Since the emergence of life on Earth, species on the planet have developed, evolved and diversified under the radiation of sunlight for tens of thousands of years. Research in fields ranging from bacterial, fungal, and plant photosynthesis to the discovery of mammalian photoreceptor cells and membrane receptors has shown that visible light has a significant impact on multiple aspects of biological systems, especially involving neural regulation, rhythm formation, metabolic changes in mammals and beyond^1,2. This indicates that there are specific molecules and proteins in the life system of organisms that receive and convert light signals. Through these targets, we can regulate physiological functions of organisms using visible light^3,4.

Based on this understanding, since Endre Mester et.al first reported low-level laser (light) therapy (LLLT) and photobiomodulation (PBM) about 50 years ago, people have recognized the various beneficial effects of visible light on living organisms⁵. This has led to an explosive growth in research on PBM, and visible light has been widely used in clinical medicine, such as using blue light to treat tissue necrosis and using red light to promote diabetic wound healing, among others^6,7. However, due to the diversity of photoreceptor targets in cells and tissues, the effects of visible light on organisms can be complex and diverse⁸. How to flexibly utilize the beneficial effects of visible light on biological tissues and to reveal the clear regulatory mechanisms of visible light in different phototherapy modalities has become a key issue for the development of phototherapy using visible light.

During the process of wound healing, the activation of signal transducer and activator of transcription 3 (STAT3) is considered crucial for the migration and proliferation of epithelial cells, as well as for establishing the inflammatory environment. Activating STAT3 can accelerate wound healing, however, excessive activation of STAT3 can worsen scar formation^9,10. The rapid healing of wounds while reducing the formation of scars seems like a natural contradiction. Interestingly, in our research, we observed that 450nm blue light and 630nm red light have natural differential regulation abilities on cell proliferation, migration, and metabolism. Furthermore, our detection of upstream transcription factors in the STAT3 signaling pathway, downstream inflammatory factors and growth factors at the cellular and tissue levels, also showed that blue and red light have differential regulatory abilities on the p-STAT3-VEGF-A/FGF-2/Mcp-1 pathway. This makes it possible to use visible light phototherapy to address the above-mentioned contradiction and accelerate wound healing while reducing scar formation.

To elucidate the mechanism by which blue and red light regulate the STAT3 signaling pathway, we conducted transcriptomic analysis on keratinocytes treated with blue and red light. We found that red light promotes wound healing by activating the PI3 kinase p110 beta (PI3Kβ)/STAT3 signaling axis, while blue light inhibits p-STAT3 at the wound site by modulating cytochrome c-P450 (CYT-P450) activity and reactive oxygen species (ROS) generation (Graphical Abstract). What’s more, in a mouse wound model, we demonstrated that irradiation with red light during the inflammatory phase of wound healing (days 0-3), followed by irradiation with blue light during the proliferative and remodeling phases (days 4-9), effectively accelerated wound healing and reduced scar formation at the wound site.

In fact, visible light itself has the advantage of mild biological effects and minimal side effects. Although the penetration depth of visible light is limited, it is sufficient to penetrate the mouse skin. Our work has discovered and reported the natural differential regulatory abilities of red and blue light on the STAT3 signaling axis. By using red and blue light as the “switch” for STAT3 activity regulation can accelerate skin wound healing and alleviate scar formation, respectively. These results fully demonstrate the advantages and potential of using visible light to address skin issues.

Graphical Abstract: Schematic diagram of the regulatory mechanism of 450nm blue light and 630nm red light on the process of skin wound healing and scar formation. Under wound conditions, ROS induced by blue light in keratinocytes inhibits the p-STAT3. In contrast, red light promotes the p-STAT3 by upregulating the expression of PI3Kβ.

References:

1          Maglio, D. H. G., Paz, M. L. & Leoni, J. Sunlight Effects on Immune System: Is There Something Else in addition to UV-Induced Immunosuppression? Biomed Research International 2016, doi:10.1155/2016/1934518 (2016).

2          Meng, J. J. et al. Light modulates glucose metabolism by a retina-hypothalamus-brown adipose tissue axis. Cell 186, 398-412, doi:10.1016/j.cell.2022.12.024 (2023).

3          Cios, A. et al. Effect of Different Wavelengths of Laser Irradiation on the Skin Cells. International Journal of Molecular Sciences 22, doi:10.3390/ijms22052437 (2021).

4          Young, A. R. Chromophores in human skin. Phys Med Biol 42, 789-802, doi:10.1088/0031-9155/42/5/004 (1997).

5          Hamblin, M. R. Mechanisms and Mitochondrial Redox Signaling in Photobiomodulation. Photochemistry and Photobiology 94, 199-212, doi:10.1111/php.12864 (2018).

6          Jere, S. W., Houreld, N. N. & Abrahamse, H. Photobiomodulation activates the PI3K/AKT pathway in diabetic fibroblast cells in vitro. J Photochem Photobiol B 237, 112590, doi:10.1016/j.jphotobiol.2022.112590 (2022).

7          Dungel, P. et al. Low Level Light Therapy by LED of Different Wavelength Induces Angiogenesis and Improves Ischemic Wound Healing. Lasers in Surgery and Medicine 46, 773-780, doi:10.1002/lsm.22299 (2014).

8          Serrage, H. et al. Under the spotlight: mechanisms of photobiomodulation concentrating on blue and green light. Photochemical & Photobiological Sciences 18, 1877-1909, doi:10.1039/c9pp00089e (2019).

9          Huynh, J., Chand, A., Gough, D. & Ernst, M. Therapeutically exploiting STAT3 activity in cancer - using tissue repair as a road map. Nature Reviews Cancer 19, 82-96, doi:10.1038/s41568-018-0090-8 (2019).

10         Wang, Y. J. et al. Aspirin inhibits inflammation and scar formation in the injury tendon healing through regulating JNK/STAT-3 signalling pathway. Cell Proliferation 52, doi:10.1111/cpr.12650 (2019).