Researchers led by a team at INSERM and King’s College London have shown how stretching the skin stimulates immune cells and increases the skin’s ability to absorb large molecules, including those present in vaccines.
Using a device that applies suction pressure to stretch the skin, the researchers reported that skin stretching activated a local immune response and increased skin permeability without tissue damage via the opening of hair follicles. They also reported that applying vaccines topically while stretching the skin resulted in more effective immunization than subcutaneously injecting the vaccine in mice.
“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 Stuart Jones, PhD, at King’s College London. “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.”
Co-senior authors Jones and immunologist Elodie Segura, PhD, at Institut Curie, INSERM, Paris, and colleagues reported on their work in Cell Reports. In their paper, titled “Transient skin stretching stimulates immune surveillance and promotes vaccine delivery via hair follicles,” the researchers concluded, “Our results shed light on the role of mechanical stimuli in fine-tuning skin immune surveillance and have important implications for drug delivery and mechanobiology.”
The skin is constantly experiencing, interpreting, and responding to environmental stimuli,” the authors wrote. “When receptors within the skin detect injuries, they stimulate an immune response. Other skin receptors detect stretching, which occurs during massage or when skin care products are rubbed in. But what hasn’t been clear is whether skin stretching without damage could also activate the skin’s immune system. “… the impact of acute skin stretching, such as skin rubbing, is poorly understood,” they continued.
To examine the impacts of skin stretching on skin permeability and the immune system, the researchers used a device that stretches the skin by applying suction pressure. “… we analyzed how skin immune surveillance and barrier properties are affected by physiological skin deformation using a custom-made device that mimics skin massage,” they explained.
The researchers found that when applied for 20 minutes, the device temporarily increased the permeability of both mouse and human skin to fluorescently labeled large molecules by rearranging the skin’s collagen fibers in a way that caused the hair follicles to open. The skin retained its usual impermeable nature after around 15 minutes.
The team also showed that skin stretching activates a local immune response. In mice, the device resulted in an increased number of immune cells within the skin 24 hours later, suggesting that immune cells were migrating to the skin in response to stretching. “Using a model of transient skin stretching, we show that a single instance of skin tension modification induces collagen fiber re-orientation, mechano-transduction in stromal cells, inflammatory mediator production, and immune cell recruitment to the skin,” they stated. “… this acute skin stretching stimulates dendritic cells (DCs) migration to the draining lymph nodes and transcutaneous permeation of macromolecules through the opening of hair follicles.” Segura added, “It was quite surprising—I would not have expected so much production of inflammatory molecules just from stretching the skin.”
Stretching in addition triggered changes in gene expression for more than 1,000 genes, including several genes that encode immune signaling molecules (cytokines). “A total of 498 genes were significantly upregulated and 593 genes downregulated in stretched conditions,” the investigators stated.
To test whether these changes in immune surveillance and skin permeability could enable needle-free vaccine delivery in mice, the researchers applied a topical lotion containing a fluorescently labeled flu vaccine in conjunction with the skin-stretching device.
The vaccine’s fluorescent marker revealed a slow, controlled uptake of the vaccine into the mice’s bloodstreams and an accumulation of vaccine antigen in nearby lymph nodes, which is where immune responses are coordinated.
Compared to intramuscular vaccine delivery, the needle-free method resulted in higher antibody levels against the H1N1 flu antigen. Including an adjuvant in the vaccine formulation (a chemical that enhances immune response to vaccination) did not improve the immune response when the vaccine was delivered via the skin, suggesting that skin-stretching alone was sufficient to boost immunization.
In summary, the authors noted, “Our results support a model whereby mechanosensing upon a single skin stretch induces a local inflammatory response from stromal cells, ultimately resulting in innate immune cell recruitment into the skin. At the same time, the reversible opening of hair follicles promotes the entry of macromolecules, including microbiota-derived compounds, which in turn stimulate DC maturation and migration.” Harnessing this process allows effective needle-free, non-invasive vaccine delivery, they reported.
Because most of these tests were conducted in mice, more work is needed to examine whether skin stretching results in similar immune activation in humans and whether it could facilitate vaccine delivery.
“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,” noted Jones. “We believe this gives a really solid foundation for our results to be translated into humans.”
Stimulation of the skin immune system by such mechanical stress could also feasibly be involved in allergen sensitization, the investigators suggested. The team plans to investigate whether this skin-opening pathway could stimulate unwanted immune responses or allergies. Segura noted, “You should be really careful about what you apply on your skin. 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.”
In their paper, the authors pointed out, “… these findings may also have important toxicological implications … the clinical application of topical agents to the skin must be reconsidered, given that the pressure applied to the skin during the ‘rubbing in’ of products will likely impact the mechanical regulation of the barrier properties.”
Further work is needed to investigate the consequences of environmental allergens being brought into direct contact with the skin’s immune system during acute episodes of skin stretching, they wrote. In conclusion, the team stated, “… our results show that acute non-invasive skin stretching participates in the fine-tuning of skin immune surveillance in homeostasis and suggest that skin stretching could also increase skin inflammation in disease conditions and promote exposure to topically applied chemicals and allergens.”
