AdipoRon exerts an antidepressant effect by inhibiting NLRP3 inflammasome activation in microglia via promoting mitophagy

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2024-08-30 DOI:10.1016/j.intimp.2024.113011

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Abstract

Depression is a serious mental disorder that threatens patients’ physical and mental health worldwide. The activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome is essential for microglia-mediated neuroinflammation and neuronal damage in depression. Numerous pathophysiological factors, such as mitochondrial dysfunction and impaired mitophagy, have an essential role in activating the NLRP3 inflammasome. AdipoRon is a potent adiponectin receptor agonist; however, its antidepressant effects have not been thoroughly investigated. In this study, we found that AdipoRon ameliorated depression-like behavior and neuronal damage induced by chronic unpredictable mild stress (CUMS). Further research demonstrated that AdipoRon inhibited the activation of the NLRP3 inflammasome and protected hippocampal neurons from microglial cytotoxicity by promoting mitophagy, increasing the clearance of damaged mitochondria, and reducing mtROS accumulation. Importantly, inhibition of mitophagy attenuated the antidepressant and neuroprotective effects of AdipoRon. Overall, these findings indicate that AdipoRon alleviates depression by inhibiting NLRP3 inflammasome activation in microglia via improving mitophagy.

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AdipoRon 通过促进有丝分裂来抑制小胶质细胞中 NLRP3 炎性体的激活，从而发挥抗抑郁作用

抑郁症是一种严重的精神疾病，威胁着全球患者的身心健康。NLR家族含吡咯啉结构域3（NLRP3）炎性体的激活是抑郁症中由小胶质细胞介导的神经炎症和神经元损伤的关键。许多病理生理因素，如线粒体功能障碍和有丝分裂障碍，在激活NLRP3炎性体方面起着至关重要的作用。AdipoRon是一种强效的脂肪连接素受体激动剂，但其抗抑郁作用尚未得到深入研究。在这项研究中，我们发现 AdipoRon 可改善慢性不可预测轻度应激（CUMS）诱导的抑郁样行为和神经元损伤。进一步的研究表明，AdipoRon 可抑制 NLRP3 炎性体的激活，并通过促进有丝分裂、增加受损线粒体的清除和减少 mtROS 的积累，保护海马神经元免受小胶质细胞毒性的伤害。重要的是，抑制有丝分裂会减弱 AdipoRon 的抗抑郁和神经保护作用。总之，这些研究结果表明，AdipoRon 可通过改善有丝分裂来抑制小胶质细胞中 NLRP3 炎性体的激活，从而缓解抑郁症。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.