Project description:Bone marrow derived cells stimulated with RANKL (receptor activator of nuclear factor kappa B ligand, also known as Tumor necrosis factor ligand superfamily member 11) to generate osteoclasts.
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. We report that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator activated receptor-alpha (PPARa) transcription and fatty acid b-oxidation (FAO), and induces monocyte chemotaxis via C-C motif chemokine ligand 2. In male mice with diet-induced MASH, blocking oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lower steatosis, inflammation, and fibrosis by inducing PPARa-driven FAO, and suppressing monocyte chemotaxis, nuclear factor-kappa B and transforming growth factor-beta targets. These findings highlight hepatic oxalate overproduction as a new target for the treatment of MASH.
Project description:Increased antigen cross-presentation but impaired cross-priming after activation of PPARγ is mediated by up-regulation of B7H1 Dendritic cells (DCs) are able to take up exogenous antigens and present antigen-derived peptides on MHC class I molecules, a process termed cross-presentation. The mannose receptor (MR), an endocytic receptor expressed on a variety of antigen-presenting cells (APCs), has been demonstrated to target soluble antigens exclusively towards cross-presentation. In this study, we investigated the role of the murine nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated transcription factor with immunomodulatory properties, in MR-mediated endocytosis and cross-presentation of the model antigen ovalbumin (OVA). We could demonstrate both in vitro and in vivo that activation of PPARγ resulted in increased MR expression, which in consequence led to enhanced MR-mediated endocytosis and elevated cross-presentation of soluble OVA. Concomitantly, activation of PPARγ in DCs induced up-regulation of the co-inhibitory molecule B7H1, which, despite enhanced cross-presentation, caused an impaired activation of naive OVA-specific CD8+ T cells and the induction of T cell tolerance. These data provide a mechanistic basis for the immunomodulatory action of PPARγ which might open new possibilities in development of therapeutical approaches aimed at the control of excessive immune responses, e.g. in T cell-mediated autoimmunity. Comparison of murine mannose receptor negative versus mannose receptor positive bone marrow-derived DCs
Project description:Emerging studies revealed an immunomodulatory role of the Aryl hydrocarbon receptor (AhR), a receptor sensing environmental contaminants, and involved in their detoxification. Besides its function as a transcription factor, AhR can participate in non-genomic signaling through ubiquitination and phosphorylation-dependent processes. In this study, a multi-PTM-omics approach, including proteome, ubiquitome, and phosphoproteome, was utilized to examine mechanisms of non-genomic AhR-signaling in endotoxin-activated monocyte-derived macrophages. This dataset entails proteome and phosphoproteome data.
Project description:Increased antigen cross-presentation but impaired cross-priming after activation of PPARγ is mediated by up-regulation of B7H1 Dendritic cells (DCs) are able to take up exogenous antigens and present antigen-derived peptides on MHC class I molecules, a process termed cross-presentation. The mannose receptor (MR), an endocytic receptor expressed on a variety of antigen-presenting cells (APCs), has been demonstrated to target soluble antigens exclusively towards cross-presentation. In this study, we investigated the role of the murine nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated transcription factor with immunomodulatory properties, in MR-mediated endocytosis and cross-presentation of the model antigen ovalbumin (OVA). We could demonstrate both in vitro and in vivo that activation of PPARγ resulted in increased MR expression, which in consequence led to enhanced MR-mediated endocytosis and elevated cross-presentation of soluble OVA. Concomitantly, activation of PPARγ in DCs induced up-regulation of the co-inhibitory molecule B7H1, which, despite enhanced cross-presentation, caused an impaired activation of naive OVA-specific CD8+ T cells and the induction of T cell tolerance. These data provide a mechanistic basis for the immunomodulatory action of PPARγ which might open new possibilities in development of therapeutical approaches aimed at the control of excessive immune responses, e.g. in T cell-mediated autoimmunity.
Project description:Overall goal was to look for the differentially expressed genes between receptor activator of nuclear factor kappa-B ligand (RANKL)-stimulated wild type (WT) bone marrow macrophages (BMMs) and the BMMs in which the expression or the enzyme activity of cyclooxygenase-2 (Cox2), the major enzyme for prostaglandin E2 (PGE2) synthesis, is absent. For this purpose, two separate microarrays (experiment 1 and 2) were done. In both the experiments, Serum Amyloid A3 (Saa3) was one of the most highly differentially expressed gene.
Project description:Toll-like receptor (TLR) signalling activation by pathogens is critical to the induction of immune responses, and demands tight regulation. Chemokine ligand 2 (CCL2) secretion triggered by TLR4 or TLR8 engagement is strongly inhibited upon simultaneous activation of both TLRs in human monocyte-derived dendritic cells (MD-DC). Impaired CCL2 secretion occurs concomitantly to IL-12 up-regulation, being part of a complex regulatory circuit ensuring optimal Th type 1 polarization. Interestingly, triggering selected TLRs or their combinations differently affects nuclear factor-kB p65 activation and microRNA expression. To investigate in details such different modulation we performed a microarray profiling of MD-DCs stimulated by different TLRs agonist or their combination in three different donors. We found that CCL2 supplies an important immunomodulatory role to DCs, and may contribute to dictate the cytokine profile in Th type 1 responses induced by DCs.
Project description:This study investigated which genes regarding root resorption are upregulated by cryopreservation and whether cryopreservation affects the expression of Macrophage –colony stimulating factor. We manufactured the customized template which was made of genes selected regarding root resorption including osteoprotegerin (OPG), receptor activator of nuclear factor-kappa B ligand (RANKL), RANKL’s cognate receptor (RANK), macrophage colony-stimulating factor (M-CSF), interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α), and bone morphogenetic proteins (BMP) and analyzed gene expression.
Project description:We compare M1 and M2 stimuli in human macrophages. Total RNA obtained from autologous serum monocyte-derived macrophages exposed to key cytokines, Lps, Glucocorticoid receptor ligand or left untreated.
Project description:This study investigated which genes regarding root resorption are upregulated by cryopreservation and whether cryopreservation affects the expression of Macrophage M-bM-^@M-^Scolony stimulating factor. We manufactured the customized template which was made of genes selected regarding root resorption including osteoprotegerin (OPG), receptor activator of nuclear factor-kappa B ligand (RANKL), RANKLM-bM-^@M-^Ys cognate receptor (RANK), macrophage colony-stimulating factor (M-CSF), interleukin-1M-NM-2 (IL-1M-NM-2), and tumor necrosis factor-alpha (TNF-M-NM-1), and bone morphogenetic proteins (BMP) and analyzed gene expression. cultured human periodontal ligament cells (control) VS cryopreserved and cultured periodontal ligament cells(cryopreserved group): 3 control replicates, 3 cryopreserved replicates