Effect of oral isotretinoin on the nucleo‐cytoplasmic distribution of FoxO1 and FoxO3 proteins in sebaceous glands of patients with acne vulgaris

Abstract

Oral isotretinoin is the most effective anti‐acne drug with the strongest sebum‐suppressive effect caused by sebocyte apoptosis. It has been hypothesized that upregulation of nuclear FoxO transcription factors and p53 mediate isotretinoin‐induced sebocyte apoptosis in vivo. It is the aim of our study to analyse the distribution of the pro‐apoptotic transcription factors FoxO1 and FoxO3 in the nuclear and cytoplasmic compartments of human sebocytes in vivo before and during isotretinoin treatment of acne patients. Immunohistochemical analysis of skin biopsies with antibodies distinguishing phosphorylated and non‐phosphorylated human FoxO1 and FoxO3 proteins was performed before isotretinoin treatment, six weeks after initiation of isotretinoin therapy, and in acne‐free control patients not treated with isotretinoin. Our in vivo study demonstrates a significant increase in the nucleo‐cytoplasmic ratio of non‐phosphorylated FoxO1 and FoxO3 during isotretinoin treatment of acne patients. Translational and presented experimental evidence indicates that upregulation of nuclear FoxO1 and FoxO3 proteins is involved in isotretinoin‐induced pro‐apoptotic signalling in sebocytes confirming the scientific hypothesis of isotretinoin‐mediated upregulation of FoxO expression.

Neuroendocrinology and neurobiology of sebaceous glands

“…In turn, PI3K/Akt/mTOR activation results in inhibitory phosphorylation of forkhead box (FoxO) transcription factors (Mirdamadi et al ., ) which, in the context of adipogenesis, inhibit PPARγ‐mediated gene transcription (Fan et al ., ). In line with this model, isotretinoin treatment in acne patients reportedly results in nuclear translocation of non‐phosphorylated FoxO1 and FoxO3 in SGs (Agamia et al ., ).…”

27TH Fondation René Touraine Annual SCIENTIFIC MEETING 2019

“…[30] Even the traditional "pilosebaceous unit" concept may have to be revised, at least in human scalp skin: here the hair follicle (HF), sebaceous gland (SG), apocrine gland, arrector pili muscle, the coil of the eccrine sweat gland and perifollicular adipocytes all appear to form an intimately connected functional unit that may best be addressed as "adnexal skin unit". [31] Increasing interest in the role of the HF and SG microbiome in the physiology of these appendages, [17,20] well beyond their long-appreciated pathophysiological importance for example in acne, [10,32] hidradenitis suppurativa [33,34] and other forms of folliculitis has carved out a new frontier in skin appendage research: that is the interaction of skin appendage epithelia with resident microbiota, namely how both parties "manage" each other and occasionally recruit help from intracutaneous immunocytes to pitch in.…”

“…[81] In fact, the last two years have seen an impressive phalanx of rodent model-based SG papers. Together with the fact that one now can make use of a rich tools box of human sebocyte cell culture models, [32,78,82,83] and fertilized by increasing insights into the lipid biology, [84] neuroendocrinology and neuropharmacology of human SGs, [85,86] this has made the SG the second-best studied of all skin appendages. Combined with the clinical relevance of the SG in the ongoing acne pathobiology debate, which is getting ever more intriguing, [10,84,[87][88][89] The regulatory function of Gata6 seems to extend to the sebaceous duct and the hair canal in murine skin, as reported by Swanson et al.…”

“…Increasing interest in the role of the HF and SG microbiome in the physiology of these appendages, well beyond their long‐appreciated pathophysiological importance for example in acne, hidradenitis suppurativa and other forms of folliculitis has carved out a new frontier in skin appendage research: that is the interaction of skin appendage epithelia with resident microbiota, namely how both parties “manage” each other and occasionally recruit help from intracutaneous immunocytes to pitch in.…”

Isotretinoin's paradoxical effects in immortalized sebocytes

“…2 Mirdamadi et al showed that isotretinoin treatment of immortalized SZ95 sebocytes increased PI3K/AKT signalling, resulting in decreased nuclear FoxO1 levels. 3 However, Agamia et al 4 recently demonstrated that isotretinoin treatment of patients with acne under in vivo conditions increased nuclear expression of FoxO1 and FoxO3a; and Shi et al 5 reported that p53 and FoxO1 increased in primary nonimmortalized human keratinocytes after addition of isotretinoin ( Fig. 1a).…”