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Tlr4 Epidermal Genetic Deletion Protects Against Acute and Tumorigenic UV Exposure in SKH-1 Mouse Skin

ABSTRACT: Solar ultraviolet (UV) exposure activates Toll-Like Receptor 4 (TLR4), initiating inflammatory signaling pathways relevant to human skin carcinogenesis. Using transcriptomic (Nanostring-based) and proteomic (reverse phase protein array-based) analysis we demonstrate that genetic deletion of epidermal Tlr4 mimics the photoprotective impact of pharmacological antagonism using topical resatorvid (RES), an effect not observed in transgenic mice harboring systemic deletion of Tlr4. These findings suggest that epidermal TLR4 represents a promising target for skin cancer photochemoprevention.

ORGANISM(S): Mus musculus

PROVIDER: GSE346544 | GEO | 2026/09/14

REPOSITORIES: GEO

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Project description:We here present a novel subtype of fibroblasts isolated from sun-exposed skin of elderly donors and characterized by its prominent and stable myo-chondrocyte-type differentiation. As we depict a similar chondrocyte-type expression pattern at sites of solar elastosis in human skin, we propose that this fibroblasts phenotype develops in the course of massive and perseverative UV-dependent damage as part of the process terminating in the most severe appearance of photoaging - solar elastosis. Along with the abnormal expression profile, these “old” fibroblasts generate a chondrocyte-type matrix with a layer of myofibroblast-differentiation in close vicinity to the epidermis, when propagated as skin equivalents (SEs) in 3D organotypic cultures. Importantly, these fibroblasts are strongly reduced in their ability to support epidermal growth and differentiation, allowing for rapid/premature epidermal atrophy. Having identified TGFß as an important player in this scenario, we show that the addition of TGFß to normal young fibroblast induces while inhibition of TGFß to the old fibroblast abolishes the myo-chondrogenic expression profile. Accordingly, inhibiting TGFß in the in vivo-like SEs, not only abrogates the aberrant phenotype but allows these fibroblasts to regain their normal mutual interaction with the epidermal keratinocytes and to support epidermal regeneration and longevity. Further, we provide evidence for a role of chronic solar UV radiation in initiating chondrogenic gene expression in young fibroblasts. Concomitantly, we show however, that the same UV treatment abolishes myofibroblast differentiation in the SEs with the “old” chondrogenic fibroblasts, and that this selective inhibition is already sufficient to restore the fibroblasts’ ability for successfully supporting epidermal growth and differentiation. From this it is tempting to suggest, that besides all damaging potential, “mild” solar UV radiation may exert also beneficial effects, e.g. in promoting activation of photoaged skin.

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Tlr4 Epidermal Genetic Deletion Protects Against Acute and Tumorigenic UV Exposure in SKH-1 Mouse Skin

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