Keratinocyte-Macrophage Crosstalk by the Nrf2/Ccl2/EGF Signaling Axis Orchestrates Tissue Regeneration
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA668615 | ENA |
REPOSITORIES: ENA
Dataset's files
| 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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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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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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