The mechanism of innate inflammation in response to cell death and it's contribution to the pathogenesis of rheumatoid arthritis

细胞死亡的先天性炎症机制及其在类风湿性关节炎发病机制中的作用

• 批准号: 23591468
• 负责人: KONO Hajime
• 金额: $ 3.41万
• 依托单位: Teikyo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23591468/
• 关键词: 自然炎症; IL-1; Cathepsin C; Caspase 1; 細胞死; インフラマソーム; 結晶; 自然免疫; 炎症

Cell death, especially necrotic cell death, induces acute inflammation. It is supposed that this acute responses underlie many pathological conditions including autoimmune diseases, but the molecular mechanisms of the danger signals to evoke inflammation or the key pathways responsible for neutrophil recruitment are not well studied.We investigated the molecular mechanisms responsible for inducing inflammatory responses to necrotic cells in vivo. In our system the inflammation to cell death depends on IL-1. IL-1 is transcribed as an immature protein and requires cleavage by Caspase-1. Here we identified a novel molecular pathway to cell death-induced inflammation that is dependent on IL-1, but not on Caspase-1. IN addition, we identified Cathepsin C as one of the key molecules involved in this Caspase-1 independent pathway in vivo. Cathepsin C is known to maturate neutrophil serene proteases including proteinase 3 that was shown to have ability to maturate IL-1 in vitro.

细胞死亡，尤其是坏死性细胞死亡，可引起急性炎症。这种急性反应被认为是包括自身免疫性疾病在内的许多病理情况的基础，但引发炎症的危险信号的分子机制或导致中性粒细胞募集的关键途径尚未得到很好的研究。我们研究了在体内诱导对坏死细胞的炎症反应的分子机制。在我们的系统中，细胞死亡的炎症依赖于IL-1。IL-1转录为一种不成熟的蛋白质，需要被Caspase-1切割。在这里，我们确定了一条新的细胞死亡诱导炎症的分子途径，它依赖于IL-1，而不依赖于Caspase-1。此外，我们在体内还发现组织蛋白酶C是参与Caspase-1非依赖途径的关键分子之一。已知组织蛋白酶C可以成熟中性粒细胞丝氨酸蛋白水解酶，包括在体外被证明具有成熟IL-1能力的蛋白酶3。

项目成果

動脈硬化と自然免疫

动脉硬化与先天免疫

• 发表时间: 2012
• 期刊: Annual Reviews循環器2012
• 作者: Ota M;Yanagisawa M;Tachibana H;Yokota K;Araki Y;Sato K;Mimura T.;河野肇
• 通讯作者: 河野肇

インフラマソーム非依存性IL-1β活性化による結晶誘発性急性炎症

晶体通过不依赖炎症小体的 IL-1β 激活诱导急性炎症

• 作者: 河野 肇;柳田 たみ子;浅子 来美;高山 真希;菊地 弘敏
• 通讯作者: 菊地 弘敏

In Vivo Evaluation of Neutrophil Recruitment in Response to Sterile Particulates

无菌颗粒反应中性粒细胞募集的体内评估

• DOI: 10.1007/978-1-62703-523-1_16
• 发表时间: 2013
• 期刊: Methods in Molecular Biology (Clifton, N.J.)
• 作者: Tamiko Yanagida;Kaoru Orihashi;Hajime Kono
• 通讯作者: Hajime Kono

BEYOND THE INFLAMMASOME: ROLE OF DIPEPTIDYL PEPTIDASE I (CATEPSIN C) IN THE MATURATION OF IL-1Β IN VIVO

超越炎性体：二肽基肽酶 I（组织蛋白酶 C）在体内 IL-1β 成熟中的作用

• 发表时间: 2011
• 作者: Ota M;Sakamoto M;Sato K;Yoshida Y;Funakubo Asanuma Y;Akiyama Y;Yamakawa M;Mimura T;Hajime Kono
• 通讯作者: Hajime Kono

The IL-1-dependent sterile inflammatory response has a substantial caspase-1-independent component that requires cathepsin C.

• DOI: 10.4049/jimmunol.1200136
• 发表时间: 2012-10-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Kono H;Orlowski GM;Patel Z;Rock KL
• 通讯作者: Rock KL