Current understanding of acne is that it is a complex and multifactorial

inflammatory disease. Recent studies are better defining the cellular and molecular
mechanisms involved in acne and the importance of inflammation and the immune
response. The pathogenesis of acne is multifaceted, and at least four factors have
been identified. These key elements (Fig. 78-6) are (1) follicular epidermal
hyperproliferation, (2) sebum production, (3) Propionibacterium acnes, and (4)
inflammation and immune response. Each of these processes are interrelated and
under hormonal and immune influence.

It is thought that all clinical lesions begin with the microcomedo and develop into
clinical lesions— comedones, inflammatory lesions, and scarring. Follicular
epidermal hyperproliferation results in the formation of a microcomedo. The
epithelium of the upper hair follicle, the infundibulum, becomes hyperkeratotic with
increased cohesion of the keratinocytes, resulting in the obstruction of the follicular
ostium, where keratin, sebum, and bacteria begin to accumulate in the follicle and
cause dilation of the upper hair follicle, producing a microcomedo. Exactly what
initiates and stimulates the hyperproliferation and increased adhesion of
keratinocytes is unknown. Several proposed factors in keratinocyte
hyperproliferation include androgen stimulation, decreased linoleic acid, increased
IL-1-activity, and effects of P. acnes. Dihydrotestosterone (DHT) is a potent
androgen that may play a role in acne. DHT is converted from
dehydroepiandrosterone sulfate (DHEA-S) by 17-hydroxysteroid dehydrogenase
(HSD) and 5-reductase enzymes (Fig. 78-7). Compared with epidermal
keratinocytes, follicular keratinocytes have increased 17-HSD and 5-reductase,
thus enhancing DHT production.36,37 DHT may stimulate follicular keratinocyte
proliferation. Also supporting the role of androgens in acne pathogenesis is the
evidence that individuals with complete androgen insensitivity do not develop
acne.38

Follicular keratinocyte proliferation is also regulated by linoleic acid, an essential

fatty acid in the skin. Low levels of linoleic acid induce follicular keratinocyte
hyperproliferation and the production of proinflammatory cytokines. The levels of
linoleic acid are decreased in individuals with acne and normalize after successful
treatment with isotretinoin.39

In addition to androgens and linoleic acid, IL-1 has been shown to contribute to
keratinocyte hyperproliferation. IL-1induces follicular keratinocyte
hyperproliferation and microcomedone formation, and IL-1 receptor antagonists
inhibit microcomedone formation.40,41 The initial event that upregulates the
production of IL-1has not been determined. Fibroblast growth factor receptor
(FGFR)-2 signaling is also involved in follicular hyperkeratinization. There is a long-
established relationship between acne and Apert syndrome, a complex bony
malformation syndrome, caused by a gain-of-function mutation in the gene
encoding FGFR-2. Mutations in FGFR-2 in a mosaic distribution underlie a nevus
comedonicuslike lesion.42 The FGFR-2 pathway is androgen dependent, and
proposed mechanisms in acne include an increased production of IL-1and 5-
reductase.43,44

The second and key feature in the pathogenesis of acne is the production of sebum
from the sebaceous gland. Human sebum are composed mainly of triglycerides
found ubiquitously and of unique lipids, such as squalene and wax esters not found
anywhere else in the body, including the surface of the skin.45 Increased sebum
secretion has been associated with acne. On average, people with acne excrete more
sebum than those without acne, and secretion rates have been shown to correlate
with the severity of clinical manifestations, although the quality of sebum is the
same between the two groups.46 The main component of sebum, triglycerides, is
important in acne pathogenesis. Triglycerides are broken down into free fatty acids
by P. acnes, normal flora of the pilosebaceous unit. In return, these free fatty acids
promote P. acnes colonization and induction of inflammation.47 Lipoperoxides also
found in sebum induce proinflammatory cytokines and activate the peroxisome
proliferator-activated receptors (PPAR) pathway, resulting in increased sebum.48,49

Androgenic hormones activate sebocyte proliferation and differentiation and the

induction of sebum production. Similar to their action on the follicular infundibular
keratinocytes, androgen hormones bind to and influence sebocyte activity.50 Those
with acne have higher average serum androgen levels (although still within normal
range) than unaffected control participants. 51,52 5-Reductase, the enzyme
responsible for converting testosterone to the potent DHT, has greatest activity in
areas of skin prone to acne, face, chest, and back.44

The role of estrogen on sebum production is not well defined. The dose of estrogen
required to decrease sebum production is greater than the dose required to inhibit
ovulation.53 The mechanisms by which estrogens may work include (1) directly
opposing the effects of androgens within the sebaceous gland, (2) inhibiting the
production of androgens by gonadal tissue via a negative feedback loop on pituitary
gonadotropin release, and (3) regulating genes that suppress sebaceous gland
growth or lipid production.54

Corticotropin-releasing hormone may also play a role. It is released by the

hypothalamus and increased in response to stress. Corticotropin-releasing hormone
receptors are present on a vast number of cells, including keratinocytes and
sebocytes, and are upregulated in the sebocytes of patients with acne.55

The microcomedo continue to expand with densely packed keratin, sebum, and
bacteria. Eventually, this distension causes follicular wall rupture. The extrusion of
the keratin, sebum, and bacteria into the dermis results in a brisk inflammatory
response. The predominant cell type within 24 hours of comedo rupture is the
lymphocyte. CD4+ lymphocytes are found around the pilosebaceous unit, and CD8+
cells are found perivascularly. One to two days after comedo rupture, the neutrophil
becomes the predominant cell type surrounding the burst microcomedo.56

It was originally thought that inflammation follows comedo formation, but there is
evidence that dermal inflammation may actually precede comedo formation.
Biopsies taken from comedo-free acne-prone skin demonstrate increased dermal
inflammation compared with normal skin. Biopsies of newly formed comedos
demonstrate even greater inflammation.57 This may suggest that inflammation
actually precedes comedo formation, again emphasizing the interplay between all of
the pathogenic factors.

P. acnes is one of the key factors involved in acne pathogenesis. P. acnes is a gram-
positive, anaerobic, microaerophilic bacterium found in the sebaceous follicle and is
the dominant bacterial inhabitant of the human sebaceous gland,58 accounting for
almost 90% of the bacterial 16S transcripts.59 P. acnes is generally believed to play a
major role in the pathogenesis of acne vulgaris, in part by eliciting a host
inflammatory response.60 S. epidermidis is also present in follicles but is located near
the surface, suggesting that it does not contribute to the deeper inflammatory
process.58 There is a significant increase in P. acnes colonization at puberty, the time
when acne commonly develops, and teenagers with acne can have as many as 100-
fold more P. acnes bacteria present on their skin than healthy age-matched
counterparts.61 However, there are no consistent data correlating the raw number of
P._acnes organisms present in a sebaceous follicle and the severity of the acne.61

Previously, a shotgun approach to target all P. Acnes with antibiotics has been used,
which has led to significant bacterial resistance in up to 60% clinical isolates, directly
correlating with antibiotic treatment failure.61-63

The recent association of specific P. acnes strains with acne versus healthy skin
supports the concept that P. acnes is an etiologic agent in the pathogenesis of acne.
Certain P. acnes strains, as identified by multilocus sequence typing, were found to
be associated with acne, designated as type IA1 or IC strains.64-67 Acneassociated
types were further investigated using full genome sequencing in conjunction with
ribotyping.59,68 Specifically, phylotype IB-1 was associated with acne, as were the
ribotype 4 and 5 subgroups of phylotype IA-2. The ribotype 1 subgroup of
phylotype IA-2, together with phylotypes IA-1, IB-2, and IB-3, was found evenly
distributed in acne patients and individuals with healthy skin. These acne-associated
types were present in significant quantity in approximately 30% to 40% of patients
but with acne rarely in individuals with healthy skin. Conversely, the phylotype II,
ribotype 6 subgroup was found to be 99% associated with healthy skin.
Additionally, P. acnes isolates belonging to phylotype III were not found in acne
lesions but composed approximately 20% of isolates from healthy skin.64 The
genomes of acne-enriched and healthy skin–associated strains were sequenced,59,68
revealing that the phylotypes associated with acne selectively harbor a plasmid and
two chromosomal regions that contain genes possibly involved in pathogenesis,
adhesion to epithelial tissues, or induction of human immune response.59,68
Moreover, the levels of porphyrin production and vitamin B12 regulation were
recently shown to be different between acne- and health-associated strains,
suggesting a potential molecular mechanism for disease-associated strains in acne
pathogenesis and for health-associated strains in skin health.69 Metabolite-mediated
interactions between the host and the skin microbiota may also play an essential role
in acne development.70

Sebocyte differentiation and proinflammatory cytokine and chemokine responses

are varied depending on the strain of P. Acnes predominating within the follicle. 35
Certain strains of P. acnes induce a differential host immune response. P. acnes
ribotypes associated with acne induced distinct T helper 1 (Th1) and Th17 responses,
which potentially contribute to inflammation in acne, but P. acnes ribotypes
associated with health-induced high levels of IL-10, which presumably regulate and
inhibit inflammatory responses.71

P. acnes directly induces inflammation through various mechanisms. The cell wall of
P._ acnes contains a carbohydrate antigen that stimulates antibody development.
Patients with the most severe acne have been shown to have the highest titers of
antibodies.72 The antipropionobacterium antibody enhances the inflammatory
response by activating complement initiating a cascade of proinflammatory
events.73 P._acnes also facilitates inflammation by eliciting a delayed-type
hypersensitivity response and by producing lipases, proteases, hyaluronidases, and
chemotactic factors.72,74 Reactive oxygen species (ROS) and lysosomal enzymes are
released by neutrophils and levels may correlate with severity.75 Additionally, P._
acnes stimulates host innate responses via secretion of proinflammatory cytokines
and chemokines from peripheral blood mononuclear cells (PBMCs) and
monocytes60,76 and inflammatory cytokines and antimicrobial peptides such as
human -defensin-2 (hBD2) from KC77,78 and sebocytes.35

The mechanisms by which P. acnes triggers the innate immune response has been
studied and includes the activation of pattern recognition receptors (PRRs), which
recognize conserved pathogen-associated molecular patterns (PAMPs) and activate
specific signaling cascades, resulting in the induction of immune response genes. P.
acnes-induced secretion of proinflammatory cytokines IL-8, IL-12, and TNF-in
monocytes has been shown to involve TLR2,60 which is expressed on macrophages
surrounding the sebaceous follicles of acne lesions,60 as well as in the epidermis of
inflammatory acne lesions.79 More recently, P. acnes has been shown to induce IL-
1secretion and inflammasome activation via NLRP3 and caspase-1 in monocytes
and macrophages,80,81 as well as sebocytes.82 Both NLRP3 and caspase-1 colocalize
with macrophages in acne lesions,80 keratinocytes,77,78 and sebocytes.35 Although
many of the P. acnes ligands that trigger these PRRs and pathways are not known,
experimental evidence points to a possible role for P. acnes peptidoglycan in TLR2
activation60,76 and a component of peptidoglycan muramyl dipeptide (MDP),
which in P. acnes is composed of the canonical N-acetylmuramic acid residue linked
to the L-alanine D-isoglutamine dipeptide.83 MDP is a ligand for NOD2,84,85 a
cytoplasmic PRR, and can also activate the inflammasome via NLRP3,86 hinting at a
possible role for NOD2 in P. acnes–induced immune activation.

The antimicrobial peptides histone H4 and cathelicidin are also secreted locally in
response to P._ acnes. Histone H4 exerts direct microbial killing, and cathelicidin
interacts with components of the innate immune system, such as defensins and
psoriasin, in response to P. acnes,87,88 Another indicator of the role of innate
immunity in the pathogenesis of acne is the differentiation of peripheral blood
monocytes to CD209+ macrophages and CD1b+ dendritic cells in response to
P._acnes.89

A role for the adaptive immune response has also been suggested based on the
detection of CD4+ T cells in the inflammatory infiltrate from early acne lesions,56
and both Th1 and Th17 responses are prominent in vitro and in vivo at the site of
disease.90-92 Both Th1 and Th17 cells can trigger antimicrobial activity against
bacteria, but the lysis of these bacteria can release components that directly activate
the innate immune response, resulting in inflammation. Moreover, Th17
characteristically induce the recruitment of neutrophils, which contribute to
antibacterial activity but also cause tissue injury. ROS and lysosomal enzymes are
also released by neutrophils and levels may correlate with severity.75,93,94

The mechanism of acne scarring is not clear, and although scar formation correlates
with inflammatory response, there is no direct correlation of severity of disease and
development of scar formation can occur in mild to moderate acne.95

It has been shown that P. acnes induces metalloproteinase (MMP) 1 and 9 and the
expression of tissue inhibitors of metalloproteinase (TIMP)-1, the main regulator of
MMP-9 and MMP-1. Furthermore, ATRA downregulates MMP and augments TIMP-
1, suggesting that one way that ATRA may improve acne scarring is through the
modulation of MMP and TIMP expression, shifting from a matrix-degradative
phenotype to a matrix-preserving phenotype.

T-cell responses also appear to determine the outcome of scar formation. In

nonscarring lesions, initial robust inflammatory response with influx of CD4+
nonspecific response with few memory T cells were shown, which subsided in
resolution. In contrast, in scarring lesions, CD4+ T-cell numbers were smaller,
although a high proportion were skin-homing memory and effector cells, and
inflammation was increased and activated in resolving lesions.96

Finally, the impact of diet on acne is an emerging area of interest in the pathogenesis
of acne. Recent studies provide evidence that high glycemic load diets may
exacerbate acne and dairy ingestion appears to be weakly associated with acne,97-99
but some studies do not support the role of diet.100,101 Both are thought to increase
insulin-like growth factor (IGF)-1 with possible increase in androgen activity and
sebocyte modulation, therefore promoting acne.97,102 Several studies have reported
that molecular interplay of forkhead box transcription factor (Fox)O1 and
mammalian target of rapamycin (mTOR)–mediated nutrient signaling are important
in acne.103,104 The roles of omega-3 fatty acids, antioxidants, zinc, vitamin A, and
dietary fiber in acne remain to be elucidated. Thus, further randomized controlled
studies are needed to have a clear understanding of how diet influences acne.