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Activation of MEK‐ERK‐c‐MYC signaling pathway promotes splenic M2 macrophage polarization to inhibit PHcH-liver cirrhosis

ABSTRACT: Portal hypertension combined with hypersplenism (PHcH) is the main cause of hypocytosis and esophagogastric variceal hemorrhage in patients with liver cirrhosis. Activated macrophages that destroy excess blood cells are the main cause of hypersplenism, but the activating pathway is not very clear. This study aims to investigate the activation types of splenic macrophages and their activation mechanisms, to provide experimental evidence for the biological treatment of splenomegaly, and aiming to find a strategy to improve liver fibrosis and inflammation by intervening in splenic immune cells. This study revealed the occurrence of M2 type polarization of macrophages and upregulation of c-Myc gene expression in the PH spleen. RNAseq, protein chip, western blot, and chip-seq were performed on macrophages and the in vitro MEK inhibitor rafametinib was used. Carbon tetrachloride and thioacetamide induced mouse cirrhosis models were separately constructed. c-Myc gene knockout in splenic macrophages reduced M2 type polarization and exacerbated liver fibrosis inflammation. c-Myc activated the MAPK signaling pathway and upregulated the expression of IL-4 and M2 related genes in PH hypersplenism through the MEK-ERK-c-Myc axis. In addition, the c-Myc gene exerted anti-inflammatory effects by upregulating IL-4-mediated signal transduction to promote M2 type differentiation and anti-inflammatory cytokine secretion. Therefore, the induction of macrophage depolarization might represent a new therapeutic approach in the cure of PH hypersplenism, making c-Myc a potential candidate for macrophage polarization therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE264544 | GEO | 2024/04/27

REPOSITORIES: GEO

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Activation of MEK‐ERK‐c‐MYC signaling pathway promotes splenic M2 macrophage polarization to inhibit PHcH-liver cirrhosis

Project description:Portal hypertension combined with hypersplenism (PHcH) is the main cause of hypocytosis and esophagogastric variceal hemorrhage in patients with liver cirrhosis. Activated macrophages that destroy excess blood cells are the main cause of hypersplenism, but the activating pathway is not very clear. This study aims to investigate the activation types of splenic macrophages and their activation mechanisms, to provide experimental evidence for the biological treatment of splenomegaly, and aiming to find a strategy to improve liver fibrosis and inflammation by intervening in splenic immune cells. This study revealed the occurrence of M2 type polarization of macrophages and upregulation of c-Myc gene expression in the PH spleen. RNAseq, protein chip, western blot, and chip-seq were performed on macrophages and the in vitro MEK inhibitor rafametinib was used. Carbon tetrachloride and thioacetamide induced mouse cirrhosis models were separately constructed. c-Myc gene knockout in splenic macrophages reduced M2 type polarization and exacerbated liver fibrosis inflammation. c-Myc activated the MAPK signaling pathway and upregulated the expression of IL-4 and M2 related genes in PH hypersplenism through the MEK-ERK-c-Myc axis. In addition, the c-Myc gene exerted anti-inflammatory effects by upregulating IL-4-mediated signal transduction to promote M2 type differentiation and anti-inflammatory cytokine secretion. Therefore, the induction of macrophage depolarization might represent a new therapeutic approach in the cure of PH hypersplenism, making c-Myc a potential candidate for macrophage polarization therapy.

2024-04-24 | GSE264420 | GEO

Identification of pharmacologic inhibitors and activators of IL-4-induced macrophage polarization [THP-1 RNA-seq]

Project description:Macrophages polarize towards different subpopulations with distinct and partly antagonistic functions in various diseases. IFNγ/LPS-polarized M1-type macrophages can have antiangiogenic activity, whereas IL-4-induced M2-type macrophages can be proangiogenic and profibrotic. Therapeutic strategies to inhibit M2-type polarization while promoting M1-type polarization could serve to inhibit pathological angiogenesis and fibrosis. Here, by combining global quantitative time-course proteomics and phosphoproteomics with a small-molecule inhibitor screen we identify signaling events that promote specifically IL-4-induced and not IFNγ/LPS-induced macrophage polarization and found that the MEK inhibitor trametinib and the HDAC inhibitor panobinostat potently prevent M2-type macrophage polarization without inhibiting M1-type polarization. In contrast, selective B-Raf inhibition promotes M2-type polarization. Trametinib and panobinostat also blocked M2-type macrophage polarization and concomitantly angiogenesis and fibrosis in models of wound healing and neovascular age-related macular degeneration in vivo. Thus, these pharmacologic inhibitors could be utilized therapeutically to selectively block IL4-induced macrophage polarization and reduce pathologic angiogenesis and fibrosis.

2021-10-16 | GSE154346 | GEO

Identification of pharmacologic inhibitors and activators of IL-4-induced macrophage polarization

2021-10-01 | GSE140235 | GEO

Identification of pharmacologic inhibitors and activators of IL-4-induced macrophage polarization [PBMC RNA-seq]

2021-10-16 | GSE154345 | GEO

Identification of pharmacologic inhibitors and activators of IL-4-induced macrophage polarization [THP-1 ChIP-seq]

2021-10-16 | GSE154343 | GEO

Identification of pharmacologic inhibitors and activators of IL-4-induced macrophage polarization [PBMC ChIP-seq]

2021-10-16 | GSE154342 | GEO

Myeloid cell-expressed heme oxygenase-1 mitigates liver injury and fibrosis via the ligand of numb-protein X1 (LNX1)-Notch1 pathway

Project description:Activation of resident macrophages (Mf) and hepatic stellate cells in the perisinusoidal space is a key event in chronic liver injury. Under these circumstances, dysregulated innate immunity and inflammatory processes drive progressive accumulation of collagen, resulting in scarring and eventually, cirrhosis with life-threatening complications. In summary, by using RiboTag-based sequencing, we identified a novel regulatory LNX1/Notch1 pathway downstream of HO-1 that drives a protective form of M2 polarization of Mf and inhibits expansion of reactive cholangiocytes and liver fibrosis.

2022-09-20 | GSE206069 | GEO

Expression data from macrophage maturation and polarization c-Myc in alternative macrophage activation experiments

Project description:In response to microenvironmental signals macrophages undergo different activation, indicated as classic/M1 and alternative/M2 polarization. C-Myc transcription factor could be an essential player in M2 polarization. Functional relevance of c-Myc in M2 macrophage biology is investigated by evaluating the effect of 100-58F4, on the transcriptional profile induced on human macrophages by IL-4. Human monocytes were obtained from normal donor buffy coats by two-step gradient centrifugation using Ficoll (Biochrom) and Percoll (Amersham). Non-adherent cells were discarded, and the purified monocytes were incubated for 7 days in RPMI 1640 (Biochom) supplemented with 10% FCS (HyClone) and 100 ng/mL M-CSF to obtain resting macrophages. Macrophage polarization was obtained by removing the culture medium and culturing cells in RPMI 1640 supplemented with 10% FCS and 100 ng/mL LPS plus 20 ng/mL IFN-gamma (M1 polarization) or 20 ng/mL IL-4 (M2 polarization) for 24 h. When needed, chemical inhibitors were added with IL-4.

2011-09-15 | E-GEOD-32164 | biostudies-arrayexpress

Expression data from macrophage maturation and polarization c-Myc in alternative macrophage activation experiments

2011-09-16 | GSE32164 | GEO

ASIC3-M-CSF-M2 macrophage-positive feedback loop modulates in skin fibrosis pathogenesis

Project description:Inflammation is one of the main pathological features leading to skin fibrosis and a key factor leading to the progression of skin fibrosis. Acidosis caused by a decrease in extracellular pH is a sign of the inflammatory process. Acid-sensing ion channels (ASICs) are ligand-gated ion channels on the cell membrane that sense the drop in extracellular pH. However, the molecular mechanisms by which skin fibroblasts are regulated by Acid-sensing ion channel 3(ASIC3) remain unknown. This study investigated whether ASIC3 is related to inflammation and skin fibrosis and explored the underlying mechanisms. We demonstrate that Macrophage colony-stimulating factor (M-CSF) is a direct target of ASIC3, and ASIC3 activation promotes M-CSF transcriptional regulation of macrophages for M2 polarization. The polarization of M2 macrophages transduced by the ASIC3-M-CSF signal promotes the differentiation of fibroblasts into myofibroblasts through transforming growth factor β1 (TGF-β1), thereby producing ASIC3-M-CSF-TGF-β1 positive feedback loop. Targeting ASIC3 may be a new treatment strategy for skin fibrosis.

2021-10-30 | GSE186739 | GEO

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