メタボリックと先天的な免疫信号は,UPRを通じて特定の炎症反応に結合する
Denis A Mogilenko1, Joel T Haas1, Laurent L'homme1
1University of Lille, EGID, INSERM, CHU Lille, Institut Pasteur de Lille, U1011, 59019 Lille, France.
Cell
|April 30, 2019
まとめ
高脂肪酸環境は,代謝を変化させることで,デンドリット細胞のトール型受容体の反応を悪化させる. これはミトコンドリアの活性酸素種と炎症の増加につながり,代謝と先天的な免疫の関係を強調します.
科学分野:
- 免疫学
- メタボリズム
- 細胞生物学
背景:
- 骨髄細胞の先天的な免疫反応は,その細胞内代謝と密接に結びついている.
- トール型受容体 (TLR) の刺激は糖分解を促進し,抗炎症信号はミトコンドリア呼吸を必要とする.
- 外部代謝シグナルが免疫反応に与える影響は,まだほとんど研究されていない.
研究 の 目的:
- 外因的代謝信号,特に脂肪酸が,デンドリット細胞 (DC) のTLR依存性免疫反応にどのように影響するかを調査する.
- 脂肪酸の代謝と免疫細胞の活性化とサイトカインの産生を結びつける分子メカニズムを解明する.
主な方法:
- 高脂肪酸 (FA) の代謝環境を利用して,TLR刺激の dendritic cells (DCs) を研究した.
- 糖分解とトリカルボキシル酸サイクルを含む代謝経路の評価
- ミトコンドリアの反応性酸素種 (mtROS) 生成と展開タンパク質応答 (UPR) を測定した.
- トランスクリプトミックプロファイルとIL-23発現を分析した.
- 代謝経路と主要なタンパク質 (例えば,XBP1) の遺伝的および化学的阻害を使用しています.
- IL - 23依存型牛皮病モデルにおける皮膚炎の評価
主要な成果:
- 高脂肪酸環境は,TLR依存のDC反応を悪化させる.
- 脂肪酸はヘキソキナーゼの活性を抑制し,トリカルボキシル酸サイクル代謝を乱します.
- 代謝の変化はmtROSの生成を高め,UPRを誘発する.
- これは,高いIL-23生産によって特徴づけられるユニークなトランスクリプトミカルシグネチャーにつながります.
- 糖分解の抑制はこれらの効果を模倣した.
- 減少したmtROSまたはXBP1欠乏は,IL-23発現と皮膚炎を弱めた.
結論:
- 生まれつきの免疫の微調整は 代謝要求の最適化に依存しています
- mtROS誘発のUPRを最小限に抑えることは,炎症反応の調節に極めて重要です.
- 脂肪酸の代謝は,特にIL-23を通して,DC機能と炎症の可能性に大きな影響を及ぼします.
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