Journal
IMMUNITY
Volume 54, Issue 8, Pages 1683-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2021.05.017
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Funding
- NIH [R21 AI109436, R01 AI162701]
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Microbe-derived acetate activates the IMD pathway in a subset of enteroendocrine cells in the anterior midgut of Drosophila. This pathway co-regulates expression of antimicrobial and enteroendocrine peptides, including a repressor of intestinal lipid synthesis. Acetate appears to enhance IMD signaling through the monocarboxylic acid transporter Tarag and histone deacetylation in enteroendocrine cells. Tip60-dependent chromatin remodeling modulates host metabolism and intestinal innate immunity via a steroid hormone axis conserved in mammals.
Microbe-derived acetate activates the Drosophila immunodeficiency (IMD) pathway in a subset of enteroendocrine cells (EECs) of the anterior midgut. In these cells, the IMD pathway co-regulates expression of antimicrobial and enteroendocrine peptides including tachykinin, a repressor of intestinal lipid synthesis. To determine whether acetate acts on a cell surface pattern recognition receptor or an intracellular target, we asked whether acetate import was essential for IMD signaling. Mutagenesis and RNA interference revealed that the putative monocarboxylic acid transporter Tarag was essential for enhancement of IMD signaling by dietary acetate. Interference with histone deacetylation in EECs augmented transcription of genes regulated by the steroid hormone ecdysone including IMD targets. Reduced expression of the histone acetyltransferase Tip60 decreased IMD signaling and blocked rescue by dietary acetate and other sources of intracellular acetyl-CoA. Thus, microbe-derived acetate induces chromatin remodeling within enteroendocrine cells, co-regulating host metabolism and intestinal innate immunity via a Tip60-steroid hormone axis that is conserved in mammals.
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