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The role of the microbiome in multiple sclerosis (MS) remains unknown. We have identified a novel commensal bacteria-produced lipodipeptide, Lipid 654 (L654), which functions as a toll-like receptor 2 agonist. We reported that L654 can be... more
The role of the microbiome in multiple sclerosis (MS) remains unknown. We have identified a novel commensal bacteria-produced lipodipeptide, Lipid 654 (L654), which functions as a toll-like receptor 2 agonist. We reported that L654 can be recovered in healthy human serum and that levels are significantly lower in patients with MS. The purpose of this study was to understand the functional relevance of the decreased serum L654 level in MS by determining: 1) if L654 attenuates clinical disease in a transfer model of EAE, and 2) the mechanism by which L654 mediates this attenuation. L654 administration significantly attenuated clinical disease severity in an adoptive transfer model of EAE in SJL/J mice (p < 0.0001). Cellular analysis of mononuclear cells in the spinal cord at day 18 showed a significant decrease in total cell number (p = 0.02) as well as a decrease in percentage of IL-17 producing, IFNγ producing and IL-17/IFNγ double-producing CD4+ T cells in mice administered L654. At day 11, we found a decrease in total mononuclear cell number and an increase in percentage of CD39+ Tregs and IL-10 producing CD11b+ cells in mice administered L654. These results suggest that L654, normally present in human serum but at significantly lower levels in MS serum, has the ability to mediate an immunoregulatory and disease inhibitory effect on CNS autoimmunity. L654 may thus have a role both in the abnormal immunoregulation in MS and as a potential therapeutic in this disease.
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The variable response to treatment options in multiple sclerosis (MS) suggests the need for genetic-based personalized therapeutic approaches. CBLB gene polymorphisms have been identified in MS, and altered T cell function and aberrant... more
The variable response to treatment options in multiple sclerosis (MS) suggests the need for genetic-based personalized therapeutic approaches. CBLB gene polymorphisms have been identified in MS, and altered T cell function and aberrant responses to interferon-β in MS patients with a CBLB mutation have been recently reported. Cbl-b is an E3 ubiquitin ligase that regulates T cell activation and Cbl-b-deficient (Cbl-b -/- ) mice show many T cell abnormalities also described in MS patients. This suggests that Cbl-b -/- mice may provide a novel approach for analyzing treatment options in patients with MS-associated CBLB mutations. We now report that Cbl-b -/- CD4 + T cells show significant trafficking-related abnormalities: decreased lymph node accumulation after adoptive transfer into RAG-1 -/- mice; increased sphingosine-1-phosphate receptor 1 (S1P 1 ) expression; and decreased CD69 expression compared to wild-type cells. These data imply that CBLB mutations may compromise the therapeutic efficacy of FTY720, an MS-approved drug that modulates S1P 1 expression. Despite altered Cbl-b -/- T cell trafficking, we observed robust inhibition of EAE by FTY720 in Cbl-b -/- mice. These results not only document a novel role for Cbl-b in T cell trafficking but also indicate that FTY270 may be effective in EAE/MS through mechanisms other than T cell lymph node trapping. Moreover, our findings suggest that FTY720 treatment is still an appropriate choice in patients with MS-associated CBLB mutations.
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FTY720 is a sphingosine-1-phosphate receptor 1 (S1P1) modulator used to treat Multiple Sclerosis (MS). While FTY720 is postulated to mediate its effect by enhancing T cell S1P1 internalization and degradation, the mechanisms underlying... more
FTY720 is a sphingosine-1-phosphate receptor 1 (S1P1) modulator used to treat Multiple Sclerosis (MS). While FTY720 is postulated to mediate its effect by enhancing T cell S1P1 internalization and degradation, the mechanisms underlying the therapeutic effect of FTY720 in MS are not fully understood. To further clarify the functional effects of FTY720 we utilized Cbl-b-deficient (Cbl-b-/-) mice. Cbl-b is an E3 ubiquitin ligase that regulates the PI3K-Akt pathway in T cells and its absence leads to resistance to regulatory T cells (Tregs) and multi-organ autoimmunity in mice. Given that MS has been associated with both SNPs in the CBLB gene and resistance to Tregs, Cbl-b-/- mice represent an important model for studying MS. We now report that Cbl-b-/- T cells demonstrate multiple functional abnormalities in S1P1. These include significantly less lymphopenia induced by the S1P lyase inhibitor, THI, (Cbl-b-/- blood CD4+ T cells decreased 19% vs 59% in wild type (WT) at 48 hrs), suggesting abnormal regulation of Cbl-b-/- T cell S1P1 in response to the endogenous ligand S1P. Paradoxically, Cbl-b-/- T cells demonstrate enhanced lymphopenia induced by the therapeutic agent FTY720 (Cbl-b-/- blood CD4+ T cells decreased 51% vs 26% in WT at 120 hrs). These results for the first time identify a complex role for Cbl-b in regulating expression and turnover of T cell S1P1 and suggest that SNPs in the CBLB gene may associate with a differential response to FTY720 in MS patients.
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Class II MHC-restricted T cells recently have been characterized as being either type 1 (Th1) or type 2 (Th2) based on their ability to both secrete different lymphokines and perform different functions. Characterization of these subtypes... more
Class II MHC-restricted T cells recently have been characterized as being either type 1 (Th1) or type 2 (Th2) based on their ability to both secrete different lymphokines and perform different functions. Characterization of these subtypes to date have indicated that Th1 cells secrete IL-2, IFN-gamma, lymphotoxin, and IL-3, whereas Th2 cells secrete IL-4, IL-5, and IL-3. Functionally, Th1 cells mediated cytotoxicity and delayed-type hypersensitivity, and have been termed "inflammatory cells," whereas Th2 cells mediate helper function for Ig secretion and have been termed, "regulatory cells." We now present evidence that not all Th1 clones are inflammatory and capable of mediating cutaneous delayed-type hypersensitivity. We have generated a number of myelin basic protein-specific Th1 clones that do not mediate swelling when injected together with myelin basic protein directly into the footpads of syngeneic mice. These results suggest that Th1 cells can be further s...
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The family of transcription factors termed peroxisome proliferator-activated receptors (PPARs) has recently been the focus of much interest for their possible role in the regulation of inflammation and immune responses. PPARα and PPARγ... more
The family of transcription factors termed peroxisome proliferator-activated receptors (PPARs) has recently been the focus of much interest for their possible role in the regulation of inflammation and immune responses. PPARα and PPARγ have been implicated in the regulation of macrophage and endothelial cell inflammatory responses. Although PPAR activation has generally been shown to have anti-inflammatory effects, opposite effects have been noted, and results often appear to depend on the ligands being used and the inflammatory parameters being measured. Recently, my laboratory and others have described a role for PPARγ in the responses of T lymphocytes. Ligands for PPARγ have been found to inhibit proliferation of activated T cells, and this appears to involve inhibition of IL-2 secretion and/or the induction of apoptosis. However, one problem in the interpretation of many of the studies of PPARγ, inflammation, and immunity is that ligands thought to be specific for PPARγ may have...
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Toll-like receptor 2 (TLR2) activation has been implicated in the pathogenesis of periodontal disease but the identity of the TLR2 agonists has been an evolving story. The serine/glycine lipids produced by Porphyromonas gingivalis are... more
Toll-like receptor 2 (TLR2) activation has been implicated in the pathogenesis of periodontal disease but the identity of the TLR2 agonists has been an evolving story. The serine/glycine lipids produced by Porphyromonas gingivalis are reported to engage human TLR2 and will promote the production of potent pro-inflammatory cytokines. This investigation compared the recovery of serine/glycine lipids in periodontal organisms, teeth, subgingival calculus, subgingival plaque, and gingival tissues, either from healthy sites or periodontally diseased sites. Lipids were extracted using the phospholipid extraction procedure of Bligh and Dyer and were analyzed using liquid chromatography/mass spectrometry for all serine/glycine lipid classes identified to date in P. gingivalis. Two serine/glycine lipid classes, Lipid 567 and Lipid 1256, were the dominant serine/glycine lipids recovered from oral Bacteroidetes bacteria and from subgingival calculus samples or diseased teeth. Lipid 1256 was the...
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The levels of cAMP are regulated by phosphodiesterase enzymes (PDEs), which are targets for the treatment of inflammatory disorders. We have previously shown that PDE8 regulates T cell motility. Here, for the first time, we report that... more
The levels of cAMP are regulated by phosphodiesterase enzymes (PDEs), which are targets for the treatment of inflammatory disorders. We have previously shown that PDE8 regulates T cell motility. Here, for the first time, we report that PDE8A exerts part of its control of T cell function through the V-raf-1 murine leukemia viral oncogene homolog 1 (Raf-1) kinase signaling pathway. To examine T cell motility under physiologic conditions, we analyzed T cell interactions with endothelial cells and ligands in flow assays. The highly PDE8-selective enzymatic inhibitor PF-04957325 suppresses adhesion of in vivo myelin oligodendrocyte glycoprotein (MOG) activated inflammatory CD4(+) T effector (Teff) cells to brain endothelial cells under shear stress. Recently, PDE8A was shown to associate with Raf-1 creating a compartment of low cAMP levels around Raf-1 thereby protecting it from protein kinase A (PKA) mediated inhibitory phosphorylation. To test the function of this complex in Teff cells...
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PPARγ plays a significant role in the induction of regulatory T cells (Tregs) by DC and can mediate enhanced conversion via secretion of retinoic acid. CD4+ CD25+ Foxp3+ Tregs are critical regulators of immune responses and autoimmune... more
PPARγ plays a significant role in the induction of regulatory T cells (Tregs) by DC and can mediate enhanced conversion via secretion of retinoic acid. CD4+ CD25+ Foxp3+ Tregs are critical regulators of immune responses and autoimmune diseases. nTregs are thymically derived; iTregs are converted in the periphery from CD4+ CD25– Foxp3– Teffs. Recent studies reported that GALT CD103+ DCs mediated enhanced iTreg conversion via the secretion of RA. However, the factors regulating RA secretion and hence, the induction of iTregs by DCs are not yet clear. Activation of the nuclear hormone receptor PPARγ has been shown to induce RA expression in human DCs, and thus, we postulated that PPARγ activation in DCs may be an important regulator of RA secretion and iTreg generation. Using in vitro and in vivo approaches, we now demonstrate that PPARγ activation enhances iTreg generation through increased RA synthesis from murine splenic DCs. In addition, we demonstrate that inhibition of DC PPARγ d...
Research Interests: Immunology, Immune response, Biology, Autoimmunity, Medicine, and 15 moreDendritic Cells, Transgenic Mice, Signal Transduction, Autoimmune Disease, Mice, Animals, Immune system, Retinoic Acid, Tretinoin, Regulator, Cell communication, Immune Tolerance, Secretion, Nuclear hormone receptor, and Down-Regulation
Porphyromonas gingivalis is a Gram-negative anaerobic periodontal microorganism strongly associated with tissue destructive processes in human periodontitis. Following oral infection with P. gingivalis, the periodontal bone loss in mice... more
Porphyromonas gingivalis is a Gram-negative anaerobic periodontal microorganism strongly associated with tissue destructive processes in human periodontitis. Following oral infection with P. gingivalis, the periodontal bone loss in mice is reported to require engagement of Toll-like receptor 2 (TLR2). Serine-glycine lipodipeptide or glycine aminolipid classes of P. gingivalis engage human and mouse TLR2 but a novel lipid class reported here is considerably more potent in engaging TLR2 and the heterodimer receptor TLR2/TLR6. The novel lipid class, termed Lipid 1256, consists of a diacylated phosphoglycerol moiety linked to a serine-glycine lipodipeptide, previously termed Lipid 654. Lipid 1256 is approximately 50-fold more potent in engaging TLR2 than the previously reported serine-glycine lipid classes. Lipid 1256 also stimulates cytokine secretory responses from peripheral blood monocytes and is recovered in selected oral and intestinal Bacteroidetes organisms. Therefore, t...
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The serine-glycine dipeptide lipid classes, including lipid 430 and lipid 654, are produced by the periodontal pathogen Porphyromonas gingivalis and can be detected in lipid extracts of diseased periodontal tissues and teeth of humans.... more
The serine-glycine dipeptide lipid classes, including lipid 430 and lipid 654, are produced by the periodontal pathogen Porphyromonas gingivalis and can be detected in lipid extracts of diseased periodontal tissues and teeth of humans. Both serine-glycine lipid classes were previously shown to engage human and mouse Toll-like receptor 2 (TLR2) and to inhibit mouse osteoblast differentiation and function through engagement of TLR2. It is not clear if other lipids related to serine-glycine lipids are also produced by P. gingivalis .
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Porphyromonas gingivalis produces unusual sphingolipids that are known to promote inflammatory reactions in gingival fibroblasts and Toll-like receptor 2 (TLR2)-dependent secretion of interleukin-6 from dendritic cells. The aim of the... more
Porphyromonas gingivalis produces unusual sphingolipids that are known to promote inflammatory reactions in gingival fibroblasts and Toll-like receptor 2 (TLR2)-dependent secretion of interleukin-6 from dendritic cells. The aim of the present study was to examine whether P. gingivalis lipids inhibit osteoblastic function. Total lipids from P. gingivalis and two fractions, phosphoglycerol dihydroceramides and phosphoethanolamine dihydroceramides, were prepared free of lipid A. Primary calvarial osteoblast cultures derived from 5- to 7-day-old CD-1 mice were used to examine the effects of P. gingivalis lipids on mineralized nodule formation, cell viability, apoptosis, cell proliferation, and gene expression. P. gingivalis lipids inhibited osteoblast differentiation and fluorescence expression of pOBCol2.3GFP in a concentration-dependent manner. However, P. gingivalis lipids did not significantly alter osteoblast proliferation, viability, or apoptosis. When administered during specific...
Research Interests: Biology, Apoptosis, Medicine, Gene expression, Toll like receptor signaling, and 15 moreBiological Sciences, Lipids, Cell Differentiation, Mice, Animals, Infection, Osteoblast, RANKL, Cell Proliferation, Osteoblasts, Ceramides, PORPHYROMONAS GINGIVALIS, Alveolar bone loss, TLR, and Medical and Health Sciences
The role of TLR signaling in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is unclear. This role is especially controversial in models of adoptive transfer EAE in which no adjuvant and no TLR ligands are... more
The role of TLR signaling in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is unclear. This role is especially controversial in models of adoptive transfer EAE in which no adjuvant and no TLR ligands are administered. We recently reported that a microbiome-derived TLR2 ligand, Lipid 654 (L654), is present in healthy human serum but significantly decreased in the serum of MS patients. This suggested that microbiome products that gain access to the systemic circulation, rather than being proinflammatory, may normally play an immune-regulatory role by maintaining a state of relative TLR tolerance. Therefore, a loss of microbiome-mediated TLR tolerance, as suggested by lower serum levels of L654, may play a role in the pathogenesis of MS. As proof of concept we asked whether administering low-level TLR2 ligands in adoptive transfer EAE induces TLR2 tolerance and attenuates disease. We administered low-level Pam2CSK4 or L654 to mice receiving encephalitogeni...
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The variable response to treatment options in multiple sclerosis (MS) suggests the need for genetic-based personalized therapeutic approaches. CBLB gene polymorphisms have been identified in MS, and altered T cell function and aberrant... more
The variable response to treatment options in multiple sclerosis (MS) suggests the need for genetic-based personalized therapeutic approaches. CBLB gene polymorphisms have been identified in MS, and altered T cell function and aberrant responses to interferon-β in MS patients with a CBLB mutation have been recently reported. Cbl-b is an E3 ubiquitin ligase that regulates T cell activation and Cbl-b-deficient (Cbl-b -/- ) mice show many T cell abnormalities also described in MS patients. This suggests that Cbl-b -/- mice may provide a novel approach for analyzing treatment options in patients with MS-associated CBLB mutations. We now report that Cbl-b -/- CD4 + T cells show significant trafficking-related abnormalities: decreased lymph node accumulation after adoptive transfer into RAG-1 -/- mice; increased sphingosine-1-phosphate receptor 1 (S1P 1 ) expression; and decreased CD69 expression compared to wild-type cells. These data imply that CBLB mutations may compromise the therapeu...
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Bacterial serine dipeptide lipids are known to promote inflammatory processes and are detected in human tissues associated with periodontal disease or atherosclerosis. Accurate quantification of bacterial serine lipid, specifically lipid... more
Bacterial serine dipeptide lipids are known to promote inflammatory processes and are detected in human tissues associated with periodontal disease or atherosclerosis. Accurate quantification of bacterial serine lipid, specifically lipid 654 [((S)-15-methyl-3-((13-methyltetradecanoyl)oxy)hexadecanoyl)glycyl-L-serine, (3S)-L-serine] isolated from Porphyromonas gingivalis,(1) in biological samples requires the preparation of a stable isotope internal standard for sample supplementation and subsequent mass spectrometric analysis. This report describes the convergent synthesis of a deuterium-substituted serine dipeptide lipid, which is an isotopically labeled homologue that represents a dominant form of serine dipeptide lipid recovered in bacteria.
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FTY720 is a sphingosine-1-phosphate receptor 1 (S1P1) modulator used to treat Multiple Sclerosis (MS). While FTY720 is postulated to mediate its effect by enhancing T cell S1P1 internalization and degradation, the mechanisms underlying... more
FTY720 is a sphingosine-1-phosphate receptor 1 (S1P1) modulator used to treat Multiple Sclerosis (MS). While FTY720 is postulated to mediate its effect by enhancing T cell S1P1 internalization and degradation, the mechanisms underlying the therapeutic effect of FTY720 in MS are not fully understood. To further clarify the functional effects of FTY720 we utilized Cbl-b-deficient (Cbl-b-/-) mice. Cbl-b is an E3 ubiquitin ligase that regulates the PI3K-Akt pathway in T cells and its absence leads to resistance to regulatory T cells (Tregs) and multi-organ autoimmunity in mice. Given that MS has been associated with both SNPs in the CBLB gene and resistance to Tregs, Cbl-b-/- mice represent an important model for studying MS. We now report that Cbl-b-/- T cells demonstrate multiple functional abnormalities in S1P1. These include significantly less lymphopenia induced by the S1P lyase inhibitor, THI, (Cbl-b-/- blood CD4+ T cells decreased 19% vs 59% in wild type (WT) at 48 hrs), suggesting abnormal regulation of Cbl-b-/- T cell S1P1 in response to the endogenous ligand S1P. Paradoxically, Cbl-b-/- T cells demonstrate enhanced lymphopenia induced by the therapeutic agent FTY720 (Cbl-b-/- blood CD4+ T cells decreased 51% vs 26% in WT at 120 hrs). These results for the first time identify a complex role for Cbl-b in regulating expression and turnover of T cell S1P1 and suggest that SNPs in the CBLB gene may associate with a differential response to FTY720 in MS patients.
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Porphyromonas gingivalis is a periodontal pathogen strongly associated with loss of attachment and supporting bone for teeth. We have previously shown that the total lipid extract of P. gingivalis inhibits osteoblast differentiation... more
Porphyromonas gingivalis is a periodontal pathogen strongly associated with loss of attachment and supporting bone for teeth. We have previously shown that the total lipid extract of P. gingivalis inhibits osteoblast differentiation through engagement of Toll-like receptor 2 (TLR2) and that serine dipeptide lipids of P. gingivalis engage both mouse and human TLR2. The purpose of the present investigation was to determine whether these serine lipids inhibit osteoblast differentiation in vitro and in vivo and whether TLR2 engagement is involved. Osteoblasts were obtained from calvaria of wild type or TLR2 knockout mouse pups that also express the Col2.3GFP transgene. Two classes of serine dipeptide lipids, termed Lipid 654 and Lipid 430, were tested. Osteoblast differentiation was monitored by cell GFP fluorescence and osteoblast gene expression and osteoblast function was monitored as von Kossa stained mineral deposits. Osteoblast differentiation and function were evaluated in calvar...
Research Interests: Engineering, Biology, Medicine, Transgenic Mice, Toll like receptor signaling, and 14 moreBiological Sciences, Cell Differentiation, Humans, Mice, Bone, Animals, Chronic Periodontitis, Osteoblasts, Elsevier, Virulence Factors, PORPHYROMONAS GINGIVALIS, Lipopeptides, Alveolar bone loss, and Medical and Health Sciences
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The variable response to therapy in multiple sclerosis (MS) suggests a need for personalized approaches based on individual genetic differences. GWAS have linked CBLB gene polymorphisms with MS and recent evidence demonstrated that these... more
The variable response to therapy in multiple sclerosis (MS) suggests a need for personalized approaches based on individual genetic differences. GWAS have linked CBLB gene polymorphisms with MS and recent evidence demonstrated that these polymorphisms can be associated with abnormalities in T cell function and response to interferon-β therapy. Cbl-b is an E3 ubiquitin ligase that regulates T cell activation and Cbl-b-deficient (Cbl-b(-/-)) mice show T cell abnormalities described in MS patients. We now show that Cbl-b(-/-) T cells demonstrate significant lymph node trafficking abnormalities. We thus asked whether the MS-approved drug, FTY720, postulated to trap T cells in lymphoid tissues, is less effective in the context of Cbl-b dysfunction. We now report that FTY720 significantly inhibits EAE in Cbl-b(-/-) mice. Our results newly document a role for Cbl-b in T cell trafficking but suggest nevertheless that MS patients with Cbl-b abnormalities may still be excellent candidates for...
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Research Interests: Leukemia, Medicine, Signal Transduction, Humans, Mice, and 3 moreAnimals, NF-kappa B, and Clinical Sciences
Research Interests: Chemistry, Dentistry, Macrophages, Medicine, Lipids, and 15 moreCell line, Cell Differentiation, Mice, Female, Animals, Osteoclasts, Tandem Mass Spectrometry, High Pressure Liquid Chromatography, Liquid Chromatography / Electrospray Ionization Mass Spectrometry, Endodontics, Osteoblasts, Virulence Factors, Ceramides, PORPHYROMONAS GINGIVALIS, and Inflammation Mediators
ABSTRACTRecent reports indicate thatPorphyromonas gingivalismediates alveolar bone loss or osteoclast modulation through engagement of Toll-like receptor 2 (TLR2), though the factors responsible for TLR2 engagement have yet to be... more
ABSTRACTRecent reports indicate thatPorphyromonas gingivalismediates alveolar bone loss or osteoclast modulation through engagement of Toll-like receptor 2 (TLR2), though the factors responsible for TLR2 engagement have yet to be determined. Lipopolysaccharide (LPS) and lipid A, lipoprotein, fimbriae, and phosphorylated dihydroceramides ofP. gingivalishave been reported to activate host cell responses through engagement of TLR2. LPS and lipid A are the most controversial in this regard because conflicting evidence has been reported concerning the capacity ofP. gingivalisLPS or lipid A to engage TLR2 versus TLR4. In the present study, we first preparedP. gingivalisLPS by the Tri-Reagent method and evaluated this isolate for contamination with phosphorylated dihydroceramide lipids. Next, the lipid A prepared from this LPS was evaluated for the presence of phosphorylated dihydroceramide lipids. Finally, we characterized the lipid A by the matrix-assisted laser desorption ionization mas...
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Immune control of effector T-cell function can be mediated by cAMP signalling and regulatory T-cell action independently of the PKA–CREM/ICER signalling pathway. EPAC may act as an alternative cAMP effector in this process.
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We found that Teff cells express PDE8 in vivo. Inhibition of PDE8 by the PDE inhibitor dipyridamole (DP) activates cAMP signaling and suppresses two major integrins involved in Teff cell adhesion. Accordingly, DP as well as the novel... more
We found that Teff cells express PDE8 in vivo. Inhibition of PDE8 by the PDE inhibitor dipyridamole (DP) activates cAMP signaling and suppresses two major integrins involved in Teff cell adhesion. Accordingly, DP as well as the novel PDE8-selective inhibitor PF-4957325-00 ...
Research Interests: Biology, Cytokines, Cell Adhesion, Membrane Proteins, Medicine, and 15 moreGene expression, Multidisciplinary, Laser Capture Microdissection, Mice, cyclic AMP, Female, Animals, PLoS one, Phosphodiesterase Inhibitors, Endothelial cell, T cell activation, Cell Proliferation, Hydrolysis, Intracellular Space, and Claudin
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Novel phosphorylated dihydroceramide (PDHC) lipids produced by the periodontal pathogen Porphyromonas gingivalis include phosphoethanolamine (PE DHC) and phosphoglycerol dihydroceramides (PG DHC) lipids. These PDHC lipids mediate cellular... more
Novel phosphorylated dihydroceramide (PDHC) lipids produced by the periodontal pathogen Porphyromonas gingivalis include phosphoethanolamine (PE DHC) and phosphoglycerol dihydroceramides (PG DHC) lipids. These PDHC lipids mediate cellular effects through Toll-like receptor 2 ( ...
Research Interests: Multiple sclerosis, Mass Spectrometry, Biology, Medicine, Multidisciplinary, and 15 moreBrain, Humans, Bacteria, Plasma, Dendritic cell, Phosphorylation, PLoS one, Intestines, Toll-like receptor, Human Disease, Experimental Autoimmune Encephalomyelitis, Ceramides, PORPHYROMONAS GINGIVALIS, Arteries, and periodontium
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ABSTRACT
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Mice sensitized to OVA and subjected to acute OVA aerosol exposures develop allergic airway disease (AAD). However, chronic continuous Ag exposure results in resolution of AAD and the development of local inhalational tolerance (LIT).... more
Mice sensitized to OVA and subjected to acute OVA aerosol exposures develop allergic airway disease (AAD). However, chronic continuous Ag exposure results in resolution of AAD and the development of local inhalational tolerance (LIT). Because we have previously observed ...
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Abolishing the inhibitory signal of intracellular cAMP is a prerequisite for effector T (Teff) cell function. The regulation of cAMP within leukocytes critically depends on its degradation by cyclic nucleotide phosphodiesterases (PDEs).... more
Abolishing the inhibitory signal of intracellular cAMP is a prerequisite for effector T (Teff) cell function. The regulation of cAMP within leukocytes critically depends on its degradation by cyclic nucleotide phosphodiesterases (PDEs). We have previously shown that PDE8A, a PDE isoform with 40-100-fold greater affinity for cAMP than PDE4, is selectively expressed in Teff vs. regulatory T (Treg) cells and controls CD4(+) Teff cell adhesion and chemotaxis. Here, we determined PDE8A expression and function in CD4(+) Teff cell populations in vivo. Using magnetic bead separation to purify leukocyte populations from the lung draining hilar lymph node (HLN) in a mouse model of ovalbumin-induced allergic airway disease (AAD), we found by Western immunoblot and quantitative (q)RT-PCR that PDE8A protein and gene expression are enhanced in the CD4(+) T cell fraction over the course of the acute inflammatory disease and recede at the late tolerant non-inflammatory stage. To evaluate PDE8A as a...
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ABSTRACTThe total cellular lipids ofPorphyromas gingivalis, a known periodontal pathogen, were previously shown to promote dendritic cell activation and inhibition of osteoblasts through engagement of Toll-like receptor 2 (TLR2). The... more
ABSTRACTThe total cellular lipids ofPorphyromas gingivalis, a known periodontal pathogen, were previously shown to promote dendritic cell activation and inhibition of osteoblasts through engagement of Toll-like receptor 2 (TLR2). The purpose of the present investigation was to fractionate all lipids ofP. gingivalisand define which lipid classes account for the TLR2 engagement, based on bothin vitrohuman cell assays andin vivostudies in mice. Specific serine-containing lipids ofP. gingivalis, called lipid 654 and lipid 430, were identified in specific high-performance liquid chromatography fractions as the TLR2-activating lipids. The structures of these lipids were defined using tandem mass spectrometry and nuclear magnetic resonance methods.In vitro, both lipid 654 and lipid 430 activated TLR2-expressing HEK cells, and this activation was inhibited by anti-TLR2 antibody. In contrast, TLR4-expressing HEK cells failed to be activated by either lipid 654 or lipid 430. Wild-type (WT) or...
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Mice sensitized to ovalbumin (OVA) develop allergic airway disease (AAD) with short-term daily OVA aerosol challenge; inflammation resolves with long-term OVA aerosol exposure, resulting in local inhalational tolerance (LIT). Cbl-b is an... more
Mice sensitized to ovalbumin (OVA) develop allergic airway disease (AAD) with short-term daily OVA aerosol challenge; inflammation resolves with long-term OVA aerosol exposure, resulting in local inhalational tolerance (LIT). Cbl-b is an E3 ubiquitin ligase involved with CD28 signaling; Cbl-b(-/-) effector T cells are resistant to regulatory T cell-mediated suppression in vitro and in vivo. The present study utilized Cbl-b(-/-) mice to investigate the role of Cbl-b in the development of AAD and LIT. Cbl-b(-/-) mice exhibited increased airway inflammation during AAD, which failed to resolve with long-term OVA aerosol exposure. Exacerbation of inflammation in Cbl-b(-/-) mice correlated with increased proinflammatory cytokine levels and expansion of effector T cells in the BAL during AAD, but did not result in either a modulation of lymphocyte subsets in systemic tissues or in OVA-specific IgE in serum. These results implicate a role for Cbl-b in the resolution of allergic airway infla...
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Multiple reaction monitoring mass spectrometry (MRM-MS) analysis of lipid extracts from human carotid endarterectomy and carotid artery samples from young individuals consistently demonstrated the presence of bacterial serine dipeptide... more
Multiple reaction monitoring mass spectrometry (MRM-MS) analysis of lipid extracts from human carotid endarterectomy and carotid artery samples from young individuals consistently demonstrated the presence of bacterial serine dipeptide lipid classes including Lipid 654, an agonist for human and mouse Toll-like receptor 2, and Lipid 430, the deacylated product of Lipid 654. The relative levels of Lipid 654 and Lipid 430 were also determined in common oral and intestinal bacteria from the phylum Bacteroidetes, and human serum and brain samples from healthy adults. The median Lipid 430/Lipid 654 ratio observed in carotid endarterectomy samples was significantly higher than the median ratio in lipid extracts of common oral and intestinal Bacteroidetes bacteria, and serum and brain samples from healthy subjects. More importantly, the median Lipid 430/Lipid 654 ratio was significantly elevated in carotid endarterectomies when compared with control artery samples. Our results indicate that...
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Multiple reaction monitoring mass spectrometry (MRM-MS) analysis of lipid extracts from human carotid endarterectomy and carotid artery samples from young individuals consistently demonstrated the presence of bacterial serine dipeptide... more
Multiple reaction monitoring mass spectrometry (MRM-MS) analysis of lipid extracts from human carotid endarterectomy and carotid artery samples from young individuals consistently demonstrated the presence of bacterial serine dipeptide lipid classes including Lipid 654, an agonist for human and mouse Toll-like receptor 2, and Lipid 430, the deacylated product of Lipid 654. The relative levels of Lipid 654 and Lipid 430 were also determined in common oral and intestinal bacteria from the phylum Bacteroidetes, and human serum and brain samples from healthy adults. The median Lipid 430/Lipid 654 ratio observed in carotid endarterectomy samples was significantly higher than the median ratio in lipid extracts of common oral and intestinal Bacteroidetes bacteria, and serum and brain samples from healthy subjects. More importantly, the median Lipid 430/Lipid 654 ratio was significantly elevated in carotid endarterectomies when compared with control artery samples. Our results indicate that...