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Our Research

Immunology is all about discriminating 'self' (host) from 'non-self' (microbes and danger-associated molecules). Unlike adaptive immunity, which utilizes clonal selection and expansion of antigen-specific T and B lymphocytes, innate immune cells discriminate "non-self" through innate immune receptors, termed pattern recognition receptors (PRRs). Our overall goal of research is to investigate the role and signaling/molecular mechanisms of PRRs in innate immune responses.  Among various innate immune cells, macrophages are key sentinel cells residing in all tissues. They sense, trigger and orchestrate immune responses. Many pathogenic bacteria and viruses sabotage macrophage immune responses to gain access and disseminate within the host by secreting various effectors. In contrast, commensal or probiotic microbes live within the host in harmony. To date, immunological and signaling interactions between commensals and macrophages are not well understood. Currently, our research focuses on the immunological and signaling mechanisms of the anthrax lethal toxin, which is notorious for its immune paralyzing effects, and the probiotic bacteria lactobacilli, which are known to be beneficial to the host, in regulating macrophage function. Furthermore, defective or aberrant activation of macrophages have shown to be involved in inflammatory/autoimmune diseases, ischemia injury and cancer. Therefore, understanding mechanisms of macrophages responding to microbial components and endogenous danger-associated molecules is fundamental for developing novel ttherapeutic approaches and reagents for infectious, as well as other diseases.

Our Recent Research Discovery
            

                                                            

A schematic presentation of  the proposed role of HDAC8 and H3K27Ac in regulating LPS-induced pro-IL-1b eRNA production in LeTx-exposed macrophages. LeTx or p38 inhibition causes hypo-acetylation of H3K27 and limits accessibility of NF-B to the pro-IL-1b enhancer region, which leads to decrease of pro-IL-1b eRNA and subsequent mRNA production. Inhibition of HDAC8 induces hyper-acetylation of H3K27, which allows NF-B access to the enhancer region in response to LPS, and reverses the inhibitory effects of LeTx or p38 inhibition.

Inhibition of interleukin (IL)-1 expression by anthrax lethal toxin (LeTx) is reversed by HDAC8 inhibition in murine macrophages (Journal of Biological Chemistry, 2016)

Many pathogenic microbes often release toxins that subvert the host immune responses to render the environment suitable for their survival and proliferation. LeTx is one of the toxins causing immune paralysis through cleaving and inactivating the mitogen-activated protein kinase (MAPK) kinases (MEKs). Here, we show that inhibition of the histone deacetylase 8 (HDAC8) by either the HDAC8-specific inhibitor PCI-34051 or small interference (si)RNAs rendered LeTx-exposed murine macrophages responsive to LPS in pro-IL-1 production. HDAC8 selectively targeted acetylated histone H3 lysine 27 (H3K27Ac), which is known to associate with active enhancers. LeTx induced HDAC8 expression, in part through inhibiting p38 MAPK, which resulted in a decrease of H3K27Ac levels. Inhibition of HDAC8 increased H3K27Ac levels and enhanced NF-B-mediated pro-IL-1 enhancer and messenger RNA production in LeTx-exposed macrophages. Collectively, this study demonstrates a novel role of HDAC8 in LeTx immunotoxicity and regulation of pro-IL-1 production likely through eRNAs. Targeting HDAC8 could be a strategy for enhancing immune responses in macrophages exposed to LeTx or other toxins that inhibits MAPKs.

    

Adoptively transferred G-CSF generated BMDM exerts a protective effect on DSS-induced mouse colitis in G-CSFR-/- mice. G-CSFR+/+, and -/- mice were given 1.5% dextran sulfate sodium (DSS) in the drinking water for 5 days, and fresh water thereafter. G-CSFR-/- mice were injected with 5 106 M-CSF (20 ng/ml)-treated (BMDM) or M-CSF + G-CSF (10 ng/ml)-treated (G-BMDM) cells 1 day before and 2 days after DSS treatment. (A) Body weight loss, diarrhea/rectal bleeding, and overall colitis scores (encompassing weight loss, stool consistency, rectal bleeding, and loss of activity) were plotted from Day 0 to 10. *, p < 0.05 by one-way ANOVA with Tukeys multiple comparison post hoc test. Symbols represent mean SEM. (B) Colon length of mice after 10 days of DSS treatment was measured and plotted. (C) Gut-homing phenotype of the adoptive transferred-M- and G-BMDM in DSS-treated G-CSFR-/- mice was evaluated by investigating the presence of mRNA expression of G-CSF receptor wild-type (G-CSFR exon 4 and 5) in colon tissues. Data shown as mean SEM [n 3; *, p < 0.05 by one-way ANOVA with Tukeys multiple comparison post hoc test; columns accompanied by the same letter (a, b or c) are not significantly different from each other].         

Protective role of G-CSF in dextran sulfate sodium-induced acute colitis through generating gut-homing macrophages (Cytokine, 2016)

Granulocyte colony-stimulating factor (G-CSF) is a pleiotropic cytokine best known for its role in promoting the generation and function of neutrophils. G-CSF is also found to be involved in macrophage generation and immune regulation; however, its in vivo role in immune homeostasis is largely unknown. Here, we examined the role of G-CSF in dextran sulfate sodium (DSS)-induced acute colitis using G-CSF receptor-deficient (G-CSFR-/-) mice. Mice were administered with 1.5 % DSS in drinking water for 5 days, and the severity of colitis was measured for the next 5 days. GCSFR-/- mice were more susceptible to DSS-induced colitis than G-CSFR+/+ or G-CSFR-/+ mice. G-CSFR-/- mice harbored less F4/80+ macrophages, but a similar number of neutrophils, in the intestine. In vitro, bone marrow-derived macrophages prepared in the presence of both G-CSF and macrophage colony-stimulating factor (M-CSF) (G-BMDM) expressed higher levels of regulatory macrophage markers such as programmed death ligand 2 (PDL2), CD71 and CD206, but not in arginase I, transforming growth factor (TGF)-, Ym1 (chitinase-like 3) and FIZZ1 (found in inflammatory zone 1), and lower levels of inducible nitric oxide synthase (iNOS), CD80 and CD86 than bone marrow-derived macrophages prepared in the presence of M-CSF alone (BMDM), in response to interleukin (IL)-4/IL-13 and lipopolysaccharide (LPS)/interferon (IFN)-Ƴ, respectively. Adoptive transfer of G-BMDM, but not BMDM, protected G-CSFR-/- mice from DSS-induced colitis, and suppressed expression of tumor necrosis factor (TNF)-, IL-1 and iNOS in the intestine. These results suggest that G-CSF plays an important role in preventing colitis, likely through populating immune regulatory macrophages in the intestine.