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Multi-omics approaches reveal TNF-mediated inhibition of tissue reparative macrophages is via a gene-selective transcriptional mechanism (ATAC-Seq)

ABSTRACT: Anti-TNF therapies are a core anti-inflammatory approach for chronic diseases such as rheumatoid arthritis and Crohn’s Disease. Previously, we and others found that TNF blocks the emergence and function of alternatively-activated or M2 macrophages involved in wound healing and tissue-reparative functions. Conceivably, anti-TNF drugs could mediate their protective effects in part by an altered balanced of macrophage activity. To understand the mechanistic basis of how TNF regulates tissue-reparative macrophages we used RNAseq, scRNAseq, ATACseq, time-resolved phospho-proteomics, gene-specific approaches, metabolic analysis and signaling pathway deconvolution. Our findings reveal that TNF controls tissue-reparative macrophage gene expression in a highly gene-specific way dependent on JNK signaling. We uncover principles of the selectively inhibition by TNF via the type 1 TNF receptor on specific populations of alternative activated macrophages.

ORGANISM(S): Mus musculus

PROVIDER: GSE185375 | GEO | 2022/01/11

REPOSITORIES: GEO

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Multi-omics approaches reveal TNF-mediated inhibition of tissue reparative macrophages is via a gene-selective transcriptional mechanism

Project description:Anti-TNF therapies are a core anti-inflammatory approach for chronic diseases such as rheumatoid arthritis and Crohn’s Disease. Previously, we and others found that TNF blocks the emergence and function of alternatively-activated or M2 macrophages involved in wound healing and tissue-reparative functions. Conceivably, anti-TNF drugs could mediate their protective effects in part by an altered balanced of macrophage activity. To understand the mechanistic basis of how TNF regulates tissue-reparative macrophages we used RNAseq, scRNAseq, ATACseq, time-resolved phospho-proteomics, gene-specific approaches, metabolic analysis and signaling pathway deconvolution. Our findings reveal that TNF controls tissue-reparative macrophage gene expression in a highly gene-specific way dependent on JNK signaling. We uncover principles of the selectively inhibition by TNF via the type 1 TNF receptor on specific populations of alternative activated macrophages.

2022-01-07 | PXD028667 | Pride

Multi-omics approaches reveal TNF-mediated inhibition of tissue reparative macrophages is via a gene-selective transcriptional mechanism (scRNA-Seq)

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Multi-omics approaches reveal TNF-mediated inhibition of tissue reparative macrophages is via a gene-selective transcriptional mechanism (bulk RNA-Seq)

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Self-maintenance of Cardiac Resident Reparative Macrophages Attenuates Doxorubicin-induced Cardiomyopathy through the SR-A1-c-Myc Axis

Project description:Rationale: Doxorubicin-induced cardiomyopathy (DiCM) is a significant cause of heart failure and mortality in cancer patients, in which macrophage-orchestrated inflammation serves as an essential pathogenic mechanism. However, the specific roles of tissue-resident and monocyte-derived macrophages in DiCM remain poorly understood. Objective: Uncovering the origins, phenotypes, and functions of proliferative cardiac resident macrophages and mechanistic insights into the self-maintenance of cardiac macrophage during DiCM progression. Methods and Results: Mice were administrated with doxorubicin to induce cardiomyopathy. Dynamic changes of resident and monocyte-derived macrophages were examined by lineage tracing, parabiosis, and bone marrow transplantation. We found that the monocyte-derived macrophages primarily exhibited a pro-inflammatory phenotype that dominated the whole DiCM pathological process and impaired cardiac function. In contrast, cardiac resident macrophages were vulnerable to doxorubicin insult. The survived resident macrophages exhibited enhanced proliferation and conferred a reparative role. Global or myeloid specifically ablation of class A1 scavenger receptor (SR-A1) inhibited proliferation of cardiac resident reparative macrophages and therefore exacerbated cardiomyopathy in DiCM mice. Importantly, the detrimental effect of macrophage SR-A1 deficiency was confirmed by transplantation of GFP+ wild type bone marrow. At the mechanistic level, we show that c-Myc, a key transcriptional factor for the SR-A1-P38-SIRT1 pathway, mediated the effect of SR-A1 in reparative macrophage proliferation in DiCM. Conclusions: The SR-A1-c-Myc axis may represent a promising target to treat DiCM through augmentation of cardiac resident reparative macrophage proliferation.

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PPARg T166 phosphorylation-mediated lipid synthesis sustains the reparative function of macrophages during tissue repair [CUT&RUN]

Project description:Macrophages exhibit a reparative phenotype that supports tissue repair and remodeling in response to tissue injury. However, the metabolic requirements that support this process have remained incompletely understood. Here, we showed that posttranslational modification (PTM) of peroxisome proliferator-activated receptor g (PPARg) regulated lipid synthesis in response to wound microenvironmental cues and that metabolic rewiring orchestrated the function of reparative macrophages. In injured tissues, repair signaling attenuated macrophage PPARg threonine 166 (T166) phosphorylation, which induced a partially active PPARg program with increased binding activity to the regulator regions of lipid synthesis-associated genes, thereby activating lipogenesis. The accumulated lipids served as signaling molecules, triggering signal transducer and activator of transcription 3 (STAT3)-mediated growth factor expression, and supporting the synthesis of phospholipids for the expansion of the endoplasmic reticulum (ER), which is required for the secretion of proteins. Genetic or pharmacological inhibition of PPARg T166 phosphorylation promoted the reparative function of macrophages and facilitated tissue regeneration. In summary, we identified that PPARg T166-regulated lipid biosynthesis was essential for the anabolic demands of the activation and function of macrophages and provided a rationale for therapeutic targeting of tissue repair.

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PPARg T166 phosphorylation-mediated lipid synthesis sustains the reparative function of macrophages during tissue repair [ChIP-seq]

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PPARg T166 phosphorylation-mediated lipid synthesis sustains the reparative function of macrophages during tissue repair [RNA-seq]

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Multi-omics approaches reveal TNF-mediated inhibition of tissue reparative macrophages is via a gene-selective transcriptional mechanism

Project description:Multi-omics approaches reveal TNF-mediated inhibition of tissue reparative macrophages is via a gene-selective transcriptional mechanism

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Macrophage MCT4 inhibition activates reparative genes and protects from atherosclerosis by histone H3 lysine 18 lactylation

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Control of the inflammatory macrophage transcriptional signature by miR-155

Project description:Classically activated (M1) macrophages protect from infection but can cause inflammatory disease and tissue damage while alternatively activated (M2) macrophages reduce inflammation and promote tissue repair. Modulation of macrophage phenotype may be therapeutically beneficial and requires further understanding of the molecular programs that control macrophage differentiation. A potential mechanism by which macrophages differentiate may be through microRNA (miRNA), which bind to messenger RNA and post-transcriptionally modify gene expression, cell phenotype and function. The inflammation-associated miRNA, miR-155, was rapidly up-regulated over 100-fold in M1, but not M2, macrophages. Inflammatory M1 genes and proteins iNOS, IL-1b and TNF-a were reduced up to 72% in miR-155 knockout mouse macrophages, but miR-155 deficiency did not affect expression of genes associated with M2 macrophages (e.g., Arginase-1). Additionally, a miR-155 oligonucleotide inhibitor efficiently suppressed iNOS and TNF-a gene expression in wild-type M1 macrophages. Comparative transcriptional profiling of unactivated (M0) and M1 macrophages derived from wild-type and miR-155 knockout (KO) mice revealed an M1 signature of approximately 1300 genes, half of which were dependent on miR-155. Real-Time PCR of independent datasets validated miR-155's contribution to induction of iNOS, IL-1b, TNF-a, IL-6 and IL-12, as well as suppression of miR-155 targets Inpp5d, Tspan14, Ptprj and Mafb. Overall, these data indicate that miR-155 plays an essential role in driving the differentiation and effector potential of inflammatory M1 macrophages. Total RNA was prepared from bone marrow-derived macrophages of miR-155 knockout mice (n=2 independent mice) treated in M0, M1 or M2 conditions (n=2 replicates per condition originating from different mice)

2016-07-15 | E-GEOD-77425 | biostudies-arrayexpress

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