene-modified mice including TLR2 KO, TLR4 KO, and TLR9 KO mice to determine the role of TLRs in CDAA-induced NASH. We also examined mice deficiency in CCR2, a chemokine receptor for MCP-1. Compared to WT mice, TLR2 KO, TLR4 KO, and TLR9 KO mice showed less steatosis, inflammation and fibrosis. Several pro-inflammatory cytokines including IL-1. were decreased in these gene-modified mice. IL-1R KO mice demonstrated lesser grades of NASH. Infiltration of inflammatory cells including macrophages was attenuated in these KO mice. A part of infiltrated macrophages were derived from bone marrow and showed inflammatory phenotype. CCR2 KO mice showed less inflammation and fibrosis. By preventing macrophage recruitment using CCR2 inhibitor, NASH was ameliorated. These results demonstrate that TLR ligands and its target macrophages play key roles in the development of NASH. Pro-inflammatory cytokines released from macrophages contribute to inflammation and promote to the progression of NASH. We will extend these experiments to develop novel immunologic therapy for NASH. To date, seven papers on NASH were accepted to scientific journals.

非酒精性脂肪性肝炎（NASH）是代谢综合征的一种肝脏表现。目前，由于NASH的复杂机制，没有有效的治疗方法。我们假设TLR配体改变的免疫应答导致肝脏中过量的脂质积累和炎症。因此，我们使用基因修饰的小鼠，包括TLR 2 KO、TLR 4 KO和TLR 9 KO小鼠，以确定TLR在CDAA诱导的NASH中的作用。我们还检查了小鼠CCR 2（MCP-1的趋化因子受体）的缺陷。与WT小鼠相比，TLR 2 KO、TLR 4 KO和TLR 9 KO小鼠显示较少的脂肪变性、炎症和纤维化。几种促炎细胞因子，包括IL-1。在这些基因修饰的小鼠中减少了。IL-1 R KO小鼠表现出较低级别的NASH。在这些KO小鼠中，炎性细胞（包括巨噬细胞）的浸润减弱。部分浸润的巨噬细胞来源于骨髓，呈炎性表型。CCR 2 KO小鼠表现出较少的炎症和纤维化。通过使用CCR 2抑制剂防止巨噬细胞募集，NASH得到改善。这些结果表明TLR配体及其靶巨噬细胞在NASH的发展中起关键作用。从巨噬细胞释放的促炎细胞因子有助于炎症并促进NASH的进展。我们将扩展这些实验以开发NASH的新免疫疗法。迄今为止，有7篇关于NASH的论文被科学期刊接受。

项目成果

Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2

• DOI: 10.1152/ajpgi.00365.2011
• 发表时间: 2012-06-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
• 影响因子: 4.5
• 作者: Miura, Kouichi;Yang, Ling;Seki, Ekihiro
• 通讯作者: Seki, Ekihiro

NASH発症および進展における腸内細菌叢と肝自然免疫の役割

肠道微生物群和肝脏先天免疫在 NASH 发病和进展中的作用

• 发表时间: 2011
• 期刊: 消化器内科
• 作者: Tada M;Kanai F;Tanaka Y;Sanada M;Nannya Y;Tateishi K;Ohta M;Asaoka Y;Seto M;Imazeki F;Yoshida H;Ogawa S;Yokosuka O;Omata M;三浦光一
• 通讯作者: 三浦光一

マクロファージをターゲットにした肝線維化抑制の試み .NASHモデルでの検討-

尝试通过针对 NASH 模型的巨噬细胞研究来抑制肝纤维化。

• 发表时间: 2012
• 作者: 三浦光一;大西洋英
• 通讯作者: 大西洋英

MCP-1 and CCR2 contribute to the development of NASH in mice

MCP-1 和 CCR2 有助于小鼠 NASH 的发展

• 发表时间: 2010
• 作者: Miura K;Seki E;Brenner DA;Ohnishi H
• 通讯作者: Ohnishi H

NASHにおけるマクロファージのリクルートとTLR-MCP1-CCR2の役割

巨噬细胞募集和 TLR-MCP1-CCR2 在 NASH 中的作用

• 发表时间: 2012
• 作者: Kawai H;Nomoto M;Suda T;Kamimura K;Tsuchiya A;Tamura Y;Yano M;Takamura M;Igarashi M;Wakai T;Yamagiwa S;Matsuda Y;Ohkoshi S;(4)Kurosaki I;Shirai Y;Okada M;Aoyagi Y;三浦光一
• 通讯作者: 三浦光一