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Research Updates

Intrinsic Factors of Acne Pathogenesis

Dane Hill, Sara Moradi Tuchayi, Steven R. Feldman, MD, PhD

Tuesday, September 01, 2015

Acne vulgaris is a chronic inflammatory disease of the pilosebaceous unit and is the most common dermatologic diagnosis in the United States.1 The cause of acne vulgaris is multifactorial and includes pathophysiologic mechanisms such as altered sebaceous gland activity associated with hyperseborrhea, 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.2,3 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, may be a major contributor to acne (Figure 1). 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.

 

Fig1

Figure 1. Pathogenic factors affecting sebocytes.  Numerous factors affect sebum production and acne. The process is complicated and becomes more complicated as new research results emerge. These findings about 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 cytokines - is associated with acne, rather than circulating steroid levels.4,5 Indeed, patients with acne have been shown to produce more testosterone and dihydrotestosterone (DHT) in their skin when compared to those without acne.6 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.6,7


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.7,8 Sebocytes of patients with acne also produce increased cyclooxygenase (COX) and lipoxygenase (LOX) enzymes.9 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.10,11


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.12 P. acnes upregulates several pro-inflammatory cytokines and Toll-like receptors in sebocytes.13 

 

 

Fig2

Figure 2. A hair follicle showing the four major components of acne pathogenesis.

 

There is also a genetic component to acne.16-18 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)19 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.20 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.21 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.22 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 our best understanding of what factors are critically important in the pathogenesis of acne.

 

References

  1. White GM. Recent findings in the epidemiologic evidence, classification, and subtypes of acne vulgaris. J Am Acad Dermatol 1998;39:S34-7.
  2. Rosenfield RL, Deplewski D, Kentsis A, et al. Mechanisms of androgen induction of sebocyte differentiation. Dermatology 1998;196:43-6.
  3. Zouboulis CC, Seltmann H, Hiroi N, et al. Corticotropin-releasing hormone: an autocrine hormone that promotes lipogenesis in human sebocytes. Proc Natl Acad Sci U S A 2002;99:7148-53.
  4. Wei B, Qu L, Zhu H, et al. Higher 17alpha-hydroxyprogesterone levels aggravated the severity of male adolescent acne in Northeast China. Dermatology 2014;229:359-62.
  5. Slominski A, Zbytek B, Nikolakis G, et al. Steroidogenesis in the skin: implications for local immune functions.  Steroid Biochem Mol Biol 2013;137:107-23.
  6. Sansone G, Reisner RM. Differential rates of conversion of testosterone to dihydrotestosterone in acne and in normal human skin-a possible pathogenic factor in acne. J Invest Dermatol 1971;56:366-72.
  7. Jeremy AH, Holland DB, Roberts SG, et al. Inflammatory events are involved in acne lesion initiation. J Invest Dermatol 2003;121:20-7.
  8. Freedberg IM, Tomic-Canic M, Komine M, et al. Keratins and the keratinocyte activation cycle. J Invest Dermatol 2001;116:633-40.
  9. Alestas T, Ganceviciene R, Fimmel S, et al. Enzymes involved in the biosynthesis of leukotriene B4 and prostaglandin E2 are active in sebaceous glands. J Mol Med 2006;84:75-87.
  10. Neufang G, Furstenberger G, Heidt M, et al. Abnormal differentiation of epidermis in transgenic mice constitutively expressing cyclooxygenase-2 in skin. Proc Natl Acad Sci U S A 2001;98:7629-34.
  11. Zhang Q, Seltmann H, Zouboulis CC, et al. Involvement of PPARγ in oxidative stress-mediated prostaglandin E2 production in SZ95 human sebaceous gland cells. J Invest Dermatol 2006;126:42-8.
  12. Fitz-Gibbon S, Tomida S, Chiu BH, et al. Propionibacterium acnes strain populations in the human skin microbiome associated with acne. J Invest Dermatol 2013;133:2152-60.
  13. Jasson F, Nagy I, Knol AC, et al. Different strains of Propionibacterium acnes modulate differently the cutaneous innate immunity. Exp Dermatol 2013;22;587-92.
  14. Lee DY, Yamasaki K, Rudsil J, et al. Sebocytes express functional cathelicidin antimicrobial peptides and can act to kill propionibacterium acnes. J Invest Dermatol 2008;128:1863-6.
  15. Graham GM, Farrar MD, Cruse-Sawyer JE, et al. Proinflammatory cytokine production by human keratinocytes stimulated with Propionibacterium acnes and P. acnes GroEL. Br J Dermatol 2004;150:421-8.
  16. Goulden V, McGeown CH, Cunliffe WJ. The familial risk of adult acne: a comparison between first-degree relatives of affected and unaffected individuals. Br J Dermatol 1999;141:297-300.
  17. Herane MI, Ando I. Acne in infancy and acne genetics. Dermatology 2003;206:24-8.
  18. Evans DM, Kirk KM, Nyholt DR, et al. Teenage acne is influenced by genetic factors. Br J Dermatol 2005;152:579-81.
  19. He L, Wu WJ, Yang JK, et al. Two new susceptibility loci 1q24.2 and 11p11.2 confer risk to severe acne. Nat Commun 2014;5:2870.
  20. Navarini AA, Simpson MA, Weale M, et al. Genome-wide association study identifies three novel susceptibility loci for severe acne vulgaris. Nat Commun 2014;5:4020.
  21. Eichenfield LF, Del Rosso JQ, Mancini AJ, et al. Evolving perspectives on the etiology and pathogenesis of acne vulgaris. J Drugs Dermatol 2015;14:263-72.
  22. Stein Gold L. What's New in Acne and Inflammation? J Drugs Dermatol 2013;12(Suppl 6):s67-9.

 

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