ノッチ・シグナリング・ドライブは,シノヴィアル・フィブロブラストのアイデンティティと関節炎の病理学

Kevin Wei¹, Ilya Korsunsky^1,2,3,4,5, Jennifer L Marshall⁶

¹Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Nature

|June 6, 2020

まとめ

NOTCH3のシグナル伝達は,関節リウマチにおける線維細胞の膨張,炎症および関節損傷を促す上で極めて重要です. この経路を遮断するとマウスモデルでの関節炎の重症度が低下します

科学分野:

免疫学
細胞生物学
リウマトロジ

背景:

リウマチ性関節炎は筋膜組織が膨張し,炎症を起こし,関節を破壊します.
リウマチ性関節炎では,サブラインする線維細胞のサブセットが拡張し,疾患活動に関連しています.
リウマチ性関節炎におけるフィブロブラストの分化と膨張を駆動する分子メカニズムは不明である.

研究の目的:

NOTCH3のシグナル伝達がシノビア線維細胞の分化と膨張における役割を調査する.
リウマチ性関節炎における線維細胞の行動の基礎となる分子メカニズムを解明する.
炎症性関節炎の潜在的治療標的としてNOTCH3シグナリングを調査する.

主な方法:

単細胞RNAシーケンシング
シノビア組織オルガノイドモデル
ネズミにおけるNotch3の遺伝的削除
マウスにおけるNOTCH3信号の遮断

主要な成果:

NOTCH3のシグナル伝達は,周縁線維芽細胞と亜線維芽細胞 (CD90+) の分化に不可欠である.
NOTCH3シグナリングは,血管内皮細胞から発生する線維芽細胞の転写および空間的グラデーションを確立します.
NOTCH3とその標的遺伝子は,活発なリウマチ性関節炎の間,シノヴィアル線維質で上位調節されます.
ネズミにおけるNOTCH3シグナル伝達の遺伝的消去またはブロックは,炎症性関節炎で炎症を緩和し,関節損傷を予防します.

結論:

シノビア線維質は,内皮由来NOTCH3信号によって調節される位置的アイデンティティを持っています.
NOTCH3シグナル伝達を含むこのストロマの交響経路は,炎症性関節炎の炎症と病理に寄与する.
NOTCH3シグナリングをターゲットにすることで,関節リウマチやその他の炎症性関節疾患の治療戦略を提供することができる.

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