TGR5, G protein-coupled receptor 19, is also known as G protein-coupled bile acid receptor 1. The... more TGR5, G protein-coupled receptor 19, is also known as G protein-coupled bile acid receptor 1. The single exon encodes a TGR5 protein composed of 330 amino acids with seven transmembrane domains. Although TGR5 is expressed in various tissues such as liver, nervous system, adipocytes, endocrine glands, gall bladder, muscles, and spinal cord, the expression level in these tissues is less than 1/10 of myeloid immune cells. Activation of TGR5 incur various signaling cascades depending on the responder cell type. For example, synthesis and secretion of bile acids, intestinal secretion and motility, energy expenditure, glucose homeostasis, and inflammation is regulated by TGR5 pathway. Although TGR5 has got much attention as a promising new target for metabolic disorders or inflammatory disorders, only deoxycholic acid was licensed for lipoma. Obeticholic acid was also licensed for cholangitis but it interacts with FXR in addition to TGR5. Recently, we showed that taurodexoycholic acid (TDCA) interacts with TGR5, reduces inflammation incurred by activation of neutrophils, increases number of myeloid derived suppressor cells and prolongs survival of mice under sepsis. TDCA changes DNA methylation pattern of chromosome, globally edit proteomes of skin cells, brain cells and myeloid cells in mice model for atopic dermatitis, Alzheimer disease and sepsis, respectively. In addition, inflammasomal activation was suppressed by down-regulating a purinergic receptor in TDCA-treated neutrophils. In addition, cAMP-PKA-NF-κB pathway was controlled by TDCA. Phase I clinical trials for atopic dermatitis using TDCA did not show significant adverse drug reactions. Taken together, TDCA might be a non-classical anti-inflammatory drug (NCAID) for various inflammatory disorders when activation of myeloid inflammatory cells are pathognomonic features.
HY209 has been reported to be a ligand for the membrane G protein–coupled receptor, TGR5. HY209 c... more HY209 has been reported to be a ligand for the membrane G protein–coupled receptor, TGR5. HY209 could inhibit inflammatory responses in sepsis by increasing number of immunosuppressive myeloid-derived suppressor cells (MDSC), suggesting the potent role of HY209 in the treatment of atopic dermatitis (AD). Here HY209 was evaluated whether it controls inflammatory immune responses in AD. We employed mouse AD model using a topical treatment of dinitrochlorobenzene (DNCB) on the dorsal skin of Balb/c mice. HY209-treated mice showed significantly reduction in Th2 immune responses, shown as lower IgE serum, and inhibition of T cells mast cells, eosinophilia and neutrophil recruitment accompanied with reduced in epidermal and dermal thickness in skin of HY209 treated mice. Interestingly, regulatory T cells noticeably increased upon to HY209 treatment along with inhibition of type 2 cytokines production. Proteogenomic analyses of mouse skin demonstrated upregulated expression of molecules re...
Scrub typhus, caused by Orientia tsutsugamushi infection, is characterized by local as well as sy... more Scrub typhus, caused by Orientia tsutsugamushi infection, is characterized by local as well as systemic inflammatory manifestations. Inflammation is initiated by O. tsutsugamushi-infected macrophages and endothelial cells in the dermis. We investigated the regulation of chemokine induction in macrophage cell line J774A.1 in response to O. tsutsugamushi infection. The mRNAs for macrophage inflammatory proteins 1␣/ (MIP-1␣/), MIP-2, and macrophage chemoattractant protein 1 were induced within 30 min, and their levels showed a transitory peak for 3 to 12 h. However, the lymphotactin, eotaxin, gamma interferon-inducible protein 10, and T-cell activation gene 3 mRNAs were not detected by RNase protection assays. Heat-killed O. tsutsugamushi induced a similar extent of chemokine responses. Induction of the chemokine genes was not blocked by the eukaryotic protein synthesis inhibitor cycloheximide, suggesting that de novo synthesis of host cell protein is not required for these transcriptional responses. The induction of chemokine mRNAs by O. tsutsugamushi was blocked by the inhibitors of NF-B activation. Furthermore, O. tsutsugamushi induced the nuclear translocation and activation of NF-B. These results demonstrate that heat-stable molecules of O. tsutsugamushi induce a subset of chemokine genes and that induction involves activation of the transcription factor NF-B. Orientia tsutsugamushi, an obligate intracellular bacterium, is the causative agent of scrub typhus (20). The disease is characterized by fever, rash, eschar, pneumonitis, menigitis, and disseminated intravascular coagulation, which leads to severe multiorgan failure (1, 11, 62). O. tsutsugamushi causes local inflammations accompanying eschars at the site of infection, which then spread systemically (6). O. tsutsugamush infects a variety of cells in vitro and in vivo, including macrophages, polymorphonuclear leukocytes (PMN), lymphocytes, and endothelial cells (26, 38, 42, 47). Analysis of early immunologic responses to O. tsutsugamushi infection in mice showed that macrophage-mediated cellular immunity is essential for resolution of this infection (8, 39). Resistance to the lethal effects of acute rickettsia infection is under unigenic dominant control by the Ric locus (21). Macrophages infiltrate both susceptible (Ric s) and resistant (Ric r) mouse strains in response to O. tsutsugamushi infection (25, 39). A slight increase occurs in the number of infiltrating cells recovered from resistant mice. Although susceptible mice experienced slower cellular infiltration, the number of infiltrating macrophages was larger than that in resistant mice (39). The resistant strain of mice was reported to have less PMN response to O. tsutsugamushi than a susceptible strain did (26). Induction of nonspecific inflammation leading to the recruitment of PMN rendered resistant mice susceptible to rickettsia infection (26). As a result, susceptible mice died within 2 weeks of infection. By contrast, Ric r strains showed a minimal level of infection over 2 weeks and survived the infection (27, 39). Mononuclear cells such as lymphocytes and macrophages as well as PMN were observed in eschars and rashes caused by scrub typhus (1). It is notable that in a patient who died after
The host cell microfilaments and microtubules (MTs) are known to play a critical role in the life... more The host cell microfilaments and microtubules (MTs) are known to play a critical role in the life cycles of several pathogenic intracellular microbes by providing for successful invasion and promoting movement of the pathogen once inside the host cell cytoplasm. Orientia tsutsugamushi, an obligate intracellular bacterium, enters host cells by induced phagocytosis, escapes to the cytosol, and then replicates in the cytosol. ECV304 cells infected with O. tsutsugamushi revealed the colocalization of the MT organizing center (MTOC) and cytosolic orientiae by indirect immunofluorescence assay. Using immunofluorescence microscopy in the presence and absence of MT-depolymerizing agents (colchicine and nocodazole), it was shown that the cytosolic oriential movement was mediated by MTs. By transfection study (overexpression of dynamitin [also called p50], which is known to associate with dynein-dependent movement), the movement of O. tsutsugamushi to the MTOC was also mediated by dynein, the minus-end-directed MT-related motor. Although the significance of this movement in the life cycle of O. tsutsugamushi was not proven, we propose that the cytosolic O. tsutsugamushi bacteria use MTs and dyneins to propel themselves from the cell periphery to the MTOC.
Inhibition of immune checkpoint proteins like programmed death 1 (PD-1) is a promising therapeuti... more Inhibition of immune checkpoint proteins like programmed death 1 (PD-1) is a promising therapeutic approach for several cancers, including non-small cell lung cancer (NSCLC). Although PD-1 ligand (PD-L1) expression is used to predict anti-PD-1 therapy responses in NSCLC, its accuracy is relatively less. Therefore, we sought to identify a more accurate predictive blood biomarker for evaluating anti-PD-1 response. We evaluated the frequencies of T cells, B cells, natural killer (NK) cells, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), mononuclear myeloid-derived suppressor cells (M-MDSCs), and Lox-1+ PMN-MDSCs in peripheral blood samples of 62 NSCLC patients before and after nivolumab treatment. Correlation of immune-cell population frequencies with treatment response, progression-free survival, and overall survival was also determined. After the first treatment, the median NK cell percentage was significantly higher in responders than in non-responders, while the me...
Myeloid-derived suppressor cells (MDSCs) consist of monocytic (M-) MDSCs and polymorphonuclear (P... more Myeloid-derived suppressor cells (MDSCs) consist of monocytic (M-) MDSCs and polymorphonuclear (PMN-) MDSCs that contribute to an immunosuppressive environment in tumor-bearing hosts. However, research on the phenotypic and functional heterogeneity of MDSCs in tumor-bearing hosts and across different disease stage is limited. Here we subdivide M-MDSCs based on CD115 expression and report that CD115− M-MDSCs are functionally distinct from CD115+ M-MDSCs. CD115− M-MDSCs increased in bone marrow and blood as tumors progressed. Transcriptome analysis revealed that CD115− M-MDSCs expressed higher levels of neutrophil-related genes. Moreover, isolated CD115− M-MDSCs had higher potential to be differentiated into PMN-MDSCs compared with CD115+ M-MDSCs. Of note, CD115− M-MDSCs were able to differentiate into both olfactomedin 4 (OLFM4)hi and OLFM4lo PMN-MDSCs, whereas CD115+ M-MDSCs differentiated into a smaller proportion of OLFM4lo PMN-MDSCs. In vivo, M-MDSC to PMN-MDSC differentiation oc...
The anti-inflammatory effects of HY209 have been identified in sepsis. However, the anti-inflamma... more The anti-inflammatory effects of HY209 have been identified in sepsis. However, the anti-inflammatory potential of HY209 in colitis has not yet been investigated. In here, we evaluated the therapy efficacy of HY209 in an acute colitis mice model which induced by using dextran sulfate sodium (DSS). Compare to vehicle mice, HY209 treated mice showed significantly less body weight loss, lower disease activity index, longer colon length, as well as a lower histology disease scores. Meanwhile, the expression of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6) were reduced in colon tissue after HY209 treatment. Furthermore, HY209 treated mice significantly reduced inflammatory macrophage, but increased anti-inflammatory macrophage in lamina propria. In vitro, HY209 showed a strong inhibition to LPS and ATP/BzATP activated NLRP3 inflammasome formation in the bone marrow derived macrophages (BMDMs). In summary, our findings demonstrated that HY209 alleviates inflammation in colitis mice thro...
Alzheimer’s disease (AD) is an inflammatory neurodegenerative condition characterized by depositi... more Alzheimer’s disease (AD) is an inflammatory neurodegenerative condition characterized by deposition of amyloid beta (Abeta) in the brain and origins dementia. Neuronal apoptosis following neuroinflammation by Abeta impairs cognition and memory. In this study we focused on Taurodeoxyxcholate (TDCA) is an active bile acid derivative with potent anti-inflammatory function. In 5× Familial Alzheimer’s disease (5xFAD) mice model, chronic administration of TDCA in 5xFAD mice improved learning and memory in different memory test compared with PBS group. TDCA treatment significantly decreased neuronal apoptosis, load of Abeta plaques, the number of activated GFAP+ astrocytes and Iba-1+ microglia in different brain region of 5xFAD mice. CD11bhiGr1intF4/80+ myeloid cells in brain and spleen increased significantly in TDCA-treated group compared to PBS-treated group when brain single cell were immune-stained. In vitro, TDCA increased phagocytosis of Abeta. TDCA suppressed NLRP3-ASC oligomerizat...
Stroke is a leading cause of permanent disability and death, causing a significant burden to the ... more Stroke is a leading cause of permanent disability and death, causing a significant burden to the rapidly aging society [1]. Stroke occurs through a sudden compromise of cerebral blood flow, which either results from occlusion or rupture of cerebral vessels. The ischemic or hemorrhagic brain receives an insufficient supply of oxygen and glucose, leading to failure of cell respiration and cell membrane rupture. Because the regenerating capacity of injured brain cells is limited, a preventive strategy is crucial to improve the outcomes before irreversible damage occurs in individuals who have had a stroke. Currently, effective medical therapies for acute ischemic stroke include tissue plasminogen activator (tPA) and neuroprotectants. The clinical use of tPA is limited due to the narrow therapeutic window, hemorrhagic side effects, and reperfusion injury. Neuroprotectants are anticipated to fill this gap; however, no drug has proven efficacious. Conventional neuroprotectants aim to prevent neuronal
TGR5, G protein-coupled receptor 19, is also known as G protein-coupled bile acid receptor 1. The... more TGR5, G protein-coupled receptor 19, is also known as G protein-coupled bile acid receptor 1. The single exon encodes a TGR5 protein composed of 330 amino acids with seven transmembrane domains. Although TGR5 is expressed in various tissues such as liver, nervous system, adipocytes, endocrine glands, gall bladder, muscles, and spinal cord, the expression level in these tissues is less than 1/10 of myeloid immune cells. Activation of TGR5 incur various signaling cascades depending on the responder cell type. For example, synthesis and secretion of bile acids, intestinal secretion and motility, energy expenditure, glucose homeostasis, and inflammation is regulated by TGR5 pathway. Although TGR5 has got much attention as a promising new target for metabolic disorders or inflammatory disorders, only deoxycholic acid was licensed for lipoma. Obeticholic acid was also licensed for cholangitis but it interacts with FXR in addition to TGR5. Recently, we showed that taurodexoycholic acid (TDCA) interacts with TGR5, reduces inflammation incurred by activation of neutrophils, increases number of myeloid derived suppressor cells and prolongs survival of mice under sepsis. TDCA changes DNA methylation pattern of chromosome, globally edit proteomes of skin cells, brain cells and myeloid cells in mice model for atopic dermatitis, Alzheimer disease and sepsis, respectively. In addition, inflammasomal activation was suppressed by down-regulating a purinergic receptor in TDCA-treated neutrophils. In addition, cAMP-PKA-NF-κB pathway was controlled by TDCA. Phase I clinical trials for atopic dermatitis using TDCA did not show significant adverse drug reactions. Taken together, TDCA might be a non-classical anti-inflammatory drug (NCAID) for various inflammatory disorders when activation of myeloid inflammatory cells are pathognomonic features.
HY209 has been reported to be a ligand for the membrane G protein–coupled receptor, TGR5. HY209 c... more HY209 has been reported to be a ligand for the membrane G protein–coupled receptor, TGR5. HY209 could inhibit inflammatory responses in sepsis by increasing number of immunosuppressive myeloid-derived suppressor cells (MDSC), suggesting the potent role of HY209 in the treatment of atopic dermatitis (AD). Here HY209 was evaluated whether it controls inflammatory immune responses in AD. We employed mouse AD model using a topical treatment of dinitrochlorobenzene (DNCB) on the dorsal skin of Balb/c mice. HY209-treated mice showed significantly reduction in Th2 immune responses, shown as lower IgE serum, and inhibition of T cells mast cells, eosinophilia and neutrophil recruitment accompanied with reduced in epidermal and dermal thickness in skin of HY209 treated mice. Interestingly, regulatory T cells noticeably increased upon to HY209 treatment along with inhibition of type 2 cytokines production. Proteogenomic analyses of mouse skin demonstrated upregulated expression of molecules re...
Scrub typhus, caused by Orientia tsutsugamushi infection, is characterized by local as well as sy... more Scrub typhus, caused by Orientia tsutsugamushi infection, is characterized by local as well as systemic inflammatory manifestations. Inflammation is initiated by O. tsutsugamushi-infected macrophages and endothelial cells in the dermis. We investigated the regulation of chemokine induction in macrophage cell line J774A.1 in response to O. tsutsugamushi infection. The mRNAs for macrophage inflammatory proteins 1␣/ (MIP-1␣/), MIP-2, and macrophage chemoattractant protein 1 were induced within 30 min, and their levels showed a transitory peak for 3 to 12 h. However, the lymphotactin, eotaxin, gamma interferon-inducible protein 10, and T-cell activation gene 3 mRNAs were not detected by RNase protection assays. Heat-killed O. tsutsugamushi induced a similar extent of chemokine responses. Induction of the chemokine genes was not blocked by the eukaryotic protein synthesis inhibitor cycloheximide, suggesting that de novo synthesis of host cell protein is not required for these transcriptional responses. The induction of chemokine mRNAs by O. tsutsugamushi was blocked by the inhibitors of NF-B activation. Furthermore, O. tsutsugamushi induced the nuclear translocation and activation of NF-B. These results demonstrate that heat-stable molecules of O. tsutsugamushi induce a subset of chemokine genes and that induction involves activation of the transcription factor NF-B. Orientia tsutsugamushi, an obligate intracellular bacterium, is the causative agent of scrub typhus (20). The disease is characterized by fever, rash, eschar, pneumonitis, menigitis, and disseminated intravascular coagulation, which leads to severe multiorgan failure (1, 11, 62). O. tsutsugamushi causes local inflammations accompanying eschars at the site of infection, which then spread systemically (6). O. tsutsugamush infects a variety of cells in vitro and in vivo, including macrophages, polymorphonuclear leukocytes (PMN), lymphocytes, and endothelial cells (26, 38, 42, 47). Analysis of early immunologic responses to O. tsutsugamushi infection in mice showed that macrophage-mediated cellular immunity is essential for resolution of this infection (8, 39). Resistance to the lethal effects of acute rickettsia infection is under unigenic dominant control by the Ric locus (21). Macrophages infiltrate both susceptible (Ric s) and resistant (Ric r) mouse strains in response to O. tsutsugamushi infection (25, 39). A slight increase occurs in the number of infiltrating cells recovered from resistant mice. Although susceptible mice experienced slower cellular infiltration, the number of infiltrating macrophages was larger than that in resistant mice (39). The resistant strain of mice was reported to have less PMN response to O. tsutsugamushi than a susceptible strain did (26). Induction of nonspecific inflammation leading to the recruitment of PMN rendered resistant mice susceptible to rickettsia infection (26). As a result, susceptible mice died within 2 weeks of infection. By contrast, Ric r strains showed a minimal level of infection over 2 weeks and survived the infection (27, 39). Mononuclear cells such as lymphocytes and macrophages as well as PMN were observed in eschars and rashes caused by scrub typhus (1). It is notable that in a patient who died after
The host cell microfilaments and microtubules (MTs) are known to play a critical role in the life... more The host cell microfilaments and microtubules (MTs) are known to play a critical role in the life cycles of several pathogenic intracellular microbes by providing for successful invasion and promoting movement of the pathogen once inside the host cell cytoplasm. Orientia tsutsugamushi, an obligate intracellular bacterium, enters host cells by induced phagocytosis, escapes to the cytosol, and then replicates in the cytosol. ECV304 cells infected with O. tsutsugamushi revealed the colocalization of the MT organizing center (MTOC) and cytosolic orientiae by indirect immunofluorescence assay. Using immunofluorescence microscopy in the presence and absence of MT-depolymerizing agents (colchicine and nocodazole), it was shown that the cytosolic oriential movement was mediated by MTs. By transfection study (overexpression of dynamitin [also called p50], which is known to associate with dynein-dependent movement), the movement of O. tsutsugamushi to the MTOC was also mediated by dynein, the minus-end-directed MT-related motor. Although the significance of this movement in the life cycle of O. tsutsugamushi was not proven, we propose that the cytosolic O. tsutsugamushi bacteria use MTs and dyneins to propel themselves from the cell periphery to the MTOC.
Inhibition of immune checkpoint proteins like programmed death 1 (PD-1) is a promising therapeuti... more Inhibition of immune checkpoint proteins like programmed death 1 (PD-1) is a promising therapeutic approach for several cancers, including non-small cell lung cancer (NSCLC). Although PD-1 ligand (PD-L1) expression is used to predict anti-PD-1 therapy responses in NSCLC, its accuracy is relatively less. Therefore, we sought to identify a more accurate predictive blood biomarker for evaluating anti-PD-1 response. We evaluated the frequencies of T cells, B cells, natural killer (NK) cells, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), mononuclear myeloid-derived suppressor cells (M-MDSCs), and Lox-1+ PMN-MDSCs in peripheral blood samples of 62 NSCLC patients before and after nivolumab treatment. Correlation of immune-cell population frequencies with treatment response, progression-free survival, and overall survival was also determined. After the first treatment, the median NK cell percentage was significantly higher in responders than in non-responders, while the me...
Myeloid-derived suppressor cells (MDSCs) consist of monocytic (M-) MDSCs and polymorphonuclear (P... more Myeloid-derived suppressor cells (MDSCs) consist of monocytic (M-) MDSCs and polymorphonuclear (PMN-) MDSCs that contribute to an immunosuppressive environment in tumor-bearing hosts. However, research on the phenotypic and functional heterogeneity of MDSCs in tumor-bearing hosts and across different disease stage is limited. Here we subdivide M-MDSCs based on CD115 expression and report that CD115− M-MDSCs are functionally distinct from CD115+ M-MDSCs. CD115− M-MDSCs increased in bone marrow and blood as tumors progressed. Transcriptome analysis revealed that CD115− M-MDSCs expressed higher levels of neutrophil-related genes. Moreover, isolated CD115− M-MDSCs had higher potential to be differentiated into PMN-MDSCs compared with CD115+ M-MDSCs. Of note, CD115− M-MDSCs were able to differentiate into both olfactomedin 4 (OLFM4)hi and OLFM4lo PMN-MDSCs, whereas CD115+ M-MDSCs differentiated into a smaller proportion of OLFM4lo PMN-MDSCs. In vivo, M-MDSC to PMN-MDSC differentiation oc...
The anti-inflammatory effects of HY209 have been identified in sepsis. However, the anti-inflamma... more The anti-inflammatory effects of HY209 have been identified in sepsis. However, the anti-inflammatory potential of HY209 in colitis has not yet been investigated. In here, we evaluated the therapy efficacy of HY209 in an acute colitis mice model which induced by using dextran sulfate sodium (DSS). Compare to vehicle mice, HY209 treated mice showed significantly less body weight loss, lower disease activity index, longer colon length, as well as a lower histology disease scores. Meanwhile, the expression of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6) were reduced in colon tissue after HY209 treatment. Furthermore, HY209 treated mice significantly reduced inflammatory macrophage, but increased anti-inflammatory macrophage in lamina propria. In vitro, HY209 showed a strong inhibition to LPS and ATP/BzATP activated NLRP3 inflammasome formation in the bone marrow derived macrophages (BMDMs). In summary, our findings demonstrated that HY209 alleviates inflammation in colitis mice thro...
Alzheimer’s disease (AD) is an inflammatory neurodegenerative condition characterized by depositi... more Alzheimer’s disease (AD) is an inflammatory neurodegenerative condition characterized by deposition of amyloid beta (Abeta) in the brain and origins dementia. Neuronal apoptosis following neuroinflammation by Abeta impairs cognition and memory. In this study we focused on Taurodeoxyxcholate (TDCA) is an active bile acid derivative with potent anti-inflammatory function. In 5× Familial Alzheimer’s disease (5xFAD) mice model, chronic administration of TDCA in 5xFAD mice improved learning and memory in different memory test compared with PBS group. TDCA treatment significantly decreased neuronal apoptosis, load of Abeta plaques, the number of activated GFAP+ astrocytes and Iba-1+ microglia in different brain region of 5xFAD mice. CD11bhiGr1intF4/80+ myeloid cells in brain and spleen increased significantly in TDCA-treated group compared to PBS-treated group when brain single cell were immune-stained. In vitro, TDCA increased phagocytosis of Abeta. TDCA suppressed NLRP3-ASC oligomerizat...
Stroke is a leading cause of permanent disability and death, causing a significant burden to the ... more Stroke is a leading cause of permanent disability and death, causing a significant burden to the rapidly aging society [1]. Stroke occurs through a sudden compromise of cerebral blood flow, which either results from occlusion or rupture of cerebral vessels. The ischemic or hemorrhagic brain receives an insufficient supply of oxygen and glucose, leading to failure of cell respiration and cell membrane rupture. Because the regenerating capacity of injured brain cells is limited, a preventive strategy is crucial to improve the outcomes before irreversible damage occurs in individuals who have had a stroke. Currently, effective medical therapies for acute ischemic stroke include tissue plasminogen activator (tPA) and neuroprotectants. The clinical use of tPA is limited due to the narrow therapeutic window, hemorrhagic side effects, and reperfusion injury. Neuroprotectants are anticipated to fill this gap; however, no drug has proven efficacious. Conventional neuroprotectants aim to prevent neuronal
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