Pharmacological Upregulation of Microglial Lipid Droplet Alleviates Neuroinflammation and Acute Ischemic Brain Injury

• Published in: Inflammation 2023-10, Vol.46 (5), p.1832-1848
• Main Authors: Li, Huiya, Liu, Pinyi, Deng, Shiji, Zhu, Liwen, Cao, Xiang, Bao, Xinyu, Xia, Shengnan, Xu, Yun, Zhang, Bing
• Format: Article
• Language: English
• Subjects: Animals; Anti-inflammatory agents; Biomedical and Life Sciences; Biomedicine; Brain Injuries - metabolism; Brain injury; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Cerebral blood flow; Flow cytometry; Immunofluorescence; Immunology; Infarction, Middle Cerebral Artery - metabolism; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; Internal Medicine; Ischemia; Ischemic Stroke - metabolism; Lipid Droplets - metabolism; Lipolysis; Mice; Microglia; Microglia - metabolism; Neuroinflammatory Diseases; Neuroprotection; Pathology; Phagocytosis; Pharmacology/Toxicology; Rheumatology; Stroke; Transcriptomics; Up-Regulation
• ISSN: 0360-3997; 1573-2576
• DOI: 10.1007/s10753-023-01844-z

Lipid droplets (LDs) were reported to play an important role in the modulation of inflammation and various cellular processes among multiple cell types. However, LDs accumulation, its function and mechanisms of its formation during ischemic stroke remained poorly-identified. In this study, we observed increased LDs accumulation in microglia at the acute stage of ischemic stroke by immunofluorescence and flow cytometry. Transcriptomic analysis indicated that microglia accumulated with LDs were associated with inflammation and phagocytosis. Both inflammatory activation and phagocytosis of tissue debris in microglia could contribute to LDs formation. Moreover, through specific LDs depletion and overload experiments by pharmacological approaches, we proposed that LDs was critical for the maintenance of anti-inflammatory properties of microglia. Furthermore, Atglistatin, a specific adipose triglyceride lipase (ATGL) inhibitor, was shown to prevent proinflammatory cytokines production in primary microglia through decreased LDs lipolysis. After Atglistatin treatment, middle cerebral artery occlusion (MCAO) mice showed decreased infarct volume and improved neurobehavioral performance at the acute stage of stroke. Our findings provided a biological basis for microglial LDs regulation as a potential therapeutic strategy for acute ischemic stroke and uncovered the neuroprotective role of Atglistatin in the treatment of MCAO mice.