Mechanical strain, such as that experienced while rubbing cream onto skin, makes skin more permeable, alters immune pathways, and opens possibilities for non-invasive drug delivery.
As the outermost layer of the body, the skin is under a constant barrage of stimuli, ranging from the benign application of sunscreen to harmful puncture wounds. Sustained mechanical stress due to injury or inflammation triggers the immune defense of the skin.1 In the case of skin stretching, cell adhesion molecules in the epidermis sense this stimulus, leading to cell proliferation, secretion of growth factors, and production of inflammatory modulators.2 For instance, continuous skin stretching during pregnancy stimulates the formation of new skin.3 However, the physiological effects of acute tissue stretching, experienced during skin rubbing or massages, are relatively unexplored.
In a new study published in Cell Reports, researchers at King’s College London and the Curie Institute reported that a single incidence of stretching makes both human and mouse skin more permeable to external macromolecules, such as skin microbiota metabolites, thus inducing the recruitment of immune cells.4 The team then harnessed these changes to administer flu vaccine through the skin in mice, foregoing the use of needles. Their findings underscore the importance of mechanical stimuli for immune responses and have potential implications for improved drug delivery.
“You should be really careful about what you apply on your skin,” said Elodie Segura, an immunologist at Curie Institute and coauthor of the study, in a statement. “We showed that we can use this pathway into the skin for vaccine delivery, but it could also allow the penetration of toxic compounds or stimulate inflammation or allergy.”
To induce skin stretching, Segura and her team built a custom set-up wherein they used a tiny suction cup to apply strain to the skin of mice for 20 minutes. They could induce skin tension within the range of forces applied to the skin during the application of moisturizer into the skin and massage therapy. The team analyzed the cells of the stretched skin sample using a multiphoton microscope and transcriptomics. They observed changes to the orientation of the collagen fibers and upregulation of pathways involved in inflammation and mechanical signaling.
“It was quite surprising—I would not have expected so much production of inflammatory molecules just from stretching the skin,” Segura said.
Next, she and her team studied how acute skin tension affected immune cells. They cultured skin explants in vitro six hours after acute stretching and observed that the cells secreted molecules that attract immune cells. A closer look revealed an increase in the number of neutrophils, monocytes, macrophages, and dendritic cells, all key elements of the immune system. In fact, stretching also led to migration of dendritic cells to the closest lymph nodes in the mice—a classic sign of early immune response.
Because changes in collagen orientation can influence the skin’s permeability, the researchers used a fluorescent dye to assess this property in mouse and human skin samples, and they observed that stretching increased tissue permeability by opening the hair follicles. Considering this, the team speculated that stretched skin might allow the entry of skin microbiota-derived compounds, which could then trigger an immune response. Using germ-free and hairless mice, they deduced that dendritic cells sense microbiota-produced metabolites that penetrate the open hair follicles in stretched skin.
“Human skin is usually much less permeable than mouse skin because it has a thicker outer layer, but in this case, it responded in the same way because the molecules are moving through the hair follicles, not through the outer skin layer,” said Stuart Jones, a pharmaceutical scientist at King’s College London and coauthor of the study. “We believe this gives a really solid foundation for our results to be translated into humans.”
The team then wondered if they could exploit the stretch-induced skin permeability and immune response for non-invasive vaccine delivery. To test this, they applied a topical solution of fluorescent flu vaccine to mice skin while stretching the skin, and they observed uptake and transport of the antigens by the dendritic cells. This method produced a stronger antibody response than an intramuscular vaccine injection.
“Just stretching the skin was more effective than delivering the same vaccine with a needle, which shows the practical relevance of this immune activation,” said Jones. “This new pathway into the skin could be used in lots of different ways—we showed its potential for vaccine delivery, but we’re also starting to think about delivering cell therapies and whether it could be used for diagnostics.”
