Intestinal inflammation requires FOXO3 and prostaglandin E2-dependent lipogenesis and elevated lipid droplets

Intestinal inflammation has been recently characterized by the dysregulation of lipids as metabolic and energy sources, revealing a novel feature of its pathophysiology. Since intracellular lipids, stored in dynamic lipid droplets (LDs), provide energy for cellular needs, we investigated if they play a role in intestinal inflammation. In the inflamed intestine of mice, elevated LDs were found in colonic and infiltrating immune cells as shown by staining for the LD coat protein PLIN2 and for lipids with BODIPY. In colonic cells, TNF stimulated LD increases by receptor signaling that relies on PI3K activation. Downstream, TNF triggered a negative regulatory loop between LDs and the transcription factor FOXO3. This was shown in the colon of Foxo3 deficient mice, where elevation in PLIN2 and lipids were further facilitated by inflammation and were more prominent relative to wild type. Whereas in colonic cells, inhibition of lipogenesis blocked the TNF mediated loss of FOXO3. Furthermore, blockade of PGE2 synthesis abrogated TNF stimulated increases in LDs and FOXO3 inactivation. We found in colonic tissue of Foxo3 deficient mice higher levels of Cox-2, a mediator of PGE2 synthesis, supporting involvement of PGE2 in the LD-FOXO3 regulatory loop. Ultimately, TNF stimulated lipogenesis leading to elevated LDs facilitated NF-κB mediated increases in IL-8 protein, which is associated with the surface of LDs found in the lumens of the endoplasmic reticulum and Golgi apparatus. This novel immuno-metabolic mechanism of colonic inflammation involving elevated LDs could provide opportunities for new treatment options.