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Keratinocyte-Macrophage Crosstalk by the Nrf2/Ccl2/EGF Signaling Axis Orchestrates Tissue Regeneration

ABSTRACT: Keratinocyte-Macrophage Crosstalk by the Nrf2/Ccl2/EGF Signaling Axis Orchestrates Tissue Regeneration

PROVIDER: PRJNA668615 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12807711_1.fastq.gz	Fastqsanger.gz
	SRR12807711_2.fastq.gz	Fastqsanger.gz
	SRR12807712_1.fastq.gz	Fastqsanger.gz
	SRR12807712_2.fastq.gz	Fastqsanger.gz
	SRR12807713_1.fastq.gz	Fastqsanger.gz

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Keratinocyte-Macrophage Crosstalk by the Nrf2/Ccl2/EGF Signaling Axis Orchestrates Tissue Regeneration

Project description:Unveiling the molecular mechanisms underlying tissue regeneration provides new opportunities to develop treatments for diabetic ulcers and other chronic skin lesions. Here, to gain insight into critical wound response mechanisms regulated by epidermal Nrf2, we micro dissected a ~2.5mm concentric ring around the 10mm wound at 5 days-post-wounding (DPW) and used flow cytometry to isolate wound-associated keratinocytes from Nrf2 +/+ Ker and Nrf2 ∆/∆ Ker mice for bulk RNA-seq. Combining in vivo and ex vivo data with next generation sequencing, we show that Ccl2 secretion by epidermal keratinocytes is directly orchestrated by Nrf2, a prominent transcriptional regulator of tissue regeneration that is activated early after cutaneous injury. Through a unique feedback mechanism, we find that Ccl2 from epidermal keratinocytes not only drives chemotaxis of macrophages into the wound, but also triggers macrophage expression of EGF, which in turn activates basal epidermal keratinocyte proliferation. Notably, we find dysfunctional activation of Nrf2 in epidermal keratinocytes of diabetic mice after wounding, which in part, explains regenerative impairments associated with diabetes. These findings provide mechanistic insight into the critical relationship between keratinocyte-macrophage signaling during tissue regeneration, providing the basis for continued investigation of the therapeutic value of Nrf2.

2020-10-12 | GSE159361 | GEO

Keratinocyte-Macrophage Crosstalk by the Nrf2/Ccl2/EGF Signaling Axis Orchestrates Tissue Repair.

Project description:Unveiling the molecular mechanisms underlying tissue regeneration provides new opportunities to develop treatments for diabetic ulcers and other chronic skin lesions. Here, we show that Ccl2 secretion by epidermal keratinocytes is directly orchestrated by Nrf2, a prominent transcriptional regulator of tissue regeneration that is activated early after cutaneous injury. Through a unique feedback mechanism, we find that Ccl2 from epidermal keratinocytes not only drives chemotaxis of macrophages into the wound but also triggers macrophage expression of EGF, which in turn activates basal epidermal keratinocyte proliferation. Notably, we find dysfunctional activation of Nrf2 in epidermal keratinocytes of diabetic mice after wounding, which partly explains regenerative impairments associated with diabetes. These findings provide mechanistic insight into the critical relationship between keratinocyte and macrophage signaling during tissue repair, providing the basis for continued investigation of the therapeutic value of Nrf2.

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Nrf2 transcript alterations

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GDF15-GFRAL orchestrates glutathione synthesis via NRF2-elicited GCLC activation to impedes cuproptosis

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The EGF Receptor Ligand Amphiregulin Controls Cell Division via FoxM1

Project description:We analyzed the effect of tetracycline (Tet)-inducible amphiregulin (AREG) silencing on the transcriptome of immortalized human N/TERT keratinocytes in the presence or absence of exogenous rhEGF. Tetracycline-mediated AREG silencing significantly altered the expression of 2,331 genes, 623 of which were not normalized towards normal by treatment with EGF. Genes irreversibly up-regulated by suppression of AREG overlapped with genes involved in keratinocyte differentiation. A significant proportion of the irreversibly down-regulated genes featured upstream binding sites recognized by FoxM1

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Gene expression changes in fibroblasts with constitutively active Nrf2 reflect a senescence-associated secretory phenotype (SASP)

Project description:Nrf2 is a key regulator of the cellular antioxidant defense system, and pharmacological Nrf2 activation is a promising strategy for cancer prevention. Here we discovered a novel role of Nrf2 as a regulator of the matrisome. Activation of Nrf2 in fibroblasts induced early onset of cellular senescence. Mechanistically, this resulted from Nrf2-mediated transcription of matrix and matrix-remodeling genes. Fibroblasts with activated Nrf2 deposited a senescence-promoting matrix, with plasminogen-activator inhibitor being the key inducer of the senescence program. In vivo, this promoted keratinocyte proliferation and re-epithelialization during wound healing, but also skin tumorigenesis. Analysis of the gene expression profile of fibroblasts with activated Nrf2 and published data sets revealed that Nrf2 activates genes characteristic for cancer-associated fibroblasts. These data identify Nrf2 as a key player in the control of the cancer-associated fibroblast phenotype and highlight the need for careful use of Nrf2-activating pharmaceuticals.

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Functional analysis of the cytoprotective transcription factor Nrf2 in keratinocytes: Identification of Nrf2-regulated miRNAs

Project description:Nrf2-regulated mRNAs are known; however, no Nrf2-regulated miRs have been identified miR microarray analysis from total RNA samples was performed to test which miRs are regulated by Nrf2 Total RNA from skin of mice with constitutively active Nrf2 (CMV-caNrf2), dominant-negative Nrf2 (dnNrf2), and correcponding control littermates (K5Cre(wt) for CMV-caNrf2 and wt for dnNrf2)

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Noncanonical pathway for regulation of CCL2 expression by an mTORC1-FOXK1 axis promotes recruitment of tumor-associated macrophages

Project description:C-C chemokine ligand 2 (CCL2) plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF)–κB signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. Mammalian target of rapamycin complex 1 (mTORC1) is a protein kinase that is activated in various tumor cell types. We have now identified a noncanonical pathway for regulation of CCL2 production that is mediated by mTORC1 but independent of NF-κB. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1) as a downstream target of mTORC1, with dephosphorylation of FOXK1 in response to mTORC1 activation resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice. Our results suggest that FOXK1 directly links mTORC1 signaling and CCL2 expression in a manner independent of NF-κB, and that CCL2 produced by this pathway contributes to tumor progression. Specific inhibition of FOXK1 may thus be a potential therapeutic strategy for cancer.

2017-11-30 | PXD007996 | Pride

Mononuclear phagocytes in muscle after notexin injury in C57Bl/6, Cx3cr1-/-, Ccl2-/-,Cx3cr1-/-Ccl2-/- mice

Project description:Muscle injury triggers inflammation in which infiltrating mononuclear phagocytes are crucial for tissue regeneration. The interaction of the CCL2/CCR2 and CX3CL1/CX3CR1 chemokine axis that guides phagocyte infiltration is incompletely understood. Here, we show that CX3CR1 deficiency promotes muscle repair and rescues Ccl2-/- mice from impaired muscle regeneration as a result of altered macrophage function, not infiltration. Transcriptomic analysis of muscle mononuclear phagocytes reveals that Apolipoprotein E (ApoE) is up-regulated in mice with efficient regeneration. ApoE treatment enhances phagocytosis by mononuclear phagocytes in vitro, and restores phagocytic activity and muscle regeneration in Ccl2-/- mice. Because CX3CR1 deficiency may compensate for defective CCL2-dependant monocyte recruitment by modulating ApoE-dependent macrophage phagocytic activity, targeting CX3CR1 expressed by macrophages might be a powerful therapeutic approach to improve muscle regeneration.

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Nrf2 orchestrates epigenetic regulation and acts as the master regulator of KLF4 expression and activity during arsenic-induced cell transformation

Project description:Emerging evidence suggests that Nrf2 plays a pro-carcinogenic role in various cancers. Our previous study showed that arsenic-induced Nrf2 activation promotes metabolic reprogramming and cancer stem-like cell formation. Here, we identify KLF4, a key pluripotency factor, as a direct transcriptional target of Nrf2 in arsenic-exposed human bronchial epithelial cells. ChIP-seq revealed multiple Nrf2 binding peaks at the KLF4 gene locus, co-localizing with the enhancer markers H3K4me1 and H3K27Ac. Nrf2 knockout reduced KLF4 expression and decreased enhancer marker enrichment, alongside a genome-wide reduction in KLF4 binding in arsenic-treated BEAS-2B cells. In BEAS-2B cells with functional Nrf2, arsenic treatment significantly increased KLF4 binding on genes involved in several oncogenic pathways, including STAT3, SOX2, Nrf2, cell growth, Hedgehog, and epithelial-to-mesenchymal transition (EMT). We also found that KLF4 participates in a self-regulating feedback loop in response to arsenic-induced Nrf2 signaling. Co-occupancy of Nrf2 and KLF4 is crucial for establishing active enhancers, suggesting that Nrf2’s oncogenic effects are, at least in part, mediated by Nrf2-dependent self-amplification of KLF4 expression and function. Thus, co-targeting Nrf2 and KLF4 may represent a promising therapeutic strategy for eliminating cancer stem-like cells.

2025-11-17 | GSE279482 | GEO

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