Our skin is constantly crawling with all sorts of microbes, from viruses to bacteria to fungi. So how do we avoid frequent infections and rashes? In a new study published in Science Immunology, researchers from the University of California, San Diego (UCSD) reported that epigenetic regulation of the protein kinase MAP2K3 in skin cells makes this possible (1). The researchers identified MAP2K3 as a new target for future therapeutic interventions in patients with inflammatory skin diseases.
“We had found previously that some of the bacteria that live on the skin produce a metabolic product that is a short chain fatty acid,” said Richard Gallo, a dermatologist at UCSD and the senior author of the study. “When skin cells were exposed to short chain fatty acid, they became very sensitive to microbes and created a stronger inflammatory response.”
Gallo’s team later discovered that these short-chain fatty acids inhibit the histone deacetylases HDAC8 and HDAC9 in keratinocytes, a type of skin cell (2). Inhibiting HDAC8 and HDAC9 leads to an increased inflammatory response in keratinocytes, suggesting that HDAC8 and HDAC9 inhibit the expression of genes involved in inflammation.
To find out which genes HDAC8 and HDAC9 regulate to control skin inflammation, Gallo and his team silenced expression of either HDAC8 or HDAC9 in keratinocytes, and then stimulated them with Toll-like receptor (TLR) ligands, which served as a proxy for a microbial stimulus. When they performed RNA sequencing on these keratinocytes, they saw increased expression of MAP2K3.
The team next showed that HDAC8 and HDAC9 directly interact with MAP2K3 and promote its transcription through the “facilitates chromatin transcription” (FACT) complex. Linking the pathway to human skin disease, the team found that skin samples from patients with inflammatory skin conditions, such as psoriasis, atopic dermatitis, and acne, had elevated levels of MAP2K3 expression compared to patients with healthy skin. Finally, by generating a mouse model with either HDAC8 or HDAC9 selectively silenced in skin cells, they showed that HDAC8 and HDAC9 regulate skin tolerance to inflammation in response to UV-treatment, induction of psoriasis, or Staphylococcus aureus infection.
“We had expected that these specific histone deacetylases would open chromatin and allow many cytokines to be directly more easily transcribed, but that was not what we observed,” Gallo explained. “Instead, the way they act was on the intermediate kinase, MAP2K3. So, it's a series of indirect events that lead to activation of canonical inflammatory signaling. That, to us, was a surprise.”
Brian Capell, a dermatologist and physician scientist at the University of Pennsylvania who was not involved in the study, was impressed by the number and scope of model systems Gallo and his team used to elucidate this new mechanism.
“They've identified potential novel targets that have not necessarily been investigated in an in-depth fashion for tamping down inflammation in the skin,” Capell said.
Gallo hopes that these findings will lead to new strategies for treating a variety of inflammatory skin diseases.
“This now provides a very select pathway that one could consider targeting to either decrease the inflammatory response when it's too high and unwanted,” he said, “or, alternatively, it's a way to also augment the inflammatory response if a greater degree of infection resistance is necessary.”
- Sawada, Y. et al. Cutaneous innate immune tolerance is mediated by epigenetic control of MAP2K3 by HDAC8/9. Science Immunology 6, eabe1935 (2021).
- Sanford, J.A. et al. Inhibition of HDAC8 and HDAC9 by microbial short-chain fatty acids breaks immune tolerance of the epidermis to TLR ligands. Science Immunology 1, eaah4609 (2016).