Urolithin A inhibits pro-inflammatory mediators through Histone deacetylase (HDAC) pathway

Urolithin-A is a gut microbial metabolite derived from ellagitannins and ellagic acid, which are major poly-phenolic compounds in pomegranates and berries. Its anti-proliferative actions have been documented, however, there has not been significant research conducted to determine the mechanism by which Urolithin-A modulates immune response. Previous research has shown that Urolithin-A can completely reverse colitis in animal models. Here, we demonstrate that Urolithin-A, which is abundant in the intestine, can modulate the function of macrophages. It was hypothesized that Urolithin-A would exert these effects through Histone Deacetylase (HDAC) inhibition. HDACs  are involved in primarily transcriptional gene repression through the compaction of the chromatin structure. Treatment of RAW 264.7 and Bone-marrow derived macrophages with Urolithin-A lead to the down regulation of LPS-induced pro-inflammatory mediators such as NOS-2, IL-6, and IL-12a. Increasing Uro-A levels also lead to a decrease in ERK phosphorylation and a increase in Acetyl-H3. These findings help elucidate a pathway by which Urolithin-A renders macrophages hyporesponsive through the down-regulation of pro-inflammatory mediators through HDAC inhibition.