INTRODUCTION
Topical retinoids are used for a number of dermatological conditions including psoriasis, pigmentary disorders, and skin cancers and are well-established acne treatments.1 These are agonists of retinoic acid receptors (RAR), which transcriptionally regulate cell proliferation, differentiation and inflammation.2 Three subtypes exist - RAR-α, RAR-β, and RAR-γ.2 This article discusses the role of RAR subtypes in the chronic inflammatory skin disease, acne.
Effects of Topical Retinoids on Acne Pathophysiology
Recently, transcriptomic studies have provided a novel platform to examine the molecular effects of topical retinoids in skin.
Acne Pathophysiology
Acne is an inflammatory disease of the pilosebaceous unit, most commonly affecting the face and trunk.3 Its complex pathophysiology involves four key interrelated factors: excess sebum production with increased levels of pro-inflammatory lipids; hyperkeratinization of the follicle wall leading to comedone formation; dysbiosis of the skin and follicle microbiome involving Cutibacterium acnes (also named as Propionibacterium acnes); and inflammatory mediator release into the surrounding dermis.3-7
The role of inflammation in acne pathogenesis is complex.7 Subclinical inflammation may be the primary event in lesion development, evolving into chronic inflammation.4,8,9 A number of genes involved in inflammatory response, leukocyte migration, neutrophil infiltration, and T cell migration are upregulated in acne.5,10 This leads to increased cellular movement and immune cell trafficking in acne lesions, including crosstalk between dendritic and natural killer cells, leukocyte extravasation signaling, dendritic cell maturation, and activation of neuroinflammatory pathways and pattern recognition receptors such as toll-like receptors (TLRs).5 Numerous inflammatory mediators are also implicated; for example, interleukin-1 (IL-1), which contributes to hyperkeratinization, IL-17 secreted by the subpopulation of Th17 lymphocytes, and matrix metalloproteinases (MMPs), which cause dermal matrix loss and scarring.4,7,11
RAR-γ: the Main Retinoic Acid Receptor in the Skin
The three RAR subtypes vary in their localization. RAR-α and RAR-β have a widespread expression within the body, whereas RAR-γ is more tissue-specific.2,12 RAR-γ comprises 90% of the receptors found in the skin, with RAR-α accounting for most of the remaining 10%. RAR-γ is mainly expressed in structural cells such as keratinocytes and fibroblasts, and RAR-α predominantly in immune cells such as Langerhans cells and T cells (Figure 1).1,2,12
Although the precise function of each subtype in acne pathogenesis is yet to be defined, evidence supports RAR-γ playing a key role.1,2 RARs are involved in tissue homeostasis, through control of skin cell differentiation and proliferation.2 Their canonical mechanism involves transcriptional regulation via binding to target gene promoters, such as those involved in keratin production, although RARs also have non-genome-related actions (Table 1).2,13
Effects of Topical Retinoids on Acne Pathophysiology
In acne, all retinoids have comedolytic and anti-comedogenic effects and anti-inflammatory actions on multiple inflammatory pathways.1,3,4,7,15 They trigger transcriptional events causing either activation or repression of retinoid-controlled gene expression that regulates genes involved in keratinocyte differentiation, cornification, desquamation, and cell adhesion.15 They also downregulate key components of the inflammatory response in acne, including TLRs and MMPs.1,4,5 Furthermore, topical retinoids may play a role in modulating the skin microbiota by regulating the quantity and quality of sebum production.1,20
Recently, transcriptomic studies have provided a novel platform to examine the molecular effects of topical retinoids in skin.
These studies have shown that the RAR-β/γ-selective topical retinoid adapalene downregulates key genes expressed in the epidermis, suggestive of increased keratinocyte turnover
