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  • New insights in the pathogenesis of acne include the unraveling of the role of androgens, the identification of PPARs, the new concept of inflammation as a primary event in acne pathogenesis, the role of neuropeptides in acne, and new knowledge on the mode of action of P. acnes.

1 Introduction

The pathogenesis of acne, the most common disease of the pilosebaceous unit, has been traditionally attributed to increased sebum production, androgen activity, follicular hyperkeratinization, and the action of Propionibacterium acnes (P. acnes) within the sebaceous follicle [1, 2].

However, our knowledge on the pathogenesis of acne has been revolutionized in the last few years by studies on the role of sebaceous glands. The development of experimental models for the in vitro study of human sebaceous gland functions overcame the lack of an ideal animal model compatible to human sebaceous glands [3–6]. These studies have fundamentally changed the view for the human sebaceous gland from “a fossil of the skin with past but no future” [7] to the “brain of the skin” [8].

New insights in the pathogenesis of acne include the unraveling of the role of androgens, the identification of PPARs, the new concept of inflammation as a primary event in acne pathogenesis, the role of neuropeptides in acne, and new knowledge on the mode of action of P. acnes [9].

2 New Concepts of Acne Pathogenesis

Skin (the sebaceous gland in particular) has been shown to be a steroidogenic tissue that possesses the enzymatic machinery to synthesize androgens (testosterone) de novo from cholesterol [3]. Androgens in turn play a central role in acne, not only by increasing the size of sebaceous glands and stimulating sebum production but also by stimulating keratinocyte proliferation in the ductus seboglandularis and the acroinfundibulum, thus contributing to comedone formation [2]. Increased 5α-dihydrotestosterone may act on infundibular keratinocytes leading to abnormal keratinization [10].

Peroxisome proliferation-activated receptors (PPAR) have been identified in human sebaceous glands, whereas PPAR ligands induce sebaceous lipogenesis in cultured human sebocytes [11]. Sebaceous lipids exhibit direct pro- and anti-inflammatory properties, whereas the induction of 5-lipoxygenase and cyclooxygenase-2 pathways in sebocytes leads to the production of pro-inflammatory lipids [12].

The order of events participating in acne pathogenesis has long been debated. Although traditionally inflammation was considered to succeed ductal hypercornification, new findings changed this concept. Bioactive interleukin (IL)1α-like material was found in open acne comedones from untreated patients [13], and the addition of IL1α induced hyperproliferation of follicular keratinocytes in isolated sebaceous follicle infundibula maintained ex vivo [14]. Thus, IL1α has a central role in cutaneous inflammation and keratinocyte proliferation and may influence the evolution of acne lesions [15]. Also, inflammatory events were detected in the very earliest stages of acne lesion development. Inflammatory factors (IL1α), increased CD4+ T cells, lack of neutrophils, and reduced Langerhans cells have been found in the perifollicular epidermis from uninvolved skin from acne patients prior to hyperproliferation or abnormal differentiation of the follicular epithelium [16].

New roles in the pathogenesis of acne have been attributed to P. acnes. A P. acnes biofilm, which penetrates into the sebum-like adhesive glue has been suggested to lead to the increased cohesiveness of corneocytes seen in acne. A biofilm is a complex aggregation of microorganisms that are placed within an extracellular polysaccharide lining which are secreted after adherence to a surface. So, the microcomedones may not be the central cause of acne, as traditionally thought, but rather result from the substances secreted by P. acnes into the sebum in its effort to attach to the follicular lining to set up a biofilm [17]. Also, Toll-like receptors (TLR), mammalian homologues of Drosophila Toll receptors, have been implicated in acne-related inflammation. P. acnes may activate keratinocytes and sebocytes of the pilosebaceous unit via TLR [18] and trigger inflammatory cytokine responses by activation of TLR2 [19]. P. acnes-conditioned medium and formalin-killed P. acnes were shown to augment intracellular lipid formation in hamster sebocytes by increasing de novo synthesis of triacylglycerols [20].

An exciting role has emerged for neuropeptides in acne, with the identification of the expression of melanocortin receptors 1 (MC1R) and 5 (MC5R) in human sebocytes in vitro and in situ [21–23] and increased in situ expression of MC1R in sebaceous glands of lesional skin in acne patients [24]. α-melanocyte-stimulating hormone (α-MSH) can stimulate sebocyte differentiation and lipogenesis [10]. Importantly, KDPT, a tripeptide derivative of α-MSH, has been shown to have anti-inflammatory action in SZ95 sebocytes via suppression of IL-1β-mediated cytokine expression [25]. Moreover, corticotrophin-releasing hormone (CRH) induces the synthesis of sebaceous lipids in vitro [26], and CRH expression by keratinocytes was induced by P. acnes [8, 27].

We have come a long way since 1975, when Dr. Albert M. Kligman described acne as “a bewitching lady, pursued with more passion than intelligence” [28]. The multifaceted acne has been pursued with dedication and many new signaling pathways have been unraveled through robust experimental data. Nevertheless, acne never ceases to bewitch us and the search for new discoveries is yet to be over.