Non‐lethal sonodynamic therapy inhibits high glucose and palmitate‐induced macrophage inflammasome activation through mtROS‐DRP1‐mitophagy pathway

• Published in: The FASEB journal 2024-11, Vol.38 (22), p.e70178-n/a
• Main Authors: Wang, Jiayu, Shen, Yicheng, Chen, Heyu, Guan, Jinwei, Li, Zhitao, Liu, Xianna, Guo, Shuyuan, Wang, Linxin, Yan, Baoyue, Jin, Chenrun, Li, He, Guo, Tian, Sun, Yun, Zhang, Weihua, Zhang, Zhiguo, Tian, Ye, Tian, Zhen
• Format: Article
• Language: English
• Subjects: Animals; beta cell; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - therapy; Dynamins - metabolism; Glucose - metabolism; inflammasome; Inflammasomes - metabolism; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Interleukin-1beta - metabolism; macrophage; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Mitochondria - drug effects; Mitochondria - metabolism; mitochondrial quality control; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Palmitates - pharmacology; Palmitic Acid - pharmacology; Reactive Oxygen Species - metabolism; sonodynamic therapy; type 2 diabetes mellitus; Ultrasonic Therapy - methods
• ISSN: 0892-6638; 1530-6860; 1530-6860
• DOI: 10.1096/fj.202402008R

Obesity plays a crucial role in the development and progression of type 2 diabetes mellitus (T2DM) by causing excessive release of free fatty acid from adipose tissue, which in turn leads to systemic infiltration of macrophages. In individuals with T2DM, the infiltration of macrophages into pancreatic islets results in islet inflammation that impairs beta cell function, as evidenced by increased apoptosis and decreased glucose‐stimulated insulin secretion. The present study aimed to investigate the effects of non‐lethal sonodynamic therapy (NL‐SDT) on bone marrow‐derived macrophages (BMDMs) exposed to high glucose and palmitic acid (HG/PA). These findings indicate that NL‐SDT facilitates the expression of DRP1 through the transient production of mitochondrial ROS, which subsequently promotes mitophagy. This mitophagy was shown to limit the activation of the NLRP3 inflammasome and the secretion of IL‐1β in BMDMs exposed to HG/PA. In co‐culture experiments, beta cells exhibited significant dysfunction when interacting with HG/PA‐treated BMDMs. However, this dysfunction was markedly alleviated when the BMDMs had undergone NL‐SDT treatment. Moreover, NL‐SDT was found to lower blood glucose levels and elevate serum insulin concentrations in db/db mice. Furthermore, NL‐SDT effectively reduced the infiltration of F4/80‐positive macrophages and the expression of CASP1 within islets. These findings provide fundamental insights into the mechanisms through which NL‐SDT may serve as a promising approach for the treatment of T2DM. Non‐lethal sonodynamic therapy (NL‐SDT) reduces blood glucose and alleviates thirst in T2DM db/db mice by targeting islet macrophages. Further findings reveal that NL‐SDT effectively inhibits inflammasome activation in macrophages exposed to high glucose and palmitic acid through mitochondrial ROS‐DRP1‐mitophagy pathway, thus leading to a reduction in the secretion of IL‐1beta. Consequently, NL‐SDT confers protection to beta cells and facilitates the restoration of glucose‐stimulated insulin secretion.