Lipids grease the wheels of the immune system

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The metabolism of lipids and their precursors is orchestrated at the genomic level by the activities of an integrated group of exquisitely tuned transcription factors. Key among these are the liver-X-receptors (LXRs), which upregulate genes involved in cholesterol export and excretion, and the sterol regulatory element-binding proteins (SREBPs), which generally play an opposing role in stimulating uptake and synthesis of sterols. In addition to these well understood roles, lipids and their transcriptional coordinators have emerged as central actors in regulation of inflammation. Macrophage lipid metabolism is rapidly reprogrammed after inflammatory stimulation [1], and pre and postcholesterol sterols such as desmosterol and 25-hydroxycholesterol potently affect immunity [2,3,4▪,5]. LXR stimulation represses proinflammatory gene expression, and recently was shown to reduce inflammation in animal models of neuroinflammation and Parkinson's disease [6,7]. However, LXR stimulation and associated changes in lipid metabolism are unlikely to represent a simple inflammation shutdown switch. Although LXR is involved in transition of macrophages to a proresolving M2 (alternatively activated) phenotype [8] and prevention of lung damage [9], it also promotes eosinophil-driven inflammation in asthma [10], and is essential for rallying against bacterial invasion. These apparently paradoxical findings hint at a level of regulatory complexity which still eludes our full understanding.
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