Intrinsic Factors of Acne Pathogenesis
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
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.
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;
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
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.
- White GM. Recent findings in the epidemiologic evidence,
classification, and subtypes of acne vulgaris. J Am Acad
- Rosenfield RL, Deplewski D, Kentsis A, et al. Mechanisms of
androgen induction of sebocyte differentiation.
- 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
- 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.
- 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.
- 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
- Jeremy AH, Holland DB, Roberts SG, et al. Inflammatory events
are involved in acne lesion initiation. J Invest Dermatol
- Freedberg IM, Tomic-Canic M, Komine M, et al. Keratins and the
keratinocyte activation cycle. J Invest Dermatol
- 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
- 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
- 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
- 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.
- 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.
- Lee DY, Yamasaki K, Rudsil J, et al. Sebocytes express
functional cathelicidin antimicrobial peptides and can act to kill
propionibacterium acnes. J Invest Dermatol
- 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.
- 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
- Herane MI, Ando I. Acne in infancy and acne genetics.
- Evans DM, Kirk KM, Nyholt DR, et al. Teenage acne is influenced
by genetic factors. Br J Dermatol 2005;152:579-81.
- He L, Wu WJ, Yang JK, et al. Two new susceptibility loci 1q24.2
and 11p11.2 confer risk to severe acne. Nat Commun
- 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.
- 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.
- Stein Gold L. What's New in Acne and Inflammation? J Drugs
Dermatol 2013;12(Suppl 6):s67-9.