SQSTM1-dependent autophagic degradation of PKM2 inhibits the production of mature IL1B/IL-1β and contributes to LIPUS-mediated anti-inflammatory effect
SQSTM1-dependent autophagic degradation of PKM2 inhibits the production of mature IL1B/IL-1β and contributes to LIPUS-mediated anti-inflammatory effect
复制标题
SQSTM1依赖性PKM2自噬降解抑制成熟IL1B/IL-1β的产生并有助于LIPUS介导的抗炎作用
DOI：
10.1080/15548627.2019.1664705
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发表时间：
2019-09-24
期刊：
影响因子：
13.3
通讯作者：
Chen, Lin
中科院分区：
文献类型：
--
作者：
Zhang, Bin;Chen, Hangang;Chen, Lin
滑膜炎与骨关节炎（OA）的病理学有关，并显著促进OA的发展。低强度脉冲超声（LIPUS）作为一种非侵入性的物理治疗手段，近年来被报道具有抗炎作用。然而，LIPUS在OA滑膜炎中的作用及其机制尚不清楚。本研究表明，LIPUS改善了内侧半月板（DMM）小鼠模型和气囊模型不稳定的滑膜炎症，并减轻了DMM小鼠的疼痛步态。在体外和体内，LIPUS显著抑制成熟IL 1B/IL-1 β（白细胞介素1 β）的产生。此外，LIPUS上调了巨噬细胞自噬/自噬水平，并加速了脂多糖（LPS）-三磷酸腺苷（ATP）处理的巨噬细胞中SQSTM 1（螯合体1）-PKM（丙酮酸激酶，肌肉）复合物的形成。此外，LIPUS下调LPS-ATP处理的巨噬细胞中PKM 2的水平，这可以被SQSTM 1敲低逆转。简而言之，本研究首次证明LIPUS部分地通过LPS-ATP处理的巨噬细胞中PKM 2的SQSTM 1依赖性自噬降解来抑制成熟IL 1B的产生，这可能进一步改善动物模型中的滑膜炎症和步态模式。我们的数据为使用LIPUS治疗滑膜炎和其他炎性疾病提供了新的线索。
Synovitis is implicated in the pathology of osteoarthritis (OA) and significantly contributes to the development of OA. As a noninvasive physical therapy, low-intensity pulsed ultrasound (LIPUS) has been reported to possess anti-inflammatory effect in recent years. However, the role of LIPUS on synovitis of OA and the underlying mechanisms are little known. The present study showed that LIPUS ameliorated synovial inflammation in destabilization of the medial meniscus (DMM) mouse model and air pouch model, and alleviated pain gait patterns of DMM mouse. LIPUS dramatically inhibited the production of mature IL1B/IL-1 beta (interleukin 1 beta) in vitro and in vivo. In addition, LIPUS upregulated the macroautophagy/autophagy level as well as accelerated the formation of an SQSTM1 (sequestosome1)-PKM (pyruvate kinase, muscle) complex in the lipopolysaccharide (LPS)-adenosine triphosphate (ATP)-treated macrophages. Besides, LIPUS downregulated the level of PKM2 in LPS-ATP-treated macrophages, which could be reversed by SQSTM1 knockdown. In brief, the present study for the first time demonstrates that LIPUS inhibits the production of mature IL1B partially via SQSTM1-dependent autophagic degradation of PKM2 in LPS-ATP-treated macrophages, which may further ameliorate the synovial inflammation and gait patterns in animal models. Our data provide new clues for the treatments of synovitis and other inflammatory diseases using LIPUS.