The Immunology Behind a Sunburn

“In the summertime, when the weather is hot, you can stretch right out and touch the sky…”

If you love 70’s classics, you must have heard these lyrics in the “In the Summertime” song by Mungo Jerry. Well, it is summertime, the weather is hot, but considering the climate change and loss of our ozone protection, UVA and UVB can do a lot more damage to our skin now than it could have potentially done in 1970s. We are all aware that sunburn due to exposure of hazardous UV rays can enhance our risk of skin cancer. Here’s how us scientists see it: staying under the sun without any protection to the skin can cause sunburns which destroys the epidermal layer of our skin and leads to inflammation of the dermal layer underneath (remember 5 signs of inflammation – color, rubor, dolor, tumor, laesio functia). But what regulates excessive skin inflammation? What kind of interplay is functioning in between skin and skin resident immune system? What factors come into play to give us a sunburn or to protect us from its extreme effects?

Some answers to these questions come from Hoeffel and colleagues. Just like our skin, these answers have multiple layers.

To start from the cellular level, the authors investigated the neuroimmunological connection between cutaneous sensory neurons and dermal macrophages. They determined a neuronal phenotype most affected by UV-skin inflammation- ATF3+GINIP+, by looking at the experimental model of a sunburn developed by irradiating UV-C on mice ears. ATF (activating transcription factor 3), commonly referred as neuronal injury marker, works in variety of cellular properties such as signaling, survival, and neuroprotection. GINIP (Gαi-interacting protein), on the other hand, plays a role in early mechanical hypersensitivity response for neuropathic pain. Further, UV-irradiation turned ear skin thicker and redder in mice without GINIP in neurons. These mice ears developed tissue shrinkage and signs of necrosis which led to loss of tissue. The authors concluded that neurons with GINIP help in preventing excessive skin inflammation and fibrosis after UV irradiation. Connecting to immune cells, these scientists report lower numbers of monocytes and macrophages in mice without GINIP.

Going from a cell to the protein level, UV exposure induced higher levels of TAFA4, a neuroprotein that can modulate mechanical hypersensitivity induced by injury. TAFA4 act as a chemoattractant of macrophages, promoting phagocytosis and enhanced reactive oxygen species release. Around 50% of ATF+ neurons produced TAFA4. Like mice without GINIP, mice without TAFA4 had pathological fibrosis suggesting a requirement for this peptide in post-irradiation skin repair.

From protein to gene level, pro-inflammatory cytokine transcripts such as il-1b, tnf, il-6 were downregulated by TAFA4 neuropeptide, whereas anti-inflammatory il-10 transcripts were upregulated. TAFA4 thus upregulates the production of IL-10 in dermal macrophages and resolves the inflammatory phase of a sunburn.

To conclude, cutaneous sensory neurons need to produce TAFA4 neuropeptide after UV exposure to end the inflammatory phase by modulating dermal macrophage homeostasis and IL-10 production. It is fascinating to know how the immune system can work against a sunburn and what would be even more interesting is to see how this research transcribes from mice to humans. Till then, it would be definitely safer to keep using sunscreen. After all, as said by Baz Luhrmann, “everybody’s free to wear sunscreen”.

Source: Hoeffel G, Debroas G, Roger A, Rossignol R, Gouilly J, Laprie C, Chasson L, Barbon PV, Balsamo A, Reynders A, Moqrich A, Ugolini S. Sensory neuron-derived TAFA4 promotes macrophage tissue repair functions. Nature. 2021 Jun;594(7861):94-99. doi: 10.1038/s41586-021-03563-7.

Article author: Ines Poljak. Ines is a MSc student at University of Copenhangen and works on multiple myeloma bone disease. She worked in several clinical laboratories before committing herself completely to research.

Editor: Sutonuka Bhar. Sutonuka is a PhD candidate at the University of Florida. Her work focuses on host immune responses against viruses and bacterial membrane vesicles.

Check out Antibuddies’ blog post “The Immunology Behind a Sunburn”.

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