Abstract
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.
Highlights
White matter hyperintensities (WMHs) are commonly observed in the brain scanning of the elderly population, which reflect the pathology of white matter lesions (WMLs) [1]
As we have shown that deficiency of leptin receptor (LepR) suppressed the Chronic cerebral hypoperfusion (CCH) induced proinflammatory cytokines expression, we wanted to confirm whether leptin would promote the proinflammatory cytokine expression in microglia under hypoxia condition in return
We found that hypoxia stimulated tumor necrosis factor-α (TNF-α) and IL-1β mRNA and protein expression in BV2 cells, and leptin treatment further promoted the expression of TNF-α and IL-1β; hypoxia failed to modify the expression of IL-6 in BV2 cells, leptin treatment triggered the expression of IL-6 (Figure 7)
Summary
White matter hyperintensities (WMHs) are commonly observed in the brain scanning of the elderly population, which reflect the pathology of white matter lesions (WMLs) [1]. WMLs occur due to chronic cerebral hypoperfusion (CCH) and the subsequent chronic cerebral hypoxia. It could contribute to cognitive decline and even dementia [2]. The mechanisms and modulating factors involved in the CCH-induced WHLs are still not fully understood. CCH induces chronic inflammation in the central nervous system (CNS), and inflammation might be the mediator of CCH-induced WMLs [3]. Microglia are the immune cells in CNS. They act as the first line of defense against pathogens, clearing up cellular debris, expressing inflammatory cytokines [4]. It was demonstrated that suppressing inflammatory responses and inactivating microglia ameliorated CCH-induced cognitive dysfunction and WMLs [5]
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