The STAT3-SETDB2 Axis Dictates NFκB-mediated Inflammation in Macrophages during Wound Repair
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ABSTRACT:
PROVIDER: PRJNA1144974 | ENA |
REPOSITORIES: ENA
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Project description:Macrophage transition from an inflammatory to reparative phenotype after tissue injury is controlled by epigenetic enzymes that regulate inflammatory gene expression. We have previously identified the histone methyltransferase, SETDB2, in macrophages drives tissue repair by repressing NFκB-mediated inflammation. Complementary ATAC and RNA sequencing of wound macrophages isolated from mice deficient in SETDB2 in myeloid cells revealed that SETDB2 suppresses the inflammatory gene program by inhibiting chromatin accessibility at NFkB-dependent gene promoters. We found that STAT3 was required for SETDB2 expression in macrophages yet, paradoxically, it also functioned as a binding partner of SETDB2 where it repressed SETDB2 activity by inhibiting its interaction with the NFKB component, RELA, leading to increased RELA/NFKB-mediated inflammatory gene expression. Further, RNA sequencing in wound macrophages from STAT3-deficient mice corroborated this and revealed STAT3 and SETDB2 transcriptionally co-regulate overlapping genes. Finally, in diabetic wound macrophages STAT3 expression and STAT3-SETDB2 binding were increased. As such, we identify what we believe to be a novel SETDB2-STAT3 axis that modulates macrophage phenotype during tissue repair and may be an important therapeutic target for nonhealing diabetic wounds.
2024-11-06 | GSE274112 | GEO
Project description:Oncogenic STAT3 functions are known in various malignancies. We found that STAT3 plays an unexpected tumor suppressive role in KRAS-mutant non-small-cell-lung cancer (NSCLC). In mice, tissue-specific inactivation of Stat3 resulted in increased Kras (G12D)-driven NSCLC initiation and malignant progression leading to markedly reduced survival. Clinically, low STAT3 expression levels correlate with poor survival in human lung adenocarcinoma patients with smoking history. Consistently, KRAS-mutant lung tumors showed reduced STAT3 levels. Mechanistically, we show that STAT3 controls NFκB-induced IL-8-expression by sequestering NFκB in the cytoplasm while IL-8 in turn regulates myeloid tumor infiltration and tumor vascularization thereby promoting tumor progression. These results identify a novel STAT3-NFκB-IL-8 axis in KRAS-mutant NSCLC with therapeutic and prognostic relevance
2015-02-05 | GSE52798 | GEO
Project description:The expression profile during wound repair of cutaneous excisional wound (2x2 cm) was studied. The tissue was sampled from the centre of the open wound (day 3/7/14) or centre of the wound scar (day 21/35/70). The microarray slide were scanned in low intensity scan and high intensity scan mode. Wound tissue (day 3, day 7, day 14, day 21, day 35, day 70, n = 4 per interval) vs. control - uninjured skin (day 0, n=4 ). In each interval two biological replicates of four were labeled with flip dyes.
2012-07-29 | E-GEOD-37947 | biostudies-arrayexpress
Project description:The expression profile during wound repair of cutaneous excisional wound (2x2 cm) was studied. The tissue was sampled from the centre of the open wound (day 3/7/14) or centre of the wound scar (day 21/35/70). The microarray slide were scanned in low intensity scan and high intensity scan mode.
2012-07-30 | GSE37947 | GEO
Project description:Lung cancer is the second leading cause of cancer death worldwide and is strongly associated with cisplatin resistance. The transcription factor STAT3 is constitutively activated in cancer cells and coordinates critical cellular processes as survival, self-renewal, and inflammation. In several types of cancer, STAT3 controls the development, immunogenicity, and malignant behavior of tumor cells while dictates the responsiveness to radio- and chemotherapy. It is known that STAT3 phosphorylation on Ser727 by mTOR is necessary for its maximal activation, but the crosstalk between STAT3 and mTOR signaling in cisplatin resistance remains elusive. In this study, using a proteomic label-based approach, we reveal important targets and signaling pathways increased and decreased in cisplatin-resistant A549 lung adenocarcinoma cells.
2022-02-17 | PXD025778 | Pride
Project description:Abstract: Human kidney function declines with age, accompanied by stereotyped changes in gene expression and histopathology, but the mechanisms underlying these changes are largely unknown. We compared age-associated changes in global gene expression patterns in the human kidney with genome-wide maps of transcription factor occupancy in human cell lines to identify potential regulators of gene expression changes in the aging kidney. The strongest associations involved three inflammation-associated transcription factors: NFκB, STAT1 and STAT3. We found that the activity of these transcription factors increases with age in epithelial compartments of the renal cortex. Stimulation of renal tubular epithelial cells with the inflammatory cytokines IL-6 (a STAT3 activator), IFN-γ (a STAT1 activator), or TNFα (an NFκB activator) recapitulated age-associated gene expression changes. We found that common DNA variants in the two genes that encode the subunits of the canonical NFκB transcription factor (RELA and NFKB1) showed significant associations with kidney function and chronic kidney disease in gene association studies, providing the first evidence for a direct link between genetic variation in NFκB and individual differences in age-related phenotypes in the kidney. Our results point to chronic inflammation, mediated by NFκB, STAT1 and STAT3, as a dominant mechanism influencing gene expression changes during kidney aging.
2015-07-01 | GSE68826 | GEO
Project description:Wound induced small-peptide mediated signalling cascade dictates growth vs defense decision in rice
| PRJNA1082395 | ENA
Project description:Non-healing wounds are a major area of unmet clinical need that remain problematic to treat; therefore, improved understanding of pro-healing mechanisms is invaluable. The enzyme arginase1 is involved in pro-healing responses with its role in macrophages best-characterised. Arginase1 is also expressed by keratinocytes; however, the function of arginase1 in these critical wound repair cells is not understood. We characterised arginase1 expression in keratinocytes during normal cutaneous repair and reveal de novo temporal and spatial expression at the epidermal wound edge. Interestingly, epidermal arginase1 expression was decreased in both human and murine delayed healing wounds. We, therefore, generated a keratinocyte specific arginase1-null mouse model (K14-cre;Arg1fl/fl) to explore arginase function. Wound repair, linked to changes in keratinocyte proliferation, migration and differentiation, was significantly delayed in K14-cre;Arg1fl/flmice. Gene expression was studied by microarray.
2021-07-07 | E-MTAB-10213 | biostudies-arrayexpress
Project description:Tissue repair processes maintain proper organ function following mechanical or infection related damage. In addition to anti-bacterial properties, MAIT cells express a tissue repair transcriptomic program and promote skin wound healing when expanded. Herein, we use a human‑like full‑thickness skin excision mouse model to assess the underlying mechanisms of MAIT cell tissue repair function. Single-cell RNAseq analysis suggests that skin MAIT cells already express a repair program at steady state. Following skin excision, MAIT cells promote keratinocyte proliferation thereby accelerating healing. Using skin grafts, parabiosis and adoptive transfer experiments, we show that MAIT cells migrate into the wound from other tissues in a TCR independent but CXCR6 dependent manner. Amphiregulin secreted by MAIT cells following excision promotes wound healing. The repair function is independent of sustained TCR stimulation. Overall, our study provides mechanistic insight into MAIT cell wound healing function in the skin.
2023-01-10 | GSE207348 | GEO
Project description:Many patients have cancers that have increased activity of a protein called STAT3 that contributes critically to the development and growth of their cancer. Despite our knowledge of STAT3’s importance to cancer, scientists and doctors have not developed a drug that targets it and that patients can take to treat their cancer more effectively than treatments that are now available. Tvardi Therapeutics, Incorporated has developed a compound, TTI-101, which can be given by mouth and acts as a direct inhibitor of STAT3. Administration of TTI-101 to mice demonstrated that it blocked growth of cancers of the breast, head and neck, lung, and liver and it was safe when administered at high doses to mice, rats, and dogs. In this application, Tvardi is proposing to further develop TTI-101 for treatment of solid tumors for which the prognosis is dismal. The investigators will determine how safe it is when administered to patients with cancer, determine whether an adequate dose can be administered to patients with cancer that will block STAT3 in their cancer, and determine whether treatment with TTI-101 leads to reduced growth of their cancer.
| 2247646 | ecrin-mdr-crc