Intrinsic Factors of Acne Pathogenesis
Acne vulgaris is a chronic inflammatory disease of the pilosebaceous unit and is the most common dermatologic diagnosis in the United States. The cause of acne vulgaris is multifactorial and includes pathophysiologic mechanisms such as altered sebaceous gland activity associated with hypermenorrhea, follicular hyperkeratinization, bacterial insult, induction of inflammation cascades, genetics, and dysregulation of the hormone microenvironment. In addition, increased androgen production can trigger cell division, differentiation, hormone metabolism, and cytokine/chemokine release. The characteristic comedone formation and local inflammation associated with acne arise from increased cell proliferation in the pilosebaceous unit obstructing the pore and cytokine activation, respectively. Lifestyle and personal behaviors can also be risk factors for acne development or worsening, but will not be covered in this brief editorial.
Hyperseborrhea, which is affected by many factors, maybe a major contributor to acne. Hyperseborrhea changes the composition of skin surface lipids and in patients with acne, the sebum contains a greater fraction of lipoperoxidases and monounsaturated fatty acids - both of which contribute to keratinocyte proliferation and differentiation.
Numerous factors affect sebum production and acne. The process is complicated and becomes more complicated as new research results emerge. These findings of acne pathogenic pathways provide numerous potential new targets for acne treatments. COX=cyclooxygenase; IGF=insulin-like growth factor; LOX=lipoxygenase.
Local overproduction of androgens - regulated by corticotropin-releasing hormone (CRH), adrenocorticotropic (ACTH), and cytokinesis associated with acne, rather than circulating steroid levels. Indeed, patients with acne have been shown to produce more testosterone and dihydrotestosterone (DHT) in their skin when compared to those without acne. These androgens increase sebaceous gland activity and subsequent keratinocyte hyperproliferation. In addition, sebaceous gland cells express androgen-metabolizing enzymes capable of converting androgens into more potent androgenic products.
Acne is also characterized by pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-ɑ) and interleukin-1 (IL-1), whose increased activity precedes hyperkeratinization of previously uninvolved follicles in inflammatory acne. Sebocytes of patients with acne also produce increased cyclooxygenase (COX) and lipoxygenase (LOX) enzymes. In a mouse model, overexpression of COX-2 results in sebaceous gland hyperplasia and excessive sebum, suggesting that COX-2-mediated prostaglandin synthesis could be involved in acne.
Propionibacterium acnes (P. acnes) is associated with acne and recent studies have demonstrated that it may not be the amount of P. acnes present in the skin, rather certain strains have a stronger link to acne than others. P. acnes upregulates several pro-inflammatory cytokines and Toll-like receptors in sebocytes.
There is also a genetic component to acne. The insulin-like growth factor 1 (IGF-1) (CA)19 polymorphism, Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma (PPARγ) gene, and the IL-6-572 G/C and IL-1A-889 C/T gene polymorphism are associated with acne, although additional studies are needed in this area. Furthermore, a Han Chinese study identified two acne susceptibility loci (1q24.2 and 11p11.2) and a UK genome-wide association study found three genes (11q13.1, 5q11.2, and 1q41) linked to the transforming growth factor-beta (TGFβ) cell-signaling pathway. Another study found the single nucleotide polymorphism rs4133274 on chromosome 8q24 (72 kb upstream of MYC) was the most significant association with severe teenage acne (p=1.7x10−6).
Recent studies have focused on several questions that show our understanding of acne is still evolving. For example, acne severity often remits in the early 20s without a significant decrease in sebum or P. Acnes. Furthermore, cellular inflammatory events, and the timing of those events, seem to be of critical importance. Inflammatory cascades may precede the acne lesion and the major components of acne pathophysiology, and may play a larger role in determining the overall duration of an acne lesion. The lesion may appear well after the initiation of these cellular events and remit prior to the completion of these events. In addition, further studies are needed to assess the part that individual cytokines and inflammatory markers play. As the potential pathologic pathways of acne are elucidated, new acne drug targets can be identified. Studies showing the efficacy of those new treatments will provide us with our best understanding of what factors are critically important in the pathogenesis of acne.