Current Research Topics
 

1. Macrophage Differentiation through Histone Acetylation and Enhancers

Macrophages are versatile and resilient immune cells that response and adapt to various environmental cues. One of the key mechanisms in responding to those cues is epigenetics. Epigenetics is a cellular mechanism that regulates gene expression by covalently modifying DNAs, RNAs and histones. Particularly, histone H3 modifications by acetylation have shown to be involved in enhancing gene expression by recruiting transcription machineries to promoters and enhancers.

Anthrax is a deadly infection caused by Bacillus anthracis that proliferates within the host without activating immune responses. The key virulence factor responsible for the immune evasion is anthrax lethal toxin (LeTx). LeTx prevents macrophage activation and induces cell death. Our recent study discovered that macrophages exposed to LeTx undergo epigenetic changes through decreasing histone H3 lysine 27 acetylation levels, rendering resistance to cell death but prolong immune suppression. We also found that the histone deacetylase 8 (HDAC8) plays a pivotal role in suppressing expression of cell death genes and inflammatory cytokines in LeTx-exposed macrophages. Currently, we are investigating the role and mechanism of HDAC8 in regulating gene expression in macrophages.

 
 
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2. Immune Modulation of Probiotics through macrophages and histone modifications. 

Probiotics are strains of commensal microbes that have been used for many years to replenish normal intestinal and vaginal microflora and even to confer a health benefit on the host. The mechanisms how these microbes maintain symbiosis with the host and immunologically inert state inside the host is not well defined. We have demonstrated that Lactobacillus rhamnosus induced auto/paracrine anti-inflammatory effects in macrophages and dendritic cells. One of the key mediators rendering immunomodulatory effects released by macrophages is the granulocyte colony-stimulating factor (G-CSF). Our study demonstrated that G-CSF plays a key role in generating immune tolerant macrophages that replenish gut macrophages. Also, G-CSF-deficient mice were more susceptible to develop colitis and patients inflicted by inflammatory bowel diseases such as Crohn’s disease have defects in producing gut G-CSF in response to commensal microbes. Furthermore, in collaboration with Dr. Bocking’s group at the University of Toronto, we have shown that L. rhamnosus and its secreted factor(s) modulate immune homeostasis in the placenta and during pregnancy. Collectively, our study unravel key roles of commensal microbes in maintaining immunological homeostasis of membranous organs such as gut and placenta. Currently, we are investigating the mechanism of commensals and G-CSF in regulating macrophage phenotypes through histone modifications.  

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