Interleukin-1α stimulation restores epidermal permeability and antimicrobial barriers compromised by topical tacrolimus

Abstract

Background: Currently tacrolimus has been widely used for many dermatologic diseases including atopic dermatitis, vitiligo, and psoriasis. Tacrolimus has anti-inflammatory and immunosuppressive effects comparable to glucocorticoids but with fewer side effects. Our previous study showed that barrier recovery was delayed after acute barrier disruption in skin treated by topical calcineurin inhibitors (TCIs), including tacrolimus. In that study, the epidermis of hairless mice treated with tacrolimus showed the decrease of number and secretion of lamellar body (LB), lipid synthesis-related enzymes, the expression of antimicrobial peptides (AMPs) and interleukin 1α (IL-1α). IL-1α is an important cytokine in improving barrier function, LB production, and lipid synthesis in keratinocytes.Objectives: We aimed to evaluate whether IL-1α stimulation would restore the barrier dysfunction observed in tacrolimus-treated skin. Methods and Results: In humans, topical tacrolimus was applied twice daily for five days, followed by the individual application of topical imiquimod cream and control cream from immediately after tape stripping until acute barrier disruption. Topical imiquimod accelerated barrier recovery compared to the control. In hairless mice, topical tacrolimus was applied twice a day and topical imiquimod was done concurrently once a day on one flank and a control cream on the other flank for four days. Topical imiquimod improved epidermal permeability barrier homeostasis compared to the control. Imiquimod-treated epidermis displayed an increase in LB number and lipid synthesis-related enzymes such as HMG-CoA reductase, serine palmitoyl transferase, and fatty acid synthases. Imiquimod also increased the expression of AMPs (CRAMP, mBD3) and IL-1α. Furthermore, intracutaneous injection of IL-1α restored permeability barrier recovery. In IL-1 type 1 receptor knockout (KO) mice, topical imiquimod failed to restore permeability barrier recovery after tacrolimus treatment. Conclusion: IL-1α stimulation induced positive effects on epidermal permeability and antimicrobial barrier functions in tacrolimus-treated skin. These positive effects were mediated by an increase in epidermal lipid synthesis, LB production, and AMP expression. These findings have clinically important implication that an IL-1α inducer such as imiquimod could prevent barrier dysfunction in tacrolimus-treated skin