The skin barrier is maintained not by a single structure, but by the coordinated action of different epithelial regions, lipid-related mechanisms, and local signaling pathways. In practice, attention is usually focused on the interfollicular epidermis. Yet the hair follicle is also in constant contact with the external environment and can therefore make a meaningful contribution to barrier maintenance.

In this study, a group of researchers from leading U.S. institutions, including the University of Colorado and the National Institutes of Health, started from that premise. The upper portion of the hair follicle — the most superficial part of the follicle, also referred to as the hair canal or infundibulum — lies at the interface between the outside environment and deeper follicular regions. That makes it more than a mere passage for the hair shaft; it is a functionally active skin compartment [1].

To test the role of the hair follicle in barrier maintenance, the authors used a conditional knockout model of Abca12. This gene causes harlequin ichthyosis, the most severe inherited disorder of the skin barrier. Using genetic engineering methods, the investigators selectively disrupted Abca12 in different structures: the interfollicular epidermis and developing and mature hair follicles. Barrier status was then assessed by permeability assays, transepidermal water loss measurements, histology, electron microscopy, and molecular genetic analyses.

Key results and regulatory mechanisms

The study showed that the upper portion of the hair follicle not only participates in skin barrier formation but also affects neighboring tissue, sebum outflow, and cell movement between the follicle and the epidermis.

Independent barrier function of the upper follicular segment

The upper portion of the hair follicle was shown to form a functional barrier on its own. The investigators identified the molecular components needed for barrier activity in this region, including barrier proteins and lamellar granules. At the same time, this follicular barrier was less resistant to external stress than the interfollicular epidermis: after acetone treatment, the follicular infundibulum showed more pronounced penetration of external substances.

Epidermal response to follicular injury

When the barrier in the upper follicular segment was disrupted, the neighboring epidermis responded. Selective loss of Abca12 in the follicular region increased the expression of genes associated with barrier defense and cellular differentiation in the adjacent interfollicular epidermis. Cell proliferation and epidermal thickness also increased. In other words, a local defect in the follicle triggered a compensatory response in the surrounding tissue.

Control of desquamation and sebum outflow

Another mechanism involved desquamation and sebum outflow. When the follicular barrier was damaged, normal cell shedding was impaired, leading to excessive keratinization within the canal. As a result, sebum became trapped in the infundibulum and could no longer reach the skin surface freely. In some cases, this was accompanied by hair loss and the formation of dense keratin plugs. These findings show that continuous cell turnover in the upper follicular segment is critical for normal sebum transport.

Migration of altered follicular cells into the epidermis

The authors also found that altered cells from the upper follicular portion migrated into the interfollicular epidermis. Cells with Abca12 disruption did not disappear over time; instead, they moved into the epidermis and helped sustain the pathologic process. This differed from epidermal cells with a similar defect, which were gradually replaced by healthy populations. In this way, the follicle can act as a reservoir of cells that maintain skin disease.

Role of interleukin-17a

The authors also showed increased expression of interleukin-17a (IL-17a) in the upper follicular segment. Neutralizing this cytokine in mice reduced epidermal thickness and cell proliferation only partially. In the model with follicular defects, this intervention also limited the migration of altered cells. However, complete recovery did not occur, so IL-17a should be viewed as an important mediator of injury rather than the sole driver of the pathologic changes.

Practical significance and conclusions

The findings expand the classic model of the skin barrier and support a broader assessment that includes not only the epidermis, but also the upper portion of the hair follicle. This is especially relevant when managing patients with follicular hyperkeratosis, impaired sebum outflow, and persistent inflammatory processes, because pathology in the follicular infundibulum may drive broader barrier damage and involve neighboring skin.

The limitations of the study should also be kept in mind: the experimental models with mosaic Abca12 knockout do not fully reproduce the systemic course of ichthyosis in humans. In addition, the modest effect of IL-17a neutralization suggests that barrier function is regulated by a complex network of interacting pathways rather than by a single factor.

Overall, the study supports the view that the upper portion of the hair follicle is a fully functional and biologically active component of the skin defense system. It contributes not only to local barrier defense but also to epidermal coordination, sebum transport, and inflammatory signaling. Recognizing the follicular compartment as a key element of skin homeostasis opens new possibilities for targeted therapeutic strategies.

Reference

1. Ford N.C., Benedeck R.E., Mattoon M.T. et al. Hair follicles modulate skin barrier function. Cell Rep.2024; 43(7): 114347. doi:10.1016/j.celrep.2024.114347.