Ablation of macrophage transcriptional factor FoxO1 protects against ischemia-reperfusion injury-induced acute kidney injury
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE250560 | GEO | 2023/12/24
REPOSITORIES: GEO
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Project description:Our objective is to determine the role of myeloid FoxO1 in regulating hepatic lipid metabolism and its contribution to nonalcoholic steatohepatitis (NASH) in mice. We generated mice with conditional FoxO1 depletion in myeloid cells, using the FoxO1-LoxP/LysM-Cre system. We then fed myeloid cell-conditional FoxO1-knockout and wild-type male mice a NASH-inducing diet for 25 weeks. Then mice in both groups were euthanized and the liver tissues were procured for the preparation of total RNAs, which were subjected to RNA-seq assay. While myeloid FoxO1 was upregulated in animal models and human subjects with NASH, the underlying mechanism is poorly understood. We found that myeloid cell conditional FoxO1-knockout mice were protected from developing NASH, culminating in the reduction of hepatic inflammation, steatosis and fibrosis. Mechanistically, FoxO1 counteracts Stat6 to skew macrophage polarization from M2 toward M1 signatures to perpetuate hepatic inflammation in NASH. FoxO1 appears as a pivotal mediator of macrophage activation in response to overnutrition and a therapeutic target for ameliorating hepatic inflammation to stem the disease progression from benign steatosis to NASH.
2022-05-24 | GSE203227 | GEO
Project description:Strict regulation of proliferation is vital for development, whereas unregulated cell proliferation is a fundamental characteristic of cancer. The polarity protein atypical protein kinase C lambda/iota (aPKC lambda) is associated with cell proliferation through unknown mechanisms. In endothelial cells, suppression of aPKC lambda impairs proliferation despite hyperactivated mitogenic signaling. Here we show that aPKC lambda phosphorylates the DNA binding domain of forkhead box O1 (FoxO1) transcription factor, a gatekeeper of endothelial growth. Although mitogenic signaling excludes FoxO1 from the nucleus, consequently increasing c-Myc abundance and proliferation, aPKC lambda controls c-Myc expression via FoxO1/miR-34c signaling without affecting its localization. We find this pathway is strongly activated in the malignant vascular sarcoma, angiosarcoma, and aPKC inhibition reduces c-Myc expression and proliferation of angiosarcoma cells. Moreover, FoxO1 phosphorylation at Ser218 and aPKC expression correlates with poor patient prognosis. Our findings may provide a new therapeutic strategy for treatment of malignant cancers, like angiosarcoma.
2019-11-12 | PXD011595 | Pride
Project description:Tight regulation of Toll-like receptor (TLR)-mediated inflammatory responses is important in innate immunity. Here, we show that T cell death-associated gene 51 (TDAG51/PHLDA1) is a novel coactivator of the transcription factor FoxO1, regulating inflammatory mediator production in the lipopolysaccharide (LPS)-induced inflammatory response. TDAG51 induction by LPS stimulation was mediated by the TLR2/4 signaling pathway in bone marrow-derived macrophages (BMMs). LPS-induced inflammatory mediator production was significantly decreased in TDAG51-deficient BMMs. In TDAG51-deficient mice, LPS- or pathogenic Escherichia coli infection-induced lethal shock was reduced by decreasing serum proinflammatory cytokine levels. The recruitment of 14-3-3 to FoxO1 was competitively inhibited by the TDAG51-FoxO1 interaction, leading to blockade of FoxO1 cytoplasmic translocation and thereby strengthening FoxO1 nuclear accumulation. TDAG51/FoxO1 double-deficient BMMs showed significantly reduced inflammatory mediator production compared with TDAG51- or FoxO1-deficient BMMs. TDAG51/FoxO1 double deficiency protected mice against LPS- or pathogenic E. coli infection-induced lethal shock by weakening the systemic inflammatory response. Thus, these results indicate that TDAG51 acts as a coactivator of the transcription factor FoxO1, leading to strengthened FoxO1 activity in the LPS-induced inflammatory response.
2023-06-24 | PXD039815 | Pride
Project description:Acute kidney injury (AKI) is a global public health concern associated with high morbidity and mortality, and currently no therapeutic interventions reliably limit injury or speed recovery after AKI. Therefore, strategies to augment endogenous repair processes and retard associated profibrotic responses are urgently required. Among them, macrophages are attractive therapeutic targets for AKI because of their critical roles in tissue homeostasis and inflammation. Despite the differentiation of macrophages into morphologically and functionally distinct phenotypes M1/M2 and their clearance of dead cells (efferocytosis) have been increasingly linked to renal inflammation and repair in AKI, the underlying mechanisms of macrophage phenotype switching and efferocytosis during AKI are largely unclear. Here, we found that JAML (junctional adhesion molecule-like protein) deficiency protected against renal AKI. By generation of bone marrow chimeric mice and tubular-specific JAML conditional knockout mice, we demonstrated macrophage JAML primarily contributed to AKI. Mechanistically, JAML mediated macrophage phenotype polarization and efferocytosis, at least in part, through a C-type lectin receptor Mincle-dependent mechanism. In addition, we also found that JAML could induce endogenous Mincle ligand such as SAP130 release from dead or dying renal tubular epithelial cells and subsequent Mincle activation in macrophages, thereby also slightly contributing to AKI. Importantly, we observed a higher expression of JAML in the kidney from subjects with AKI and the level of JAML was correlated with serum creatinine. Collectively, our studies for the first time explore new biological functions of JAML in macrophages and conclude that JAML is an important mediator and biomarker of AKI. Pharmacologic targeting of JAML-Mincle mediated signaling pathways may provide a novel therapeutic strategy for patients with AKI.
2021-12-23 | GSE192532 | GEO
Project description:Myeloid FoxO1 in Nonalcoholic Steatohepatitis
| PRJNA839093 | ENA
Project description:Mucus produced by goblet cells in the gastrointestinal (GI) tract forms a biological barrier that protects the intestine from invasion by commensals and pathogens. However, the host-derived regulatory network that controls mucus secretion and thereby changing gut microbiota has not been well studied. We found Forkhead box protein O1 (Foxo1) regulates mucus secretion by goblet cells and determines intestinal homeostasis. Loss of Foxo1 in intestinal epithelial cells (IECs) results in a defect in goblet cell autophagy and mucus secretion, leading to impaired gut microenvironment and dysbiosis.
2021-06-23 | GSE178650 | GEO
Project description:Activation of the systemic and myocardial rennin-angiotensin-aldosterone system (RAAS) by hyperglycemia plays a critical role in the development of diabetic cardiomyopathy. To test the hypothesis that AngIV protects against diabetic cardiomyopathy via stimulation of AT4R and inhibition of overactive autophagy, diabetic mice were treated with low-, medium- and high-dose AngIV, AT4R antagonist divalinal, forkhead box protein O1 (FoxO1) inhibitor AS1842856 (AS) or their combinations. In vitro, cardiomyocytes were treated with different concentrations of glucose, low-, medium- and high-dose AngIV, divalinal, FoxO1-overexpression plasmid (FoxO1-OE), AS or their combinations. The results showed that AngIV treatment dose-dependently attenuated left ventricular dysfunction, remodeling, fibrosis, and myocyte apoptosis in diabetic mice. Besides, autophagy and FoxO1 protein expression enhanced by diabetes were dose-dependently suppressed by AngIV treatment. However, these cardioprotective effects of AngIV were completely abolished by divalinal administration. Bioinformatic analyses revealed that the differentially expressed genes were enriched in autophagy, apoptosis, and FoxO signaling pathways among control, diabetes, and diabetes+high-dose AngIV groups. Similar to AngIV, AS treatment ameliorated diabetic cardiomyopathy in mice. In vitro, AngIV inhibited collagen expression, apoptosis, overactive autophagy flux, and FoxO1 nuclear translocation induced by high glucose in cardiomyocytes. However, these protective effects of AngIV were completely blocked by the use of divalinal or FoxO1-OE, and these detrimental effects were reversed by the additional administration of AS. In summary, AngIV treatment dose-dependently attenuated left ventricular dysfunction and remodeling in a mouse model of diabetic cardiomyopathy, and the mechanism involved stimulation of AT4R, suppression of FoxO1 nuclear translocation and inhibition of FoxO1-mediated overactive autophagy.
2020-07-30 | GSE155377 | GEO
Project description:Bone marrow derived macrophages from C57BL/6 mice were stimulated into M1 and M2 polarization state. Analysis of BMDMs from LysMcre;FoxO1Fl/FL mice and control littermates. Results provide insight into the regulatory role of FoxO1 during macrophage polarization. BMDMs were stimulated with 100ng/ml LPS plus 20ng/ml IFN-γ into M1 polarization, and stimulated with 10ng/ml IL-4 plus 10ng/ml IL-13 into M2 polarization. Both for 24 hours. Unstimulated cells as M0 state.
2018-09-01 | GSE97260 | GEO
Project description:Alveolar rhabdomyosarcoma (aRMS) is an aggressive sarcoma of skeletal muscle characterized by expression of the PAX3-FOXO1 fusion gene. Despite its discovery over almost 20 years ago, PAX3-FOXO1 remains an enigmatic tumor driver. Previously, we reported that PAX3-FOXO1 supports aRMS initiation by enabling bypass of cellular senescence. Here, we show that bypass occurs in part by PAX3-FOXO1-mediated upregulation of RASSF4, a Ras-association domain family (RASSF) member, which then suppresses the evolutionarily conserved mammalian Hippo/Mst1 pathway. RASSF4 loss-of-function activates Hippo/Mst1 and inhibits downstream YAP, causing aRMS cell cycle arrest and senescence. This is the first evidence for an oncogenic role for RASSF4, and a novel mechanism for Hippo signaling suppression in human cancer. Human skeletal muscle myoblasts (HSMMs) were retrovirally transduced with either an empty vector (Vp, pK1) or PAX3-FOXO1 (PFp, pK1-PAX3-FOXO1) and selected on puromycin. Presenescent (presen) cells were harvested before the senescence checkpoint. Since cells expressing PAX3-FOXO1 can bypass the senescence checkpoint, postsenescent (postsen) cells expressing PAX3-FOXO1 were also harvested. the gene expression affected by the introduction of PAX3-FOXO1
2014-05-15 | E-GEOD-40543 | biostudies-arrayexpress
Project description:It is well known that rennin-angiotensin-aldosterone system (RAAS) plays a critical role in the development of diabetic cardiomyopathy. The present study was aimed to clarify the role of a novel member of RAAS, angiotensin IV (Ang IV) and its downstream mediator forkhead box protein O1 (FoxO1), in the pathogenesis of diabetic cardiomyopathy. In vivo, diabetic mice were treated with low-, medium- and high-dose Ang IV, AT4R antagonist divalinal, FoxO1 inhibitor AS1842856 (AS), or their combinations. In vitro, cardiomyocytes and cardiofibroblasts were treated with different concentrations of glucose, low-, medium- and high-dose Ang IV, divalinal, FoxO1-overexpression plasmid (FoxO1-OE), AS or their combinations. The results showed that Ang IV treatment dose-dependently attenuated left ventricular dysfunction, fibrosis, and myocyte apoptosis in diabetic mice. Besides, enhanced autophagy and FoxO1 protein expression by diabetes were dose-dependently suppressed by Ang IV treatment. However, these cardioprotective effects of Ang IV were completely abolished by divalinal administration. Bioinformatics analysis revealed that the differentially expressed genes were enriched in autophagy, apoptosis, and FoxO signaling pathways among control, diabetes, and diabetes+high-dose Ang IV groups. Similar to Ang IV, AS treatment ameliorated diabetic cardiomyopathy in mice. In vitro, high glucose stimulation increased collagen expression, apoptosis, overactive autophagy flux and FoxO1 nuclear translocation in cardiomyocytes, and upregulated collagen and FoxO1 expression in cardiofibroblasts, which were substantially attenuated by Ang IV treatment. However, these protective effects of Ang IV were completely blocked by the use of divalinal or FoxO1-OE, and these detrimental effects were reversed by the additional administration of AS. In summary, Ang IV treatment dose-dependently attenuated left ventricular dysfunction and remodeling in a mouse model of diabetic cardiomyopathy, and the mechanisms involved stimulation of AT4R and suppression of FoxO1-mediated fibrosis, apoptosis, and overactive autophagy.
2020-09-03 | GSE157331 | GEO