Related Experiment Video

Updated: May 14, 2026

Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate (DMBA-TPA)
04:12

Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate (DMBA-TPA)

Published on: December 19, 2019

Epidermal PPARγ Signaling as a Suppressor of Toll-like Receptor-Mediated Inflammation and Fibrosis: Relevance to

Raymond L Konger1,2,3, Ethel Derr-Yellin1

  • 1Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

International Journal of Molecular Sciences
|May 13, 2026
PubMed

Insights

Loss of epidermal peroxisome proliferator-activated receptor gamma (PPARγ) increases skin cancer risk by upregulating damage-associated molecular patterns (DAMPs) and TLR4 signaling, promoting inflammation and fibrosis.

Area of Science:

  • Dermatology
  • Molecular Biology
  • Immunology

Background:

  • Reduced PPARγ signaling is observed in actinic keratoses (AKs) and cutaneous squamous cell carcinomas (cSCCs).
  • Mice lacking epidermal PPARγ (Pparg-/-epi) show increased skin cancer development.

Purpose of the Study:

  • To investigate the molecular mechanisms linking epidermal PPARγ loss to cutaneous carcinogenesis.
  • To explore the role of damage-associated molecular patterns (DAMPs) and Toll-like receptor 4 (TLR4) signaling in this process.

Main Methods:

  • Transcriptomic analysis of Pparg-/-epi mouse skin, human AKs, and cSCCs.
  • Single-cell sequencing to analyze cell-type-specific gene expression.
  • Bioinformatic prediction of upstream regulators.

Main Results:

  • Upregulated genes in Pparg-/-epi skin, AKs, and cSCCs encode DAMPs, which are TLR4 ligands.
  • TLR4 signaling activation is predicted in both Pparg-/-epi mouse skin and tumor datasets.
  • DAMP expression is elevated in myeloid cells and myofibroblasts of Pparg-/-epi mice, with associated transcriptional changes indicating TLR4 signaling.
  • Loss of PPARγ expression and activity was observed in myeloid cells.
  • Fibroblasts exhibit profiles resembling those in cancer and fibrotic diseases, with increased dermal fibrosis linked to TLR4 and TGFβ signaling.

Conclusions:

  • Loss of epidermal PPARγ disrupts the balance between PPARγ and TLR4 signaling.
  • This disruption contributes to chronic inflammation and fibrosis, key features of skin cancer development.
  • PPARγ plays a crucial role in counterbalancing inflammatory and fibrotic pathways in the skin.
Keywords:
fibrosisinflammationnon-melanoma skin cancerperoxisome proliferators activated receptor gammatoll-like receptorstumor microenvironmenttumor–stromal crosstalk

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