Autocrine and Paracrine Regulation of Keratinocyte Proliferation through a Novel Nrf2-IL-36γ Pathway

Area of Science:

• Molecular Biology
• Cell Biology
• Immunology

Background:

• The Nrf2 transcription factor (Nrf2) is recognized for cytoprotective roles in detoxification.
• Recent findings suggest Nrf2 also possesses proinflammatory activities and stimulates epithelial cell proliferation.
• Mechanisms and target genes underlying these dual functions of Nrf2 remain largely unexplored.

Purpose of the Study:

• To identify novel Nrf2 target genes involved in its proinflammatory and proliferative effects.
• To elucidate the role of Nrf2 in regulating the expression of the cytokine IL-36γ.
• To investigate the contribution of the Nrf2-IL-36γ axis to keratinocyte proliferation.

Main Methods:

• Gene expression profiling to identify differentially expressed genes.
• Chromatin immunoprecipitation (ChIP) to determine direct Nrf2 binding.
• Targeted proteomics (selected reaction monitoring) for protein quantification.
• In vitro and in vivo studies in keratinocytes and hepatocytes.

Main Results:

• The gene encoding IL-36γ was identified as a novel direct Nrf2 target in keratinocytes and hepatocytes.
• Genetic or pharmacological Nrf2 activation led to increased IL-36γ expression in the epidermis and liver.
• IL-36γ directly stimulated keratinocyte proliferation, partly via induction of fibroblast-derived mitogens, suggesting a double paracrine loop.

Conclusions:

• Nrf2 directly regulates the expression of the proinflammatory cytokine IL-36γ.
• The Nrf2-IL-36γ pathway contributes to keratinocyte proliferation and inflammation.
• These findings offer mechanistic insights into Nrf2's dual role in controlling inflammation and cell growth.