Similar Datasets
Project description:Liver fibrosis, a pathogical change commonly existing in various chronic liver diseases, can ultimately develop into life-threatening liver cirrhosis, but effective antifibrotic therapy is absent due to limited understanding of fibrogenic process. The characteristic fibrotic scar in fibrosis is stiff and disorganized extracellular matrix (ECM) yielded by ECM remodeling, a pathogenic process with vigorous participation of aberrantly activated macrophages. Prolyl endopeptidase (PREP) is a dipeptidyl peptidase that possess both proteolytic and non-proteolytic functions. Using Prep knockout mouse, we found aggravated liver fibrosis in a NASH-related fibrosis murine model, as well as significantly altered transcriptome by in vitro M1/M2 polarization in primary macrophages after PREP ablation. Most importantly, a PREP-mediated direct transcriptional regulation to active cis-regulatory genomic regions was identified for the first time as a novel non-proteolytic function of PREP, based on significant nuclear localization of PREP and CUT&Tag-seq results. Among the PREP-downstream genes, Ctsb and Ctsd, genes encoding ECM remodeling-related profibrogenic cathepsin B and D respectively, were excessively expressed in PREP-ablated macrophages in vitro and in vivo. Our results indicates that PREP is a newly found transcriptional regulator in macrophage, and is a promising therapeutic target for fibrosis-related aberrant macrophage activation.
2023-08-09 | GSE213049 | GEO
Project description:Liver fibrosis, a pathogical change commonly existing in various chronic liver diseases, can ultimately develop into life-threatening liver cirrhosis, but effective antifibrotic therapy is absent due to limited understanding of fibrogenic process. The characteristic fibrotic scar in fibrosis is stiff and disorganized extracellular matrix (ECM) yielded by ECM remodeling, a pathogenic process with vigorous participation of aberrantly activated macrophages. Prolyl endopeptidase (PREP) is a dipeptidyl peptidase that possess both proteolytic and non-proteolytic functions. Using Prep knockout mouse, we found aggravated liver fibrosis in a NASH-related fibrosis murine model, as well as significantly altered transcriptome by in vitro M1/M2 polarization in primary macrophages after PREP ablation. Most importantly, a PREP-mediated direct transcriptional regulation to active cis-regulatory genomic regions was identified for the first time as a novel non-proteolytic function of PREP, based on significant nuclear localization of PREP and CUT&Tag-seq results. Among the PREP-downstream genes, Ctsb and Ctsd, genes encoding ECM remodeling-related profibrogenic cathepsin B and D respectively, were excessively expressed in PREP-ablated macrophages in vitro and in vivo. Our results indicates that PREP is a newly found transcriptional regulator in macrophage, and is a promising therapeutic target for fibrosis-related aberrant macrophage activation.
2023-08-09 | GSE213050 | GEO
Project description:Prolyl endopeptidase-mediated transcriptional regulation in quiescent and activated bone marrow-derived macrophages
| PRJNA878832 | ENA
Project description:Prolyl endopeptidase-mediated transcriptional regulation in quiescent and activated bone marrow-derived macrophages (CUT&Tag)
| PRJNA878828 | ENA
Project description:Prolyl endopeptidase-mediated transcriptional regulation in quiescent and activated bone marrow-derived macrophages (Bulk RNA-seq)
| PRJNA878835 | ENA
Project description:Glucocorticoids (GC) display pleiotropic effects on the immune system. Macrophages are a major target for GC action. Here we show that dexamethasone (DEX), a synthetic GC, decreased viability of naïve bone marrow-derived macrophages (BMDM), involving an apoptotic mechanism. Administration of DEX together with lipopolysaccharide (LPS) protected BMDM against DEX-mediated cell death, suggesting that activated BMDM respond to DEX differently than naïve BMDM. An insight to the molecular basis of LPS actions was provided by a 7 fold increase in mRNA levels of glucocorticoid receptor beta (GRβ), a GR dominant-negative splice variant which inhibits GRα's transcriptional activity. LPS did not inhibit all DEX-mediated effects on BMDM; DEX significantly reduced the percentage of BMDM expressing high levels of the cell surface markers F4/80 and CD11b and led to a decrease in macrophage inflammatory protein 1 alpha (MIP1-α) mRNA and protein levels. These two DEX-mediated effects were not prevented by LPS. Our finding that LPS did not reduce the DEX-induced elevation of glucocorticoid-induced leucine zipper (GILZ), a mediator of GCs anti-inflammatory actions, may provide an underlying mechanism. These findings enable a better understanding of clinical states, such as sepsis, in which macrophages are activated by endotoxins and treatment by GCs is considered.
| S-EPMC3948355 | biostudies-other
Project description:Slit2 exerts antitumor effects in various cancers; however, the underlying mechanism, especially its role in regulating the immune, especially in the bone marrow niche, system is still unknown. Elucidating the behavior of macrophages in tumor progression can potentially improve immunotherapy. Using a spontaneous mammary tumor virus promoter-polyoma middle T antigen (PyMT) breast cancer mouse model, we observed that Slit2 increased the abundance of antitumor M1 macrophage in the bone marrow upon differentiation in vitro. Moreover, myeloablated PyMT mice injected with Slit2-treated bone marrow allografts showed a marked reduction in tumor growth, with enhanced recruitment of M1 macrophage in their tumor stroma. Mechanistic studies revealed that Slit2 significantly enhanced glycolysis and reduced fatty acid oxidation in bone marrow-derived macrophages (BMDMs). Slit2 treatment also altered mitochondrial respiration metabolites in macrophages isolated from healthy human blood that were treated with plasma from breast cancer patients. Overall, this study, for the first time, shows that Slit2 increases BMDM polarization toward antitumor phenotype by modulating immune-metabolism. Furthermore, this study provides evidence that soluble Slit2 could be developed as novel therapeutic strategy to enhance antitumor immune response.
| S-EPMC8581492 | biostudies-literature
Project description:Macro-autophagy is a highly conserved catabolic process among eukaryotes affecting macrophages. This work studies the genetic regulatory network involving the interplay between autophagy and macrophage polarization (activation). Autophagy-related genes (Atgs) and differentially expressed genes (DEGs) of macrophage polarization (M1-M2) were predicted, and their regulatory networks constructed. Naïve (M0) mouse bone marrow-derived monocytes were differentiated into M1 and M2a. Validation of the targets of Smad1, LC3A and LC3B, Atg16L1, Atg7, IL-6, CD68, Arg-1, and Vamp7 was performed in vitro. Immunophenotyping by flow cytometry revealed three macrophage phenotypes: M0 (IL-6 + /CD68 +), M1 (IL-6 + /CD68 + /Arg-1 +), and M2a (CD68 + /Arg-1). Confocal microscopy revealed increased autophagy in both M1 and M2a and a significant increase in the pre-autophagosomes size and number. Bafilomycin A increased the expression of CD68 and Arg-1 in all cell lineages. In conclusion, our approach predicted the protein targets mediating the interplay between autophagy and macrophage polarization. We suggest that autophagy reprograms macrophage polarization via CD68, arginase 1, Atg16L1-1, and Atg16L1-3. The current findings provide a foundation for the future use of macrophages in immunotherapy of different autoimmune disorders.
| S-EPMC10060350 | biostudies-literature
Project description:Persistent macrophage activation is associated with the expression of various pro-inflammatory genes, cytokines and chemokines, which may initiate or amplify inflammatory disorders. A novel synthetic BET inhibitor, JQ1, was proven to exert immunosuppressive activities in macrophages. However, a genome-wide search for JQ1 molecular targets has not been undertaken. The present study aimed at evaluating the anti-inflammatory function and underlying genes that are targeted by JQ1 in LPS-stimulated primary bone marrow-derived macrophages (BMDMs) using global transcriptomic RNA sequencing and quantitative real-time PCR. Among the annotated genes, transcriptional sequencing of BMDMs that were treated with JQ1 revealed a selective effect on LPS-induced gene expression in which the induction of cytokines/chemokines, interferon-stimulated genes, and prominent (transcription factors) TFs was suppressed. Additionally, we found that JQ1 reduced the expression of previously unidentified genes that are important in inflammation. Importantly, these inflammatory genes were not affected by JQ1 treatment alone. Furthermore, we confirmed that JQ1 reduced cytokines/chemokines in the supernatants of LPS treated BMDMs. Moreover, the biological pathways and gene ontology of the differentially expressed genes were determined in the JQ1 treatment of BMDMs. These unprecedented results suggest that the BET inhibitor JQ1 is a candidate for the prevention or therapeutic treatment of inflammatory disorders.
| S-EPMC4652239 | biostudies-literature
Project description:Impaired synaptic integrity and function due to accumulation of amyloid β-protein (Aβ42) oligomers is thought to be a major contributor to cognitive decline in Alzheimer's disease (AD). However, the exact role of Aβ42 oligomers in synaptotoxicity and the ability of peripheral innate immune cells to rescue synapses remain poorly understood due to the metastable nature of oligomers. Here, we utilized photo-induced cross-linking to stabilize pure oligomers and study their effects vs. fibrils on synapses and protection by Aβ-phagocytic macrophages. We found that cortical neurons were more susceptible to Aβ42 oligomers than fibrils, triggering additional neuritic arborization retraction, functional alterations (hyperactivity and spike waveform), and loss of VGluT1- and PSD95-excitatory synapses. Co-culturing neurons with bone marrow-derived macrophages protected synapses against Aβ42 fibrils; moreover, immune activation with glatiramer acetate (GA) conferred further protection against oligomers. Mechanisms involved increased Aβ42 removal by macrophages, amplified by GA stimulation: fibrils were largely cleared through intracellular CD36/EEA1+-early endosomal proteolysis, while oligomers were primarily removed via extracellular/MMP-9 enzymatic degradation. In vivo studies in GA-immunized or CD115+-monocyte-grafted APPSWE/PS1ΔE9-transgenic mice followed by pre- and postsynaptic analyses of entorhinal cortex and hippocampal substructures corroborated our in vitro findings of macrophage-mediated synaptic preservation. Together, our data demonstrate that activated macrophages effectively clear Aβ42 oligomers and rescue VGluT1/PSD95 synapses, providing rationale for harnessing macrophages to treat AD.
| S-EPMC7005081 | biostudies-literature