Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Laboratory for the Prevention and Rehabilitation of Military Training Related Injuries, Daping Hospital, Army medical University (Third Military Medical University) , Chongqing, China.
Autophagy. 2020 Jul;16(7):1262-1278. doi: 10.1080/15548627.2019.1664705. Epub 2019 Sep 22.
UNLABELLED: 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-1β (interleukin 1 beta) and . 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. ABBREVIATIONS: 3-MA: 3-methyladenene; ATG7: autophagy-related 7; ATP: adenosine triphosphate; BafA1: bafilomycin A; BMDMs: bone marrow derived macrophages; CHX: cycloheximide; DMM: destabilization of the medial meniscus; ELISA: enzyme-linked immunosorbent assay; GFP: green fluorescent protein; IL1B/IL-1β: interleukin 1 beta; LIPUS: low-intensity pulsed ultrasound; LIR: LC3-interacting region; LPS: lipopolysaccharide; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MDP: muramyl dipeptide; NFKB/NF-κB: nuclear factor kappa B; NLRP3: NLR family, pyrin domain containing 3; OA: osteoarthritis; PKM/PKM2: pyruvate kinase M1/2; PMA: phorbol-12-myristate-13-acetate; PYCARD/ASC; PYD and CARD domain containing; RFP: red fluorescent protein; siRNAs: small interfering RNAs; SQSTM1: sequestosome 1; TEM: transmission electron microscopy.
未加标签：滑膜炎与骨关节炎（OA）的病理学有关，并显著促进 OA 的发展。作为一种非侵入性的物理治疗方法，近年来低强度脉冲超声（LIPUS）已被报道具有抗炎作用。然而，LIPUS 对 OA 滑膜炎的作用及其潜在机制知之甚少。本研究表明，LIPUS 改善了不稳定内侧半月板（DMM）小鼠模型和气囊模型中的滑膜炎症，并缓解了 DMM 小鼠的疼痛步态模式。LIPUS 显著抑制成熟 IL1B/IL-1β（白细胞介素 1β）和 的产生。此外，LIPUS 上调了巨自噬/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 SQSTM1（自噬体相关蛋白 1）-PKM（丙酮酸激酶，肌肉）复合物的形成。此外，LIPUS 降低了 LPS-ATP 处理的巨噬细胞中 PKM2 的水平，而 SQSTM1 的敲低可逆转这一现象。简而言之，本研究首次证明，LIPUS 通过 LPS-ATP 处理的巨噬细胞中 SQSTM1 依赖的 PKM2 自噬降解，部分抑制成熟 IL1B 的产生，这可能进一步改善动物模型中的滑膜炎和步态模式。我们的数据为使用 LIPUS 治疗滑膜炎和其他炎症性疾病提供了新的线索。 缩写词：3-MA：3-甲基腺嘌呤；ATG7：自噬相关 7；ATP：三磷酸腺苷；BafA1：巴弗霉素 A；BMDMs：骨髓衍生巨噬细胞；CHX：环己酰亚胺；DMM：不稳定内侧半月板；ELISA：酶联免疫吸附测定；GFP：绿色荧光蛋白；IL1B/IL-1β：白细胞介素 1β；LIPUS：低强度脉冲超声；LIR：LC3 相互作用区；LPS：脂多糖；MAP1LC3B/LC3B：微管相关蛋白 1 轻链 3β；MDP：乳酰二肽；NFKB/NF-κB：核因子 kappa B；NLRP3：NLR 家族，pyrin 域包含 3；OA：骨关节炎；PKM/PKM2：丙酮酸激酶 M1/2；PMA：佛波醇 12-肉豆蔻酸 13-乙酸酯；PYCARD/ASC；PYD 和 CARD 结构域包含；RFP：红色荧光蛋白；siRNAs：小干扰 RNA；SQSTM1：自噬体相关蛋白 1；TEM：透射电子显微镜。
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