Mouse skin structure after stretching, using histological staining. The scale bar corresponds to 100 micrometers. © Darawan Tabtim-On and Renaud Leclère – Experimental Pathology Platform, Institut Curie

What if vaccination could be administered by simple skin application rather than injection? A team of researchers from Inserm, Institut Curie, and King’s College London investigated the impact of external mechanical constraints (skin stretching, friction, etc.) on skin impermeability in animals and humans. They observed that, under the effect of massage of similar intensity to that of applying cream, the temporary opening of hair follicles was associated with the triggering of an inflammatory reaction mobilizing the skin’s adaptive immunity. The research shows that exploiting these mechanisms can elicit a qualitative immune response in mice in response to the application of a vaccine by skin massage. These results, to be published in Cell Reports, provide new insights into the role of mechanical stimuli in the skin’s immune responses and pave the way for new alternatives to drug injections.

The skin acts as the body’s protective barrier against environmental aggressors such as UV rays and toxic molecules. It must constantly adapt to perform its role effectively.

It is also constantly subjected to intrinsic mechanical stresses inherent to its complex structure[1]. When the skin is injured or inflamed, this ‘mechanical stress’ plays a major role in the immune system, particularly by finely modulating the action of certain immune cells that are sensitive to variations in skin tension.

However, with regard to external mechanical stresses, the physiological impact of mechanical stress caused by temporary stretching of the skin – such as during rubbing or massage – remains poorly understood.

A team of researchers coordinated by Élodie Segura, Inserm Research Director at the Immunity and Cancer Laboratory (Inserm/Institut Curie), and Stuart A. Jones, Professor and Director of the Centre for Pharmaceutical Medicine Research at the Institute of Pharmaceutical Science (King’s College London), investigated how mechanical stress caused by massage could affect the immune system. A. Jones, Professor and Director of the Centre for Pharmaceutical Medicine Research at the Institute of Pharmaceutical Science (King’s College London), investigated how mechanical stress caused by massage could affect immunity and the protective impermeability of the skin.

The scientists used a tool to stretch the skin in order to mimic, for 20 minutes and without causing any damage, a massage applying tension to the skin similar to that of a therapeutic massage or the application of cream. They then compared several mechanical, microbiological and physiological parameters of the skin with and without massage in mice and, in some cases, in human volunteers.

They first observed that massage made the skin temporarily permeable to very large molecules (or macromolecules) in both humans and animals. This permeability appeared to be linked to an opening of the hair follicles (the cavity in which the hair originates), which, encouraged by massage, allowed macromolecules on the surface to penetrate the skin tissue.

In rodents, researchers also observed that this opening of the hair follicles allowed compounds derived from bacteria naturally present on the skin’s surface (the skin microbiota) to enter the skin. This phenomenon then triggered an immune response, leading in particular to a local inflammatory reaction and the initiation of the so-called ‘adaptive’ immune response. This immunity, which enables the highly specific elimination of pathogens, is the basis of the immune system’s memory and is stimulated by vaccination.

‘These results suggest that mechanical stress acts as a danger signal within the skin,’ says Élodie Segura. ‘The entry of microbiota compounds into the skin, facilitated by stretching, could thus alert the local immune system to the loss of impermeability of the skin barrier and activate it to respond to the potential danger.’

Based on these observations, the team explored the possibility of exploiting these properties to develop a non-invasive vaccination technique involving skin application. They massaged a flu vaccine (H1N1) into the skin of mice and compared the immune response to that produced by a conventional intramuscular injection of the vaccine.

‘Human trials must be conducted to confirm these results observed in mice, as there are well-known differences between the skin of our two species,’ explains Élodie Segura. ‘We also need to understand how each type of skin cell reacts specifically to mechanical stress and precisely which microbiota products stimulate the inflammatory response. Mastering these processes in humans could thus lead to the development of needle-free, non-invasive methods of vaccination or drug administration,’ concludes the researcher.

However, these findings could also have significant implications from a toxicological perspective. They suggest that rubbing or massaging the skin could promote the penetration of harmful molecules – pollutants or allergens present on the skin or in skin creams – into the body and stimulate unwanted immune responses (inflammatory or allergic). However, to date, chemical risk assessments of products do not include the possibility that a macromolecule could enter the skin. Further studies could therefore focus on the links between mechanical stress and allergen sensitisation.

[1]The skin has a complex multi-layered structure, stratified into three main layers: the epidermis (the outermost layer), the dermis and the hypodermis (the innermost layer). Each of these three layers is composed of different types of cells and varies in thickness depending on the part of the body and also from one individual to another.

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