酸化したリンパ脂は,LNK ((SH2B3) 欠乏症におけるNETosisと動脈血栓形成を促進する
Huijuan Dou1, Andriana Kotini2, Wenli Liu1
1Molecular Medicine, Columbia University Medical Center, New York (H.D., W.L., T.F., K.E.-U., T.X., S.A., M.Y., B.H., N.W., A.R.T.).
Circulation
|November 30, 2021
まとめ
血液形成のLnk欠乏は中性粒子の細胞外トラップ (NET) 形成と動脈血栓形成を促進する. 酸化フォスホリピド (OxPL) を標的とする治療は,特定の遺伝的プロファイルを持つ冠動脈疾患の患者にとって有益である.
科学分野:
- 心血管生物学
- 免疫学
- 血液学
背景:
- LNK/SH2B3タンパク質は,ジャヌスキナーゼ/シグナルトランスデューサーおよびトランスクリプションアクティベーター (JAK/STAT) のシグナリングを調節する.
- 一般的なLNK多形性 (R262W) は中性愛,血栓細胞症,冠動脈疾患と関連しています.
- ネズミのLNK欠乏は血小板中性粒子の集積,加速度性動脈硬化,および血栓形成につながり,中性粒子の細胞外トラップ (NET) の役割を示唆する.
研究 の 目的:
- 血液生成性Lnk欠乏症のマウスの動脈硬化と血栓形成におけるNETの役割を調査する.
- LNK欠乏が酸化リンパ脂 (OxPL) を含むNETosisを促進するメカニズムを探求する.
- 特定の遺伝子変異を持つヒトにおけるこれらの発見の関連性を評価する.
主な方法:
- LnkとPAD4 (NETosisに不可欠な酵素) の併合欠乏した生殖マウス.
- Ldlr-/- マウスへの骨髄移植 動脈血栓症の評価
- 人間の誘発性多能幹細胞由来細胞と英国バイオバンクデータを用いて,ヒトにおける関連性と臨床関連性を確認した.
主要な成果:
- Lnk欠乏したマウスは,PAD4欠乏によって逆転した加速血栓とNETosisを示した.
- Lnk欠乏症の血小板と中性粒子は,酸化フォスホリピド (OxPL) によって媒介される相互作用とNETosisの増加を示した.
- OxPLを標的にする抗体の断片であるE06- scFvは,Lnk欠乏したマウスのNETosis,動脈硬化,および血栓を逆転させた. 人間の研究では,LNK (TT) ゲノタイプによるNETosisの増加が確認され,JAK2VF変異のキャリアにおけるLNK R262Wアレルと冠動脈疾患のリスクの増加が関連付けられました.
結論:
- 血液形成のLnk欠乏症は,OxPLに依存する経路を通じてNETosisと動脈血栓形成を促進する.
- R262W変異によるLNK機能の低下はNETosisを促進し,JAK2VF変異を有する個体では冠動脈疾患のリスクを高めます.
- 特定の遺伝的に定義された集団において,OxPLを標的とした治療は,冠動脈疾患の治療上の利益をもたらす可能性があります.
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