Epithelial HMGB1 delays skin wound healing and drives tumor initiation by priming neutrophils for NET formation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA577725 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10287067.fastq.gz | Fastqsanger.gz | |||
| SRR10287068.fastq.gz | Fastqsanger.gz | |||
| SRR10287069.fastq.gz | Fastqsanger.gz | |||
| SRR10287070.fastq.gz | Fastqsanger.gz | |||
| SRR10287071.fastq.gz | Fastqsanger.gz |
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Project description:Regenerative responses predispose tissues to tumor formation by largely unknown mechanisms. High-mobility group box 1 (HMGB1) is a danger-associated molecular pattern contributing to inflammatory pathologies. Here, we show that HMGB1 derived from keratinocytes, but not myeloid cells, delays cutaneous wound healing and drives skin tumor formation. In wounds of mice lacking HMGB1 selectively in keratinocytes, a marked reduction in neutrophil extracellular trap (NET) formation is observed. Pharmacological targeting of HMGB1 or NETs prevents skin tumorigenesis and accelerates wound regeneration. HMGB1-dependent NET formation and skin tumorigenesis is orchestrated by the cytokine TNF and requires RIPK1 kinase activity. NETs are present in the microenvironment of keratinocyte-derived tumors in mice and lesional and tumor skin of patients suffering from Recessive Dystrophic Epidermolysis Bullosa (RDEB), a disease in which skin blistering predisposes to tumorigenesis. We conclude that tumorigenicity of the wound microenvironment depends on epithelial-derived HMGB1 regulating NET formation, thereby establishing a mechanism linking reparative inflammation to tumor initiation.
2019-10-16 | GSE138918 | GEO
Project description:Testing the consequences of the absence of the chromatin-associated HMGB1 protein on the transcriptome in Arabidopsis. Keywords: Comparison of mutant and wildtype samples. Four replicate RNA extractions were performed of each genotype using independent pools of plants. hmgb1#1 (Cy5) vs. Col-0#1 (Cy3) Col-0#2 (Cy5) vs. hmgb1#2 (Cy3) dye-swap hmgb1#3 (Cy5) vs. Col-0#3 (Cy3) Col-0#5 (Cy5) vs. hmgb1#4 (Cy3) dye-swap Samples were hybridized in two dye-swaps. The data were normalized over all 4 hybridizations to obtain one, single log-ratio(Sample/Reference). The raw data files of all four of the hybridizations are attached to the Sample.
2008-11-23 | E-GEOD-10638 | biostudies-arrayexpress
Project description:High Mobility Group Box 1 (HMGB1) is a highly abundant and evolutionarily conserved non-histone chromatin component with the ability to bind and bend DNA. The protein is involved in fundamental nuclear processes including nucleosome sliding, transcription, replication, V(D)J recombination and DNA transposition. To assess the functional impact of HMGB1 on transcription we performed gene expression profile analyses of mouse embryonic fibroblasts, wild-type or knockout for the Hmgb1 gene 2 genetic backgrounds: wild-type (Wt), Hmgb1-/- (KO), 3 biological replicates (rep1, rep2, rep3; S phase synchronized cells in duplicate only), no technical replicates. Each pair of wt and Hmgb1-/- MEFs was isolated from embryos born from a single Hmgb1+/- mother crossed with a Hmgb1 +/- male. Total RNAs from three pairs of MEFs, derived from three different mothers and cultured up to passage 3, were extracted using mirVana miRNA Isolation Kit (Ambion) and analyzed on the Illumina BeadsArray platform.
2013-10-01 | E-GEOD-18463 | biostudies-arrayexpress
Project description:High mobility group box 1 (HMGB1) is tightly connected to the process of tissue organization upon tissue injury. Here we show that HMGB1 controls epithelium and connective tissue regeneration both in vivo and in vitro during palatal wound healing. Heterozygous HMGB1 (Hmgb1+/-) mice and Wild-type (WT) mice were subjected to palatal injury. Maxillary tissues were stained with Mallory Azan or immunostained with anti-HMGB1, anti-proliferating cell nuclear antigen (PCNA), anti-nuclear factor-κB (NF-κB) p50 and anti-vascular endothelial growth factor (VEGF) antibodies. Palatal gingival explants were cultured with recombinant HMGB1 (rHMGB1) co-treated with siRNA targeting receptor for advanced glycation end products (RAGEs) for cell migration and PCNA expression analysis. Measurement of the wound area showed differences between Hmgb1+/- and WT mice on Day 3 after wounding. Mallory Azan staining showed densely packed of collagen fibers in WT mice, whereas in Hmgb1+/- mice weave-like pattern of low density collagen bundles were present. At three and seven days post-surgery, PCNA, NF-κB p50 and VEGF positive keratinocytes of WT mice were greater than that of Hmgb1+/- mice. Knockdown of RAGE prevents the effect of rHMGB1-induced cell migration and PCNA expression in gingival cell cultures. The data suggest that HMGB1/RAGE axis has crucial roles in palatal wound healing.
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Project description:Storage temperature affects the rate and extent of wound-healing in a number of root and tuber crops. The effect of storage temperature on wound-healing in sugarbeet (Beta vulgaris L.) roots, however, is largely unknown. Wound-healing of sugarbeet roots was investigated using surface-abraded roots stored at 6 and 12°C for 28 days. Surface abrasions are common injuries of stored roots, and the storage temperatures used are typical of freshly harvested or rapidly cooled roots. Transpiration rate from the wounded surface and root weight loss were used to quantify wound healing. At 12°C, transpiration rate from the wounded surface declined within 14 days and wounded roots lost weight at a rate similar to unwounded controls. At 6°C, transpiration rate from the wounded surface did not decline in the 28 days after injury, and wounded roots lost 44% more weight than controls after 28 days storage. Melanin formation, lignification, and suberization occurred more rapidly at 12°C than at 6°C, and a continuous layer of lignified and suberized cells developed at 12°C, but not at 6°C. Examination of enzyme activities involved in melanin, lignin, and suberin formation indicated that differences in melanin formation at 6 and 12°C were related to differences in polyphenol oxidase activity, although no relationships between suberin or lignin formation and phenylalanine ammonia lyase or peroxidase activity were evident. Wound-induced respiration was initially greater at 12°C than at 6°C. However, with continued storage, respiration rate of wounded roots declined more rapidly at 12°C, and over 28 days, the increase in respiration due to injury was 52% greater in roots stored at 6°C than in roots stored at 12°C. The data indicate that storage at 6°C severely slowed and impaired wound-healing of surface-abraded sugarbeet roots relative to roots stored at 12°C and suggest that postharvest losses may be accelerated if freshly harvested roots are cooled too quickly.
| S-EPMC4830815 | biostudies-literature
Project description:High Mobility Group Box 1 (HMGB1) is a highly abundant and evolutionarily conserved non-histone chromatin component with the ability to bind and bend DNA. The protein is involved in fundamental nuclear processes including nucleosome sliding, transcription, replication, V(D)J recombination and DNA transposition. To assess the functional impact of HMGB1 on transcription we performed gene expression profile analyses of HeLa cells stably transfected with an anti-HMGB1 shRNA expressing plasmid or a control plasmid. 2 stable clones: control HeLa, Hmgb1-knocked down HeLa, 3 technical replicates. Hmgb1 knockdown HeLa cells were prepared by stable transfection with the plasmid Hmgb1shRNA-pSuperior.puro or, as a mock control, with the empty vector pSuperior.puro (Invitrogen). Transfection was made starting from 500 thousands (500K) or 5 milions (5mil) cells. Transfected cells were selected with puromycin and single resistant clones were picked, amplified and analyzed for HMGB1 expression by western blot. A clone containing less then 10% of the wt amount of HMGB1 was selected for further experiments. Total RNAs were extracted using Quiagen RNeasy kit and analyzed on the Illumina BeadsArray platform in 2 technical replica (2 arrays).
2011-06-28 | E-GEOD-18721 | biostudies-arrayexpress
Project description:Periostin is a matricellular protein involved in development, maintenance, and regulation of tissues and organs via by binding to cell surface integrin receptors. Pathologically, periostin plays an important role in the process of wound healing: as a deficiency of the Postn gene delays wound closure and periostin is consistently up-regulated in response to injury and skin diseases. However, the functional role of elevated periostin in the process of wound healing has not been tested. In this study, we generated Postn-transgenic mice under the control of the CAG promoter/enhancer to investigate the effects of constitutive overexpression of full length periostin during its pathophysiological roles. Transgenic mice showed significant overexpression of periostin in skin, lung, and heart, but no morphological changes were observed. However, when these transgenic mice were injured, periostin overexpression delayed the closure of excisional wounds. Expression of IL-1β and TNFα, pro-inflammatory cytokines important for wound healing, was significantly decreased in the transgenic mice, prior to delayed healing. Infiltration of neutrophils and macrophages, the main sources of IL-1β and TNFα, was also down-regulated in the transgenic wound sites. From these data, we conclude that enforced expression of periostin delays wound closure due to reduced infiltration of neutrophils and macrophages followed by down-regulation of IL-1β and TNFα expression. This suggests that regulated spatiotemporal expression of periostin is important for efficient wound healing and that constitutive periostin overexpression interrupts the normal process of wound closure.
| S-EPMC5906136 | biostudies-literature
Project description:Wound healing consists of a complex, dynamic and overlapping process involving inflammation, proliferation and tissue remodeling. A better understanding of wound healing process at the molecular level is needed for the development of novel therapeutic strategies. Receptor-interacting protein kinase 3 (RIPK3) controls programmed necrosis in response to TNF-α during inflammation and has been shown to be highly induced during cutaneous wound repair. However, its role in wound healing remains to be demonstrated. To study this, we created dorsal cutaneous wounds on male wild-type (WT) and RIPK3-deficient (Ripk3-/-) mice. Wound area was measured daily until day 14 post-wound and skin tissues were collected from wound sites at various days for analysis. The wound healing rate in Ripk3-/- mice was slower than the WT mice over the 14-day course; especially, at day 7, the wound size in Ripk3-/- mice was 53% larger than that of WT mice. H&E and Masson-Trichrome staining analysis showed impaired quality of wound closure in Ripk3-/- wounds with delayed re-epithelialization and angiogenesis and defected granulation tissue formation and collagen deposition compared to WT. The neutrophil infiltration pattern was altered in Ripk3-/- wounds with less neutrophils at day 1 and more neutrophils at day 3. This altered pattern was also reflected in the differential expression of IL-6, KC, IL-1β and TNF-α between WT and Ripk3-/- wounds. MMP-9 protein expression was decreased with increased Timp-1 mRNA in the Ripk3-/- wounds compared to WT. The microvascular density along with the intensity and timing of induction of proangiogenic growth factors VEGF and TGF-β1 were also decreased or delayed in the Ripk3-/- wounds. Furthermore, mouse embryonic fibroblasts (MEFs) from Ripk3-/- mice migrated less towards chemoattractants TGF-β1 and PDGF than MEFs from WT mice. These results clearly demonstrate that RIPK3 is an essential molecule to maintain the temporal manner of the normal progression of wound closure.
| S-EPMC4599740 | biostudies-literature
Project description:Mutant ataxin-1 (Atxn1), which causes spinocerebellar ataxia type 1 (SCA1), binds to and impairs the function of high mobility group box 1 (HMGB1), a critical nuclear protein that regulates DNA architectural changes essential for DNA damage repair and transcription. In this study, we established that transgenic or virus vector-mediated supplementation of HMGB1 ameliorates motor dysfunction and elongates lifespan in mutant Atxn1 knock-in (Atxn1-KI) mice. We identified mitochondrial DNA damage repair by HMGB1 as a novel molecular basis for this effect, in addition to the mechanisms already associated with HMGB1 function, such as nuclear DNA damage repair and nuclear transcription. The dysfunction and the improvement of mitochondrial DNA damage repair functions are tightly associated with the exacerbation and rescue, respectively, of symptoms, supporting the involvement of mitochondrial DNA quality control by HMGB1 in SCA1 pathology. Moreover, we show that the rescue of Purkinje cell dendrites and dendritic spines by HMGB1 could be downstream effects. Although extracellular HMGB1 triggers inflammation mediated by toll-like receptor and receptor for advanced glycation end products, upregulation of intracellular HMGB1 does not induce such side effects. Thus, viral delivery of HMGB1 is a candidate approach by which to modify the disease progression of SCA1 even after its onset.
2015-01-05 | E-MTAB-2987 | biostudies-arrayexpress