Innate immune recognition of intracellular DNA as 'stranger' and 'danger' signal

Skin cells can alert our immune systems when they detect a virus or DNA damage, discovered researchers on EU project IFNDNA. The findings may help to improve treatments for autoimmune conditions and diseases like cancer in the future.

Researchers at the British universities Lancaster and Dundee have learnt how skin cells alert the immune system when they detect a virus or when their DNA is damaged by sunburn, pollution or chemotherapy drugs.

The research suggests human skin cells might play a more important role in starting an immune response than previously thought, says Dr Leonie Unterholzner, co-ordinator of four-year project IFNDNA. The results pave the way for a better understanding of the immune system, crucial to developing therapies to treat autoimmune conditions and other diseases.

IFNDNA’s breakthrough, published in journals including Nature Communications and Molecular Cell, has surprised the scientific community. “Our findings were quite controversial at the start because they were so unexpected,” said Dr Unterholzner.

With support from the Marie Curie programme, Dr Unterholzner’s team of doctorate students and post-doctoral researchers worked first at a laboratory at the University of Dundee and then at Lancaster University. Researchers at the universities of St Andrews in Scotland, Trinity College in Dublin and the Aarhus University in Denmark also collaborated.

DNA protector?

It had long been known that if our skin is exposed to a virus or bacteria, our cells can switch on an immune response. Dr Unterholzner’s team found how that signalling worked and how damage to DNA can lead to a similar immune response, activated in a different way.

The researchers damaged the DNA in skin cells using the chemotherapy drug Etoposide, finding the damage was detected by proteins in the cell's nucleus. “When we started the work, it was clear that dead cells could send out danger signals that would alert the immune system to the damage,” said Dr. Unterholzner. “But we didn’t know whether cells could communicate with the immune system when they were damaged but still alive and able to repair the damage.”

Our cells use a protein called cGAS to recognise the presence of virus DNA. cGAS then activates the immune adaptor STING (Stimulator of Interferon Genes), which switches on an anti-viral immune response. In the case of damaged DNA, a DNA binding protein in the cell’s nucleus, called IFI16, activated STING.

IFI16 and STING relay the signal from the damaged DNA to start an immune response: the damaged skin cells release substances which alert more specialised immune cells to the danger. The immune response is responsible for sunburn when our skin cells are damaged by UV light, for instance, and Dr Unterholzner thinks it might also alert the immune system to cancer cells damaged by radio- or chemotherapy.

“It is possible that our immune system uses this alarm to detect damaged skin cells and prevents them from becoming cancerous,” she said.

The project’s funding helped train several postdoctoral research fellows and graduate students, a new generation of scientists keen to continue work in this complex field.

“This is a very exciting first step, but much more work needs to be done to find out how this discovery may be used for medical applications, for instance in cancer immunotherapy,” said Dr Unterholzner.

Reference source: Innate immune recognition of intracellular DNA as 'stranger' and 'danger' signal