Effects of Imiquimod on Hair Follicle Stem Cells and Hair Cycle Progression

Abstract

Topical imiquimod (IMQ) application is widely used as a model for psoriasiform-like skin inflammation in mice. Although the effects on the epidermis are well characterized, it is unclear how IMQ affects hair follicles and cycling. Here we investigated how IMQ affects hair follicle stem cells and whether the timing of IMQ application influences the immune infiltrate. Our results show that IMQ application at mid and late telogen activated hair follicle stem cells leading to premature hair cycle entry (anagen), which was accompanied by massive infiltration of inflammatory macrophages and gamma delta T cells, whereas the number of the respective resident populations decreased. Interestingly, high resident macrophage numbers were present in Rag2 mice and were maintained after IMQ treatment explaining why IMQ-induced anagen was reduced. This could be rescued after macrophage depletion suggesting that resident macrophages inhibit whereas inflammatory infiltrating macrophages stimulate hair follicle stem cell activation. The expression of the anagen-inhibiting factor BMP-4 was reduced by IMQ treatment as well as the activating factors Wnt showing that IMQ-induced hair follicle stem cell activation occurs by a Wnt-independent mechanism involving inflammatory cytokines such as CCL2 and TNF-α. On the basis of our findings, we recommend conducting experiments with IMQ during mid and late telogen as the biggest differences in immune cell composition are observed.

Effects of Depilation Methods on Imiquimod-Induced Skin Inflammation in Mice

“…does not affect hair follicles (HF), whereas wax stripping results in depletion of HF stem cells leading to anagen entry (Amberg et al, 2016;Paus et al, 1994). The effects of depilation cream have not been carefully investigated yet.…”

Immune cell regulation of the hair cycle

“…However, exposure to harsh chemicals also results in a degree of inflammation in the interfollicular epidermis and might induce cytokine/chemokine release characteristic of a wound response. In fact, models of induced skin inflammation with topical imiquimod also promote the telogen‐to‐anagen transition in mice . In the epidermis, there is an increase in DETCs following depilation, in a manner reminiscent of the wound healing process …”

The role of macrophages in skin homeostasis

“…Furthermore, Amberg, et al ., found that inflammatory macrophages and dermal resident macrophages have different effects in the hair cycle. They showed that resident macrophages inhibit activation of hair follicle stem cells, preventing the entrance to anagen, while inflammatory infiltrating macrophages promote anagen [2]. …”

“…Effective depletion of macrophages was confirmed through Mac1 and F4/80 levels, while depletion of LCs and DCs was confirmed MHC class II in the epidermis and the dermis, respectively. Moreover, topical treatment with imiquimod, a drug that is FDA-approved to treat superficial BCC, results in increased infiltration of macrophages and T cells in mice [2]. In addition, tumor peptide-pulsed intra-dermal Langerhans cell vaccines have been shown to be effective at eliciting immunity against melanoma antigens in Phase I clinical trials in patients with stage III or IV melanoma [58].…”