Homeostasis of the sebaceous gland and mechanisms of acne pathogenesis

Abstract

Summary Background Sebaceous glands (SGs) are appendages of mammalian skin that produce a mixture of lipids known as sebum. Acne vulgaris is an exceptionally common skin condition, characterized by elevated sebum production, altered sebum composition, and the formation of infundibular cysts, called comedones. Comedo‐associated SGs are atrophic, suggesting that comedo formation involves abnormal differentiation of progenitor cells that generate the SG and infundibulum: the ‘comedo switch’. Understanding the biological processes that govern SG homeostasis promises to highlight potential aetiological mechanisms underlying acne and other SG‐associated skin disorders. Results In this review, we discuss the clinical data, genetic mouse models and in vitro research that have highlighted major hormones, paracrine factors, transcription factors and signalling pathways that control SG homeostasis. These include, but are not limited to androgens, progestogens and oestrogens; retinoids; receptor tyrosine kinases such as ErbB family receptors, fibroblast growth factor receptor 2 and insulin/insulin‐like growth factor 1 receptors; peroxisome proliferator‐activated receptor γ; aryl hydrocarbon receptor; and the Wnt signalling pathway. Where possible, the cellular and molecular mechanisms by which these regulatory factors control SG biology are indicated, along with considerations as to how they might contribute to acne pathogenesis. Conclusions Future research should seek to establish the relative importance, and causative relationships, of altered sebum production, sebum composition, inflammation and abnormal differentiation of sebaceous progenitors to the process of comedo formation in acne. Such an understanding will allow for therapeutic targeting of regulatory factors that control SG homeostasis, with the aim of treating acne.

PPAR‐γ signalling as a key mediator of human hair follicle physiology and pathology

“…Since all PPARs are widely expressed in human skin and its appendages, there is increasing interest in their role in maintaining cutaneous homeostasis and in dermatological disorders . PPAR‐mediated signalling has attracted special interest in psoriasis, atopic dermatitis, acne, skin ageing, scleroderma, melasma, lipodystrophy and skin cancer . In the context of this Focus Theme Issue , this development encourages one to also take a closer look at why and how exactly PPARs are of special interest in a translational hair research context, with a strict focus on their best‐investigated isoform, PPAR‐γ.…”

“…PPARs are nuclear hormone receptors abundantly expressed in tissues that display high fatty acid metabolism, including human skin and its appendages . Three different isoforms of PPARs exist—PPAR‐α, PPAR‐β/δ and PPAR‐γ, which demonstrate diverse functional capabilities, including—to name but a few examples—the control of lipogenesis, cell cycle and inflammatory gene expression (Figure ) …”

What does acne genetics teach us about disease pathogenesis?

“…113,114 The role of Notch in controlling stem cell maintenance and proliferation via mediators such as Lrig1 has wide implications for tissue homeostasis and tissue remodelling during sebaceous gland maturation (reviewed by Clayton et al in this issue of the BJD). 15,42,115 Lrig1 is a direct target of c-MYC, genetically implicated in acne vulgarism and can act in a negative feedback loop to control stem cell progenitors. 33,44 Mice with loss-of-function alleles in c-secretase were reported as having abnormal epidermal differentiation.…”

“…Onset of acne vulgaris during puberty coincides with androgen-induced sebaceous gland enlargement and subsequent increased sebum production, driving major changes in skin physiology during pathogenesis (reviewed by Clayton et al in this issue of the BJD). 15,16 As well as alterations to sebum production, pathogenic mechanisms that have been proposed include altered keratinization in the infundibulum, microbial infection and chronic inflammation as an end result. [16][17][18][19] More recent insights from genetics implicate abnormalities in differentiation of sebaceous progenitor cells and tissue remodelling in the pathogenesis of the acne vulgaris phenotype.…”

Acne in the 21st century

“…In this scholarly review issue, renowned experts together with talented young investigators survey the state of the art and chart a path towards addressing the unmet needs surrounding acne. Much can be learned about the pathogenesis of acne when one contemplates the molecular biology of the sebaceous gland in the context of acne genetics . As it turns out, comedones probably do not form as a consequence of follicular hyperkeratosis.…”