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Leptin Receptor Deficiency Protects Mice against Chronic Cerebral Hypoperfusion-Induced Neuroinflammation and White Matter Lesions
Mediators of Inflammation ( IF 4.6 ) Pub Date : 2020-12-18 , DOI: 10.1155/2020/7974537 Yu Du 1 , Yufei Song 1 , Xiaojie Zhang 1 , Yan Luo 1 , Wenying Zou 1 , Jiawei Zhang 1 , Jianliang Fu 1
Mediators of Inflammation ( IF 4.6 ) Pub Date : 2020-12-18 , DOI: 10.1155/2020/7974537 Yu Du 1 , Yufei Song 1 , Xiaojie Zhang 1 , Yan Luo 1 , Wenying Zou 1 , Jiawei Zhang 1 , Jianliang Fu 1
Affiliation
Leptin participates in the inflammatory responses in multiple cell types and animal models. Chronic cerebral hypoperfusion (CCH) induces inflammation in the central nervous system (CNS), which acts as one of the main reasons for CCH-induced white matter lesions (WMLs). But whether leptin participates in the pathogenesis of CCH-induced WMLs remains unknown. Therefore, we performed bilateral common carotid artery stenosis (BCAS) to induce CCH on the leptin receptor- (LepR-) deficient db/db mice, aiming to evaluate the possible involvement of leptin in CCH-induced cognitive impairment, WMLs, and neuroinflammation, and further explore the effect of leptin on chronic hypoxia-induced inflammation using the BV2 microglial cell line. After four weeks of BCAS, wild-type mice showed significant working memory deficits, WMLs, activation of microglia and astrocytes, decrease in the number of oligodendrocytes, downregulation of myelin basic protein expression, and increase in the expression of TNF-α and IL-1β; however, four weeks of BCAS failed to induce significant changes in the LepR-deficient db/db mice but elevated the production of anti-inflammatory cytokines and activated the M2 microglia. We further confirmed that leptin would aggravate the hypoxia-induced proinflammatory cytokine expression in the BV2 microglia cell line. These results suggested that LepR deficiency would protect mice against the CCH-induced cognitive impairment and WMLs by inhibiting glial activation and suppressing proinflammatory responses as well as promoting anti-inflammatory cytokine expression and M2 microglia activation in the white matter.
中文翻译:
瘦素受体缺乏保护小鼠免受慢性脑灌注不足引起的神经炎症和白质病变
瘦素参与多种细胞类型和动物模型的炎症反应。慢性脑灌注不足 (CCH) 会引起中枢神经系统 (CNS) 的炎症,这是 CCH 引起的白质病变 (WML) 的主要原因之一。但瘦素是否参与 CCH 诱导的 WMLs 的发病机制尚不清楚。因此,我们对瘦素受体 (LepR-) 缺陷型 db/db 小鼠进行双侧颈总动脉狭窄 (BCAS) 诱导 CCH,旨在评估瘦素在 CCH 诱导的认知障碍、WML 和神经炎症中的可能参与,并使用 BV2 小胶质细胞系进一步探索瘦素对慢性缺氧诱导的炎症的影响。BCAS 4 周后,野生型小鼠表现出明显的工作记忆缺陷、WML、α和 IL-1 β;然而,4 周的 BCAS 未能在 LepR 缺陷型 db/db 小鼠中引起显着变化,但增加了抗炎细胞因子的产生并激活了 M2 小胶质细胞。我们进一步证实瘦素会加重 BV2 小胶质细胞系中缺氧诱导的促炎细胞因子表达。这些结果表明,LepR 缺乏将通过抑制神经胶质激活和抑制促炎反应以及促进白质中抗炎细胞因子的表达和 M2 小胶质细胞的激活来保护小鼠免受 CCH 诱导的认知障碍和 WML。
更新日期:2020-12-18
中文翻译:
瘦素受体缺乏保护小鼠免受慢性脑灌注不足引起的神经炎症和白质病变
瘦素参与多种细胞类型和动物模型的炎症反应。慢性脑灌注不足 (CCH) 会引起中枢神经系统 (CNS) 的炎症,这是 CCH 引起的白质病变 (WML) 的主要原因之一。但瘦素是否参与 CCH 诱导的 WMLs 的发病机制尚不清楚。因此,我们对瘦素受体 (LepR-) 缺陷型 db/db 小鼠进行双侧颈总动脉狭窄 (BCAS) 诱导 CCH,旨在评估瘦素在 CCH 诱导的认知障碍、WML 和神经炎症中的可能参与,并使用 BV2 小胶质细胞系进一步探索瘦素对慢性缺氧诱导的炎症的影响。BCAS 4 周后,野生型小鼠表现出明显的工作记忆缺陷、WML、α和 IL-1 β;然而,4 周的 BCAS 未能在 LepR 缺陷型 db/db 小鼠中引起显着变化,但增加了抗炎细胞因子的产生并激活了 M2 小胶质细胞。我们进一步证实瘦素会加重 BV2 小胶质细胞系中缺氧诱导的促炎细胞因子表达。这些结果表明,LepR 缺乏将通过抑制神经胶质激活和抑制促炎反应以及促进白质中抗炎细胞因子的表达和 M2 小胶质细胞的激活来保护小鼠免受 CCH 诱导的认知障碍和 WML。