Recent Advances in Acne Pathogenesis

Implications for Therapy

Shinjita Das; Rachel V. Reynolds

Disclosures

Am J Clin Dermatol. 2014;15(6):479-488. 

In This Article

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

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