HISTONE DEACETYLASES IN EPIGENETIC MODULATION OF MACROPHAGE ACTIVATION AND TRAINING

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Macrophages are key immune cells which reside in all tissues and orchestrate immune responses. These cells need to be resilient to changing micro-environments to appropriately respond to various challenges. Particularly, adaptation (or training) of macrophages by local microbes and cytokines are crucial for maintaining immunological homeostasis. To date, how macrophages are trained by various microbes and cytokines remains largely unknown. This research will study the mechanisms of macrophage adaptation mediated by live bacteria (L. rhamnosus), bacterial components (anthrax lethal toxin G-CSF) as model systems. The overall goal of our research program is to understand the mechanisms by which macrophages sense, respond and adapt to bacterial microbes and cytokines. Under this goal, we will focus on the following research Aims:Aim 1. Examining the role and epigenetic mechanism of the histone deacetylase (HDAC) 8 in macrophage training. Epigenetics is a cellular mechanism that regulates gene expression without altering genomic sequences in response to environmental cues. Among various epigenetic mechanisms, we found that HDAC8 plays a key role in training macrophages by a bacterial toxin, known as anthrax lethal toxin. However, the regulatory mechanisms of HDAC8 and its down-stream pathway involved in macrophage training remain to be addressed. This Aim will study the role and mechanism of HDAC8 in macrophage training by LeTx, L. rhamnosus and G-CSF in the expression of the inflammatory cytokine interleukin-1 as model systems. This Aim will provide new information on the biology of HDAC8 and its mechanism in training macrophages.Aim 2. Examining the role of HDACs in macrophage training by intestinal commensals. Training macrophages to respond in an appropriate manner is imperative for immune homeostasis of the intestine, since macrophages must tolerate a heavy load of microbial components, and yet remain vigilant to invading pathogens. In addition to HDAC8, other HDACs are likely involved in training macrophages in the expression of different cytokines. This Aim will examine the role of other HDACs than HDAC8 in regulating expression of different cytokines in macrophages trained by L. rhamnosus and G-CSF as model systems. In addition, this Aim will purify/identify the L. rhamnosus-secreted factor(s) that trains macrophages. Collectively, this Aim will provide new information on the role of HDACs in training macrophages by intestinal microbes and cytokines.Overall, our research will provide fundamental information on the epigenetic mechanisms that train macrophages to appropriately respond to microbial components and maintain immunological homeostasis.