Recent Advances in Acne Pathogenesis
Implications for Therapy
Shinjita Das, Rachel V. Reynolds
Am J Clin Dermatol. 2014;15(6):479-488.
Abstract and Introduction
Abstract
Acne pathogenesis is a multifactorial process that occurs at the level of the pilosebaceous unit.
While acne was previously perceived as an infectious disease, recent data have clarified it as an
inflammatory process in which Propionibacterium acnes and innate immunity play critical roles in
propagating abnormal hyperkeratinization and inflammation. Alterations in sebum composition, and
increased sensitivity to androgens, also play roles in the inflammatory process. A stepwise approach
to acne management utilizes topical agents for mild to moderate acne (topical retinoid as mainstay ±
topical antibiotics) and escalation to oral agents for more resistant cases (oral antibiotics or
hormonal agents in conjunction with a topical retinoid or oral isotretinoin alone for severe acne).
Concerns over antibiotic resistance and the safety issues associated with isotretinoin have prompted
further research into alternative medications and devices for the treatment of acne. Radiofrequency,
laser, and light treatments have demonstrated modest improvement for inflammatory acne (with
blue-light photodynamic therapy being the only US FDA-approved treatment). However,
limitations in study design and patient follow-up render these modalities as adjuncts rather than
standalone options. This review will update readers on the latest advancements in our understanding
of acne pathogenesis and treatment, with emphasis on emerging treatment options that can help
improve patient outcomes.
Introduction
Acne vulgaris is a chronic inflammatory skin disease that develops around the pilosebaceous
apparatus and manifests as open and closed comedones as well as inflammatory papules, pustules,
and nodules. Commonly involved sites are the face, chest, upper back, and upper arms.
Inflammatory acne can result in potentially disfiguring scarring and post-inflammatory
hyperpigmentation, highlighting the importance of treatment.
Acne pathogenesis begins with abnormal keratinization that causes impaction and distension of the
lower portion of the infundibulum, forming the comedo.[1–3] Other factors include a complex
interplay among sebum production, with changes in lipid composition, hypersensitivity to androgen
stimulation, Propionibacterium acnes, and local inflammatory cytokines elaborated by the innate
immune system.[4–10]
The general principles of acne treatment involve targeting the various pathogenic factors. The
therapeutic ladder ranges from topical therapies for mild to moderate acne (retinoids and
antimicrobials) to oral agents for moderate to severe acne (antibiotics, hormonal agents, and
isotretinoin; of note, all oral treatments [except isotretinoin] should be prescribed in conjunction
with topical treatment). More recently, physical modalities, such as radiofrequency, photodynamic
therapy (PDT), and laser therapies have been studied.
Acne Pathogenesis
Overview of Innate Immunity
The innate immune system (rapid response but no memory to specific pathogens) underlies the
inflammatory basis for acne pathogenesis.[11] Through the physical barrier and acidic environment
of the stratum corneum (which limits bacterial colonization), skin provides first-line defense within
the innate immune system.[12–14] Skin also elaborates soluble factors (including complement factors,
antimicrobial peptides, chemokines, and cytokines) and expresses pattern recognition receptors
(PRRs) that mediate inflammatory responses against pathogen-associated molecular patterns
(PAMPs).[15–17] For ease of reference, Table 1 lists key inflammatory mediators of acne
pathogenesis.
Toll-like Receptors
Toll-like receptors (TLRs) are a subtype of PRR that can activate innate immune responses through
keratinocytes, neutrophils, monocytes/macrophages, natural killer cells, and dendritic cells
(including Langerhans cells). There are nearly a dozen different TLRs, but TLR2 and TLR4 appear
to be specific for acne pathogenesis. Microbial ligands (such as P. acnes) can activate several
pathways that ultimately converge to activate nuclear factor (NF)-κB transcription factor.
Downstream release of inflammatory cytokines (such as interleukin [IL]-1, IL-6, IL-8, IL-10, IL-12,
and tumor necrosis factor [TNF]-α) mediate pathogen destruction via effector cells.[18–21] TLR
activation also leads to release of antimicrobial peptides (such as human β defensin 1 [HβD1] and
human β defensin 2 [HβD2]) that play an important role in innate immune defenses.[21,23] TLR-
mediated cytokines also induce matrix metalloproteinases (MMPs) that play roles in acne
inflammation, dermal matrix destruction, and scar formation.[17,23]
Innate Immune System-mediated Inflammation
Inflammation both initiates and propagates acne pathogenesis. IL-1α is the critical comedogenic
cytokine, and one hypothesis for IL-1α stimulation is increased sebum production and decreased
linoleic acid (which contributes to loss of the skin barrier).[24,25] Other factors that drive IL-1
expression include TLR2 induction by P. acnes and NF-κB mediated transcription (stimulated by
oxidized squalene). IL-1 secretion by keratinocytes is stimulated by activation of TLRs (2 and 4) by
P. acnes, which promotes further keratinocyte proliferation, migration, and production of IL-
1.[1,26,27] In vitro studies have demonstrated that IL-1 is necessary for comedo formation.[26] Studies
demonstrating that IL-1α receptor blockade inhibits follicular hyperkeratinization support the notion
that an inflammatory milieu is necessary for acne pathogenesis and that the process is IL-1
specific.[2,28] Follicular IL-1α stimulates surrounding vascular endothelial cells to elaborate further
inflammatory markers (E-selectin, vascular cell adhesion molecule-1, intercellular adhesion
molecule-1, and human leukocyte antigen-DR).[1]
In the following sections, we discuss the role of acne mediators and treatment strategies.
Hyperkeratinization in Acne
Subclinical microcomedones are the initial acne lesions that mature into clinically apparent
comedones and inflammatory lesions. Acne lesions express higher levels of inflammatory factors
than normal skin, with notable inflammation and follicular epithelial hyperproliferation, even at the
level of the microcomedo. While it was previously thought that abnormal keratinization occurred
first, recent studies have demonstrated that expression of IL-1α (found within open comedones)
precedes abnormal keratinization.[1,19] Hyperkeratinization results from both follicular epithelial
hyperproliferation and retention of keratinocytes, thereby forming a keratin plug at the follicular
infundibulum. Epithelial hyperproliferation (comedo formation) is driven by rises in and sensitivity
to androgens, sebum lipid composition, P. acnes overgrowth, and local cytokines. Biofilm produced
by P. acnes also contributes to comedone formation by limiting desquamation of ductal
keratinocytes and propagating the infundibular plug.[1,29]
Sebum Abnormalities in Acne
Sebum is composed of triglycerides and free fatty acids (57.5 %), wax esters (26 %), squalene (12
%), and cholesterol and cholesterol esters (4.5 %) and provides lubrication and hydration, UVB
photoprotection, and lipophilic antioxidants for skin/hair. Sebum oleic and palmitoleic acids are
also antibacterial.[7]
Sebum production is at least partly regulated by androgen and retinoids. Androgen receptors are
located within the basal layer of sebaceous glands and keratinocytes, and androgens promote
sebaceous gland growth and sebum secretion.[30] On the other hand, systemic retinoids inhibit
sebocyte differentiation and cause sebaceous gland shrinkage.[31,32] Peroxisome proliferator-
activated proteins (PPARs) are nuclear transcription factors that dimerize with retinoid receptors to
regulate sebum production and keratinocyte differentiation.[33,34] New findings suggest that
sebaceous glands are also involved in neuroendocrine function and the stress response. For
example, melanocortins (melanocyte-stimulating hormone and adrenocorticotropic hormone) and
corticotropin-releasing hormone (in response to physiologic stress) bind to their respective receptors
within sebaceous glands to stimulate sebum production.[35–39] Insulin-like growth factor-1 can
induce sterol response binding protein-1 (SREBP-1), which stimulates sebaceous gland
lipogenesis.[40]
Sebum production is necessary but not sufficient for acne pathogenesis, and the composition of
sebum lipids can influence inflammation. Alterations in sebum lipid composition (such as increased
desaturation of free fatty acids, squalene, and squalene peroxide, or reduced levels of linoleic acid)
have been associated with follicular hypercornification through direct and indirect modulation of
the innate immune system.[34,41–44] Lipid peroxidation products can increase inflammatory cytokines
(including IL-1α) and activate PPARs, particularly PPARα. Oxidized squalenes also upregulate 5-
lipoxygenase (5-LOX), which promotes conversion of arachidonic acid to leukotriene B4 and
subsequent recruitment of inflammatory cells via PPARα.[45–47] PPARs activate T cells through
activator protein 1 (AP-1) and NFκB-mediated transcriptional regulation.[27,48]
Sebum-mediated inflammation is linked to P. acnes proliferation. Sebaceous glands and sebum
lipids provide an anaerobic setting for P. acnes growth. As sebum passes through the follicular duct,
lipases produced by P. acnes hydrolyze triglycerides into pro-inflammatory free fatty acids.[12–14] P.
acnes also binds TLR2 and TLR4 on sebaceous glands to stimulate sebocyte production of
antimicrobial peptides (HβD1 and HβD2) and inflammatory cytokines (TNFα, IL-1α, and IL-
8).[22,49–51] These observations suggest a role of sebaceous glands in pathogen recognition and
stimulation of the innate immune system.
Androgens in Acne
While produced in larger quantities by adrenal glands and gonads, androgens are also made locally
within sebaceous glands, where they promote keratinocyte and sebaceous gland proliferation.[52,53]
Adrenal and gonadal androgens are converted to testosterone and dihydrotestosterone by type 1 5α-
reductase found within the follicular infundibulum. Puberty has been associated with the onset of
acne vulgaris, as the rise in androgens during this period stimulates sebum production through
binding of receptors on sebaceous glands and pilosebaceous ducts. In fact, acneprone skin prone has
higher levels of androgen receptors and increased 5α-reductase activity.[54] Clinically, patients with
polycystic ovarian syndrome, congenital adrenal hyperplasia, and hormonal tumors (androgen
excess states) have higher rates of acne, while those with androgen deficiency or insensitivity do not
tend to develop acne.[55–57] Androgens also promote comedogenesis through regulation of growth
factors and IL-1α, which stimulate hyperkeratinization within the follicular duct and
infundibulum.[28]
Propionibacterium Acnes
P. acnes is a Gram-positive rod that thrives in the anaerobic environment of the pilosebaceous
apparatus. This commensal bacterium drives inflammatory responses that lead to acne pathogenesis.
P. acnes-secreted lipases digest sebum triglycerides into free fatty acids that stimulate antimicrobial
peptides (HβD1 and 2, cathelicidin, and granulysin) and downstream inflammatory responses.[58] P.
acnes also directly engages TLR2 and TLR4 found on keratinocytes and inflammatory cells to
propagate cytokines and chemokines (IL-1, IL-6, IL-8, and TNFα) that recruit neutrophils (through
IL-8) and macrophages to the follicle.[18,49] The ensuing inflammatory response causes follicular
wall rupture. Macrophages propagate the cycle by releasing more IL-8 (for neutrophil recruitment)
and IL-12 (for T-helper 1 cell [Th1] response).[28,49–51] TLRmediated cytokines also stimulate AP-1,
which induces MMPs that lead to tissue destruction and scar formation.[59,60] TLRs can also
stimulate expression of antimicrobial peptides.[22,27,61]
P. acnes promotes follicular hyperkeratinization by inducing integrin (cell adhesion protein) and
filaggrin (found in higher concentrations in sebaceous duct and infundibulum of acne-prone
skin).[18,62] Biofilm (a polysaccharide lining produced by P. acnes that surrounds microbes and
improves adherence to the follicle) further promotes hyperkeratinization and increases P. acnes
resistance to antibiotics.[29]
Figures 1 and 2 summarize the new data on acne pathophysiology.
Figure 1.
Propionibacterium acnes mediates acne pathogenesis through innate immune activation. AP
activator protein, FFA free fatty acid, IL interleukin, MMP matrix metellaproteinases, NF nuclear
factor, PMNs polymorphonuclear leukocytes, TLR toll-like receptor, TNF tumor necrosis factor
Figure 2.
Hyperkeratinization (which underlies microcomedo formation) is promoted by sebum production,
androgen stimulation, and Propionibacterium acnes via innate immune mechanisms. IL interleukin,
NF nuclear factor, TLR toll-like receptor
Acne Treatment
The therapeutic ladder for acne management ranges from topical to oral agents, with more recent
advances in the development of physical modalities, including radiofrequency, PDT, and laser
treatments.
Topical Retinoids
Topical retinoids (first-generation all-trans retinoic acid [tretinoin] and third-generation adapalene
and tazarotene) are the therapeutic cornerstone for acne comprising mild comedonal and
inflammatory papules.[63] By binding to nuclear membrane retinoic acid receptors (RARs), they
normalize follicular keratinocyte differentiation and cohesion of corneocytes to promote
comedolysis and inhibit comedogenesis.[64] Specifically, tretinoin binds all three RARs with
moderate affinity (RAR-α, β, γ); adapalene preferentially binds RAR-β, γ; and tazarotene has
highest affinity for RAR-β. Furthermore, adapalene also downregulates 5-lipoxygenase, leukotriene
production, and AP-1 transcription factor (thus inhibiting MMP-mediated tissue destruction and
scarring).[65] Adapalene also plays an anti-inflammatory role by inhibiting neutrophil chemotaxis.
Both tretinoin and adapalene inhibit monocyte expression of TLR2 and have been demonstrated to
prevent release of oxygen free radicals by neutrophils.[66,67] Topical retinoids can facilitate
percutaneous absorption of benzoyl peroxide and topical antibiotics.
Topical Antibacterial Agents
Benzoyl peroxide causes bacterial oxidation and is bactericidal. Of note, benzoyl peroxide
does not induce bacterial resistance.
Clindamycin and erythromycin are the two most commonly prescribed topical antibiotics
with coverage against Staphylococcus aureus and P. acnes. They function by binding the
50S ribosomal subunit and inhibit protein synthesis. Concomitant use with benzoyl peroxide
can limit development of bacterial resistance.
Azelaic acid inhibits mitochondrial activity and DNA synthesis.
Dapsone inhibits dihydropteroate synthetase and nucleic acid synthesis.
Sodium sulfacetamide also inhibits bacterial dihydropteroate synthetase.
Oral Antibiotics
Oral antibiotics are useful for moderate to severe inflammatory acne refractory to topical therapy.
They exhibit their effects via both antimicrobial and direct anti-inflammatory properties.
Specifically, antibiotics have been shown to inhibit bacterial lipase, down-regulate inflammatory
cytokines, prevent neutrophil chemotaxis, and inhibit MMPs.[68–70]
Tetracyclines (doxycycline and minocycline, in particular, which bind 30S ribosomal
subunit) are the most frequently prescribed oral antibiotics for acne. Lowdose tetracyclines
(e.g. doxycycline 20 mg twice daily) are recommended for anti-inflammatory effect and to
minimize the risk of antibiotic resistance.[71]
Macrolides, such as erythromycin and azithromycin, are also utilized, as they suppress P.
acnes proliferation within the follicle. They are implemented as secondline agents after
tetracycline antibiotics.
Oral Hormonal Treatment
Hormonal therapy may benefit women with signs of hyperandrogenism (premenstrual flares,
jawline distribution, hirsutism, and presentation or worsening of acne in adulthood). Oral
contraceptives inhibit ovarian and adrenal production of androgens and most contain both estrogen
and progestin to reduce the risk of endometrial cancer. The three US FDA-approved oral
contraceptives for acne treatment include norgestimate-ethinyl estradiol, ethinylestradiol with
norethindrone, and ethinyl estradiol with drospirenone.[72,73] Newer formulations also show
antiandrogen effects. Spironolactone, which has dual function through androgen receptor blockade
and inhibition of 5αreductase, can reduce sebum production and improve acne.[73,74] Flutamide
(FDA-approved for the treatment of prostate cancer) is a non-steroidal androgen receptor blocker
that has also been effective, but cost and hepatotoxicity significantly limit its use.[75] Outside of the
USA, clinicians can prescribe anti-androgen cyproterone acetate at low dosage (2 mg/day) or higher
dosage (50 mg/day) combined with estrogen; of note, patients on higher-dosage cyproterone acetate
should be monitored for hepatotoxicity.
Oral Retinoids
Isotretinoin (13-cis-retinoic acid) is FDA-approved for treatment-resistant severe, nodulocystic acne
and exerts an in vitro anti-androgen effect through inhibition of the 3αhydroxysteroid activity of
retinol dehydrogenase. While 13-cis-retinoic acid does not directly bind any of the nuclear retinoic
acid receptors, its metabolites are thought to bind RAR and retinoid X receptor (RXR). The RAR-
RXR heterodimer then binds the retinoid ligand and transcriptionally regulates genes involved in
inhibition of inflammation, promotion of follicular keratinocyte differentiation, and decrease in
sebaceous gland activity. RAR-RXR can also antagonize AP-1, which limits activation of MMPs
that cause tissue destruction and acne scarring.[76–79]
Isotretinoin exerts anti-sebocyte effect through a unique non-retinoid receptor mechanism that
recruits neutrophil gelatinase-associated lipocalin (NGAL), which can induce apoptosis in
sebocytes during isotretinoin treatment. Interestingly, an increase in NGAL after isotretinoin
treatment occurs before decreases in sebum production and P. acnes. Ongoing research will
elucidate mechanisms by which NGAL mediates the isotretinoin effect.[80] Another recent study
noted that isotretinoin impacts the antimicrobial peptide expression in acne lesions. Specifically,
isotretinoin therapy was associated with reduced expression of cathelicidin, HβD2, lactoferrin,
psoriasin, and koebnerisin; however, only cathelicidin and koebnerisin levels normalized after a full
6-month course of treatment. Isotretinoin was noted to have no impact on other antimicrobial
peptides, including granulysin, perforin, and dermcidin, among others. These findings raise the
possibility of specifically targeting antimicrobial peptides in the treatment of acne.[81]
Devices for Acne Treatment
Most acne treatments provide short-term clearance, and isotretinoin is the only medication that
offers the best chance at long-term remission. However, the burden of monitoring programs for
teratogenicity and the risk of adverse effects have prompted continued research to identify other
treatments. Increasing antibiotic resistance is another important factor in seeking new treatment
approaches.[82,83] Radiofrequency, light, and laser devices are active areas of research and
development. Of note, randomized double-blinded clinical trials with sufficient numbers of patients
and with comparisons of devices with standard therapies (topical and systemic drugs) are lacking.
Furthermore, data are limited regarding frequency of relapses after treatment with devices. It is not
possible to evaluate the real benefit of medical devices, and at this time these devices should be
viewed as useful adjuncts to established therapies rather than as standalone treatment options.
Radiofrequency Devices. Non-ablative radiofrequency devices use radio waves to heat the dermis
and subcutaneous tissue while sparing the epidermis. Initially designed to improve skin laxity,
radiofrequency devices have recently been studied in the treatment of inflammatory acne. High
temperatures are thought to kill bacteria and shrink sebaceous glands. While preliminary studies
show promise, the study samples were small.[84–87] More recently, fractional radiofrequency
treatment with insulated microneedles targeting the middermis has shown promise in treating
inflammatory acne lesions.[86] Common side effects include pinpoint bleeding at the sites of
treatment, pain, and redness. Unlike lasers, radiofrequency treatments do not cause
hyperpigmentation (no epidermal heating), and thus may be a viable option for patients with darker
skin types.
Light and Laser Treatments for Acne. Non-Coherent Light Sources: Non-coherent light sources
harness the photochemical effect of visible or ultraviolet light on endogenous bacterial porphyrins
to produce free radicals and reactive oxygen species that can cause membrane damage to P. acnes
(major porphyrin is protoporphyrin IX). The optimal wavelengths for killing P.acnes in this manner
are in the blue light region (400–420 nm).
Intense pulse light (IPL) provides non-coherent pulses of visible light (longer wavelength than blue
light) that are thought to penetrate deeper into the follicle to photoactivate P. acnes porphyrins.[88]
Efficacy data are conflicting, and newer devices combine IPL source with suction devices
('photopneumatic' devices) with some improved efficacy.[89] Major limitations include lack of
properly controlled evaluation.
Blue light treatment is FDA-approved for acne treatment. Initial studies demonstrated that 8 weeks
of blue light therapy for acne can reduce the number of inflammatory, but not comedonal, acne
lesions (patients should continue a topical retinoid).[90] Others have reported improvement of acne
on the face and trunk with broadspectrum green and violet wavelengths.[91] The FDA recently
approved the use of narrow-band light sources for home-use laser devices.
PDT utilizes exogenous photosensitizers that preferentially absorb into the pilosebaceous unit and
enhance the effect of light treatments. Because aminolevulinic acid (ALA) and methyl-
aminolevulinate (M-ALA) are only FDA-approved for treatment of actinic keratoses, their
application in acne treatment is considered off-label. PDT requires at least 70–90 min incubation of
photosensitizer on the skin, followed by exposure to either blue (415 nm, ALA) or red (635 nm, M-
ALA) light. The longer wavelength of red light penetrates deeper into the dermis where sebaceous
glands reside (500–1,000 μm) and thus offers better efficacy.[92,93]
Variations of PDT include 'high dose' (optimized to target the sebaceous glands but with more side
effects) and 'low dose' (gentler parameters with fewer side effects but less effective). There can be
40–70 % improvement in inflammatory lesions lasting 3–6 months, with further improvement noted
on repeat treatment. PDT can cause significant inflammatory side effects, including pain, post-
procedure photosensitivity, and phototoxic effect (edema, blistering—downtime for 7–10 days post-
procedure).[94] This side effect profile may be tolerable for patients with moderate to severe acne
who have failed or want to avoid isotretinoin, do not want to receive an oral contraceptive, or are
planning to become pregnant.
Lasers for Acne Treatment: Pulsed-dye lasers (PDL) cause selective photothermolysis of dilated
blood vessels within acne lesions. While there is no direct effect on P. acnes or sebum production,
the soluble factor transforming growth factor (TGF)-β (a cytokine involved in wound healing) is
up-regulated after non-ablative PDL therapy. TGF-β seems to mediate an anti-inflammatory effect
that manifests as a global improvement in acne appearance rather than limited to the treated site.
The lack of high-quality controlled trials have made it difficult to interpret conflicting reports of
PDL efficacy.[95,96]
Mid-infrared lasers gained attention when the 1,450 nm diode laser was shown to damage
sebaceous glands in a rabbit ear model and in ex vivo human skin.[97] Photothermolysis at the level
of the sebaceous gland and alteration in follicular hyperkeratinization may play a role. A
preliminary split-back randomized controlled trial showed significant decrease in acne lesion counts
compared with control sites.[97] In follow-up studies, most of the patients were concomitantly
receiving either an oral or topical acne regimen during the laser treatment.[98] A subsequent splitface
study in 38 subjects showed no benefit using the Revised Acne Grading scale. However, global
improvement in acne was observed, again suggesting the role of a soluble factor (not identified in
the paper).[99]
More recently, Sakamoto et al.[101] have spear-headed efforts to utilize selective photothermolysis of
lipids within sebaceous glands. Anderson et al.[100] have identified 1,210 and 1,720 nm as
wavelengths where the absorption coefficient of lipid exceeds that of water. In vitro studies of fresh
porcine skin samples have demonstrated selective thermal damage to fat but not overlying skin near
the 1,210 nm wavelength. Furthermore, artificially prepared sebum has absorption peaks near
1,210, 1,728, 1,760, 2,306, and 2,346 nm.[101] These data suggest the potential for sebum to be
targeted as a chromophore in the selective photothermolysis of sebaceous glands. Preliminary
studies (ex vivo specimens of skin) have shown that 1,700 nm for 100–135 ms pulse durations
selectively target sebaceous glands without damage to the epidermis or dermis. Studies are
underway to further characterize these observations.
Conclusions
Acne is an inflammatory disease that results from multiple factors within the pilosebaceous
apparatus. New data about the physiopathology of acne show that acne is an inflammatory (rather
than infectious) disease in which innate immunity and P. acnes play a crucial role.
While acne treatment is multimodal, the mainstay of therapy remains prevention of comedone
formation. Topical agents are used for the treatment of mild to moderate acne, whereas oral agents
are generally reserved for moderate to severe disease. Of the currently available treatments,
isotretinoin offers the most sustained improvement and even cure. However, the side effect profile,
government-mandated monitoring process, and teratogenicity, render it cumbersome to prescribe.
This has prompted further research into both medical and device options. While radiofrequency,
laser, and light treatments offer some improvement for inflammatory acne (with blue-light PDT
being the only FDA-approved treatment), these options are not effective standalone modalities.
Future studies will offer further insights into acne pathogenesis and, in turn, spark the development
of novel targeted treatments.
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