HDAC5: a New Player in Macrophage Activation and Intestinal Homeostasis

Histone deacetylases (HDACs) are key players in the process of gene regulation as they modulate chromatin structure and thereby gene transcription. Moreover they modify non-histone proteins as nuclear factor-κB (NF-κB). While inhibition of HDACs is well known for its anti-proliferative potency in various tumor models, recent studies revealed HDACs as essential mediators in chronic inflammation, especially in inflammatory bowel disease and colitis associated cancer. Here, we analyzed the immunological function and the expression profile of HDAC5 in macrophages. Furthermore, we investigate its relevance for gut homeostasis in mice with regard to macrophage-epithelial cell interaction, which has a direct impact on the integrity of the intestinal epithelial barrier. In the macrophage cell lines RAW 264.7 and U937, expression of HDAC5 mRNA is significantly down-regulated after toll-like receptor activation. HDAC5 overexpression in RAW 264.7 resulted in an increased LPS-dependent secretion of pro-inflammatory cytokines. Subsequently, knockdown of HDAC5 mRNA by specific siRNA significantly reduced the secretion of these cytokines. These effects were accompanied by a corresponding change in NF-κB activity, indicating a critical role of HDAC5 in the inflammatory response of macrophages. To address the impact of HDAC5 on colonic barrier function, colon samples of dextran sulfate sodium-treated knockout mice were analyzed by Ussing chamber experiments. Here, a decreased trans-epithelial resistance as well as a decreased flux of horseradish peroxidase was detected. These results indicate a regulatory function of HDAC5 in the pro-inflammatory response of macrophages and further point to a distinct role within intestinal homeostasis during experimental colitis.