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Regulation of macrophage migration inhibitory factor expression and its role in stroke and Alzheimer’s disease. Zhang, Si


As a pleiotropic protein, macrophage migration inhibitory factor (MIF) participates in many cellular activities including inflammatory response, energy metabolism, and apoptosis. Dysregulation of MIF has been associated with chronic inflammatory conditions, and inhibition of its activity has been proposed as a therapeutic strategy. However, MIF gene knockout shows detrimental effects under stress-induced acute conditions such as infection and ischemia/reperfusion (I/R). Compared to a large body of research regarding the role of MIF outside of the central nervous system, limited studies have been carried out to address its role in neurological conditions. Previous studies showed that MIF protects cardiomyocytes from I/R induced detrimental effects. Since strokes are detrimental to neurons in a similar way that heart attacks are to cardiomyocytes, MIF may exert similar effects to protect neurons. Therefore, we aimed to study the regulation of MIF expression and its potential role in strokes. We identified two functional cis-acting NFκB binding elements on the MIF gene promoter and demonstrated that NFκB regulates MIF expression by transcriptional activation of the MIF gene promoter via these two sites. Under hypoxic conditions, MIF gene transcription is reduced by activation of NFκB signaling, which contributes to the down-regulation of MIF expression in the ischemic territory during strokes. We further demonstrated that MIF reduces caspase-3 activation and protects neurons from oxidative stress-induced and I/R-induced apoptosis in vitro. Using a stroke model, we showed that MIF gene knockout results in elevated caspase-3 activation, exacerbates neuronal death, and accelerates infarct development. These results suggest that MIF exhibits neuroprotective effects following a stroke. As stroke increases the risk of developing Alzheimer’s disease (AD), we further evaluated whether MIF could serve as a molecular link between stroke and AD by exploring the expression profile of MIF and its role in AD. We have provided first-hand evidence suggesting that elevation of MIF expression is induced by a pathological increase of Aβ deposits at the late stage of AD, but this effect does not recover its role in mediating normal behavioral functions in AD, because it is sequestered on the Aβ deposits in a loss-of-function fashion.

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