alexa AMP-activated protein kinase restricts IFN-γ signaling.


Journal of Clinical & Cellular Immunology

Author(s): Meares GP, Qin H, Liu Y, Holdbrooks AT, Benveniste EN

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Abstract Inflammation in the CNS contributes to neurologic disorders. Neuroinflammation involves the release of inflammatory molecules from glial cells, such as astrocytes and microglia, and can lead to neuronal damage if unabated. In multiple sclerosis, peripheral immune cells, including IFN-γ-producing Th1 cells, infiltrate the CNS and are important in shaping the inflammatory microenvironment, in part through cytokine-mediated interactions with glial cells. Recent evidence suggests that AMP-activated protein kinase (AMPK), a central regulator of energetic metabolism, can regulate inflammatory gene expression. In this study, we identified that IFN-γ induces biphasic AMPK signaling, suggestive of negative-feedback mechanisms. Activation of AMPK suppresses several IFN-γ-induced cytokines and chemokines in primary astrocytes and microglia. IFN-γ regulates gene expression through activation of STAT1, and deletion of AMPK results in a marked increase in basal expression of STAT1. Conversely, activation of AMPK blocks IFN-γ-induced STAT1 expression. Deletion of AMPK leads to increased basal and IFN-γ-induced expression of inflammatory molecules, including TNF-α, CXCL10, and CCL2. AMPK does not affect the phosphorylation of STAT1, but instead attenuates nuclear translocation of STAT1, DNA binding, and subsequent gene expression. In vivo, AMPK signaling during experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, is downregulated in the brain at onset and peak of disease. Diminution of AMPK signaling in vivo correlates with increased expression of IFN-γ and CCL2 in the CNS. Overall, these findings provide the first link between AMPK and STAT1 and may provide important clues about how bioenergetics and inflammation are linked.
This article was published in J Immunol and referenced in Journal of Clinical & Cellular Immunology

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