Epithelial Cells in the Hair Follicle Bulge do not Contribute to Epidermal Regeneration after Glucocorticoid-Induced Cutaneous Atrophy

Abstract

One of the major adverse effects of glucocorticoid therapy is cutaneous atrophy, often followed by the development of resistance to steroids. It is accepted that epithelial stem cells (SCs) located in the hair follicle bulge divide during times of epidermal proliferative need. We determined whether follicular epithelial SCs and their transit amplifying progeny were stimulated to proliferate in response to the chronic application of glucocorticoid fluocinolone acetonide (FA). After first two applications of FA, keratinocyte proliferation in the interfollicular epidermis (IFE) and hair follicles was minimal and resulted in significant epidermal hypoplasia. We observed that a 50% depletion of the interfollicular keratinocyte population triggered a proliferative response. Unexpectedly, less than 2% of the proliferating keratinocytes were located in the bulge region of the hair follicle, whereas 82% were in IFE. It is known that cell desensitization to glucocorticoids is mediated via temporary decrease of glucocorticoid receptor (GR) expression. We found that GR expression was significantly decreased in IFE keratinocytes after each FA treatment. In contrast, many bulge keratinocytes retained GR in the nucleus. Our results indicate that bulge keratinocytes, including follicular SCs, are more sensitive to the antiproliferative effect of glucocorticoids than basal keratinocytes, possibly due to the incomplete process of desensitization.

Glucocorticoid receptors, epidermal homeostasis and hair follicle differentiation

“…These results suggest that the increased sensitivity of bulge keratinocytes to the antiproliferative effect of GCs is due to the contribution of the epidermal stem cells located in this compartment. 68 The examination of additional stem cell populations located in the IFE and sebaceous glands would add to this conclusion. 27 Despite its relevance, the mechanisms underlying GR function in HFs are not well characterized.…”

“…It was postulated that GC-induced desensitization could be due to differential responses in distinct keratinocyte subpopulations. 68 Chebotaev and coworkers reported that topical chronic GC treatment of mouse adult skin significantly decreased GR expression in interfollicular epidermal keratinocytes but not in the hair follicle bulge keratinocytes. These results suggest that the increased sensitivity of bulge keratinocytes to the antiproliferative effect of GCs is due to the contribution of the epidermal stem cells located in this compartment.…”

Nanocarriers for optimizing the balance between interfollicular permeation and follicular uptake of topically applied clobetasol to minimize adverse effects

“…Nonetheless, some major drawbacks of topically applied glucocorticoids are the high occurrence of local adverse effects due to high dermal absorption. Cutaneous atrophy, one of the most challenging local side effects associated with glucocorticoids, is characterized by a reduction in the viable epidermis and stratum corneum (SC) thickness, decreased number of keratinocytes, changes in the organization of collagen and elastin fibers, elimination of fatty tissue, and loss of mast cells [11,12]. Yet, the degree of this adverse event observed in patients is directly related to factors like skin site ("thicker" on scalp or forearm vs. "thinner" on eyelid ), age, potency, and use of occlusion [13].…”

Important role of kallikrein 6 for the development of keratinocyte proliferative resistance to topical glucocorticoids

“…Since mouse skin develops resistance to FA anti-proliferative effects by the end of a 2-week-treatment [11], we wanted to determine whether induced KLK6 expression was associated with keratinocyte proliferation. Using double immunostaining for KLK6 and the proliferation marker BrdU, we found that even though KLK6 protein was expressed in non-proliferating suprabasal keratinocytes, KLK6 + cells were frequently adjacent to BrdU + cells in the basal layer (Figure 1e).…”

“…We and others previously showed that after two weeks of topical steroid treatment, interfollicular keratinocytes in mouse skin lost sensitivity to glucocorticoid-induced anti-proliferative effects, and that keratinocyte proliferation that was drastically reduced at the beginning of treatment (10-15% of control level) returned to, or exceeded, the control level later after chronic treatment [10,11]. As discussed below, steroid tachyphylaxis in patients is also well documented, even though in some cases it may reflect irregular steroid use [8,9,12–14].…”