Journal of Receptors and Signal Transduction

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/irst20

A strategic review on the involvement of

receptors, transcription factors and hormones in
acne pathogenesis

Sneha Bharti & Harini Chowdary Vadlamudi

To cite this article: Sneha Bharti & Harini Chowdary Vadlamudi (2020): A strategic review on the
involvement of receptors, transcription factors and hormones in acne pathogenesis, Journal of
Receptors and Signal Transduction, DOI: 10.1080/10799893.2020.1805626

To link to this article: https://doi.org/10.1080/10799893.2020.1805626

Published online: 13 Aug 2020.

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JOURNAL OF RECEPTORS AND SIGNAL TRANSDUCTION
https://doi.org/10.1080/10799893.2020.1805626

REVIEW ARTICLE

A strategic review on the involvement of receptors, transcription factors and

hormones in acne pathogenesis
Sneha Bharti and Harini Chowdary Vadlamudi
Department of Pharmaceutics, Acharya & BM Reddy College of Pharmacy, Bangalore, India

ABSTRACT ARTICLE HISTORY

Acne vulgaris is a very common pilosebaceous inflammatory disease occurring primarily on the face Received 23 January 2020
and also rare on the upper arms, trunk, and back, which is caused by Propionibacterium, Revised 27 July 2020
Staphylococcus, Corynebacterium, and other species. Pathophysiology of acne comprises of irregular Accepted 27 July 2020
keratinocyte proliferation, differentiation, increased sebum output, bacterial antigens and cytokines
KEYWORDS
induced inflammatory response. Treatment of acne requires proper knowledge on the pathophysi- Androgens; toll like
ology then only the clinician can come out with a proper therapeutic dosage regimen. Understanding receptor; sebocytes;
the pathophysiology not only includes the mechanism but also involvement of receptors. Thus, this follicular hyperproliferation;
review is framed in such a way that the authors have focused on the disease acne vulgaris, patho- dihydrotestosterone; rete-
physiology, transcription factors viz. the Forkhead Box O1 (FoxO1) Transcription Factor, hormones like noid receptor
androgens and receptors such as Histamine receptors, Retinoic receptor, Fibroblast growth factor
receptors, Toll like receptor, Androgen receptor, Liver X-receptor, Melanocortin receptor, Peroxisome
proliferator-activated receptor and epidermal growth factor receptors involvement in the progression
of acne vulgaris.

Introduction Development of acne may be individual or site-specific,

with only a few follicles presenting the inflamed area yet at
Acne vulgaris is the skin disorder which impacts nearly all
some stage in serious disease manifestations [5]. Enhanced
individuals at least once during their lifetime and its severity
is immediately associated with sebum manufacturing, which production of sebum, hyperkeratinization of the follicle, skin
is itself stimulated by expanded sebaceous glands following bacteria colonization at sebaceous gland and inflammation
androgenic stimulants [1]. Multiple physiological factors of skin are thought to contribute to acne growth by four
could be discovered in acne pathogenesis, including follicular major variables [6]. An interesting region of latest progress in
hyperproliferation and enhanced sebum manufacturing acne knowledge has emerged from research centered on the
accompanied by follicle blockage and colonization of mul- skin ‘microbiome’, the complicated habitat of the microbes
tiple microorganisms such as Propionibacterium acnes. It is such as bacteria, viruses and fungi at the surface of the epi-
believed to be a complicated P. acnes-related chronic dis- thelial layers seem to encompass distinctive skin features [7].
ease. Despite the variety of medicines and products on the The lipophilic Cutibacterium or Propionibacterium species
market, there is still no formula that can ensure all families dominated sebaceous sites, while in Staphylococcus and
with acne a long-term advantage. Antibiotics are the largest Corynebacterium species were abundant in moist regions [8].
part of the frequently used medicine in treatment of acne, Cornyebacterium Acnes has long been considered a patho-
but in the long run they are not effectual [2]. genic reason for the progression of acne, but it is a signifi-
Evidence since commencing preclinical instigation till their
cant skin commensal to avoid colonization and incursion of
clinical management of active lesions now supports the cru-
pathogenic microbes by hydrolyzing sebum triglycerides and
cial position of cellular inflammatory occurrences at all
releasing antimicrobial fatty acids and contributing to the
phases of the growth of acne lesion [3]. Therefore, emphasis
has shifted from acne to an inflammatory skin disorder as a acid pH of the skin surface [9].
disease mainly concerned with the hyperproliferation of the By targeting the sebaceous gland and reducing sebum
sebaceous follicle. Drugs with antibacterial and anti-inflam- output, the most efficient acne therapies operate [10].
matory prospective has to be investigated in terms of the Clinicians often use combination treatment to manage acne,
release of inflammatory mediators into the follicle as well as using topical medicines such as antibacterials, antibiotics,
dermis owing to sebaceous gland colonization of bacteria and retinoids before prescribing oral medication, hormone
which is a consequence of bacterium is the main cause of therapy, or oral isotretinoin. Light and laser equipment also
acne development [4]. showed usefulness [11]. The suggested strategy is to design

CONTACT Harini Chowdary Vadlamudi [email protected] Department of Pharmaceutics, Acharya & BM Reddy College of Pharmacy, Bengaluru,
560107, India
ß 2020 Informa UK Limited, trading as Taylor & Francis Group
2 S. BHARTI AND H. C. VADLAMUDI

rational therapeutic regimens based on the predominant strains are detected with reduced effectiveness of these
kinds of acne lesions and general clinical severity. therapies. On the other side, it is not necessary to draw a
The availability of fresh treatment choices to complement conclusive conclusion that antibiotics also have anti-inflam-
the current armamentarium should assist to accomplish matory results [19].
effective therapy for more patients with acne, guarantee bet-
ter tolerability and meet patient expectations [12]. To
achieve this one should have a sound knowledge on the
Role of sebum
pathophysiology of acne, receptors involved in the progres- The most crucial influences in the incidence of acne are con-
sion of acne. Thus, this review paper is focused on the sidered to be shifts in sebum. Increased sebum secretion can
pathophysiology and receptors involved in the progression cause acne, and growing evidence shows that variations in
of acne. sebum components are specifically associated with acne [20].
The normal function of sebaceous glands is Sebum, a set
of complex oils including triglycerides and fatty acid break-
Pathophysiology
down products, wax esters, squalene, cholesterol esters.
Acne pathophysiology is associated with abnormal keratino- Increased sebum excretion, altered lipid content and the
cytes proliferation and differentiation, enhanced serum man- lipid oxidant/antioxidant ratio of the skin surface are import-
ufacturing, P. acnes and inflammatory reaction by bacterial ant activities correlated with acne development [21]. In acne
antigens and cytokines [13]. On the other hand, surplus man- twins in wax esters rather than in acne-free twins, lower
ufacturing of male hormone androgen and oil generating essential fatty acid levels were found. Decreased levels of
glands also progresses acne condition. All these attributes to linoleic acid were also found in the lipids of the skin surface
the development of two types of non-inflammatory lesions of acne patients.
in acne such as closed comedone (whitehead) and ripen The sebum trait of patients with acne is the presence of
comedone (blackhead). When the contents break, these lipoperoxides, primarily because of squalene peroxidation
lesions can advance to inflammatory papules and pus- and a reduction of vitamin E, the main antioxidant sebum
tules [14]. [22]. Both lipoperoxides and monounsaturated fatty acid
Factors that promote acne development are raised sebum (MUFA) can alter the proliferation and differentiation of kera-
production by sebaceous glands, ductal cornification, pilose- tinocytes, whereas peroxides can promote the development
baceous duct colonization by bacteria, and inflammation. of influenza [21].
Although seborrhea is associated by the rigorousness of
acne vulgaris, the disease is related to the follicular infundib-
Hormone levels
ula. In mild acne, one can experience hypercornification,
hyperkeratinization, and hypodesquamation of the infundibu- Acne patients have higher levels of testosterone and 5a-
lum keratinocytes consequence in the development of come- dihydrotestosterone than people who are not affected, indi-
dones. The infundibulum ruptures in severe acne to initiate cating a link between androgens and the incidence of acne
sebum increment in the dermal layer, where it is highly [23]. Research has suggested that high levels of androgen
inflammatory [15]. are associated with improved secretion of sebum, thus the
induction in acne; however, some research suggests that the
secretion of androgen is independent of sebum incidence.
Propionibacterium acnes and their role in acne
Nonetheless, gross testosterone, free testosterone, and pro-
The theory of the microorganism present in acne lesions gesterone levels in patients having acne were decreased,
being the direct cause of acne was first proposed in 1896, and free testosterone and globulin-binding sex hormone
and subsequent studies supported its function in the disease levels in severe acne patients were also improved [22,24].
[16]. Another analysis showed P. acnes’ inflammatory effects The use of soy isoflavones by Riyanto et al. [22] to inhibit
by showing that P. acnes inserted into sterile keratinous cysts 3b-hydroxysteroid dehydrogenase, 7b-hydro-hydroxystroid
resulted in inflammation breakdown. Propionibacterium acnes dehydrogenase, and 5a-reductase activities was found to
can also be significantly increased in the pilosebaceous units decrease the level of androgen.
of patients with acne [17]. In the early 1960s, a debate on P.
acnes started how it was involved throughout acne, when a
Androgens
study revealed that P. acnes often exists on healthy human
skin and that P. acnes surface levels are comparable between Androgens are prime concern for sebum production which
patients with acne and control. It was also found that the contributes for acne vulgaris. Further explain that, in pre-
number of viable P. acnes in follicles did not correspond with puberty castrated males, occurrence of acne is negligible.
the degree of inflammation and that there were no viable Post-adolescent castration or oophorectomy in patients with
bacteria in some inflamed lesions [18]. New evidence to sup- acne results in their acne being slowly healed and their
port the theory that microorganisms were involved in acne sebum excretion levels drop below those of healthy subjects
was given when antibiotics that have been clinically tested [25]. Dihydrotestosterone (DHT) and dehydroepiandrosterone
to boost acne by reducing the skin surface P. acnes (such as sulfate (DHEAS) are the androgens most often involved in
erythromycin and clindamycin) and when resistant P. acnes the development of acne. Females with more severe acne
 JOURNAL OF RECEPTORS AND SIGNAL TRANSDUCTION 3

have much higher circulating DHEAS rates than their coun- the superfamily of steroid/thyroid hormone are expressed in
terparts with mild to medium acne or normal controls. human sebocytes [31]. The cellular and molecular mecha-
The correlation of acne severity with DHEAS levels is quite nisms of retinoid activity in the retinoid receptor pathways
common, as there were no significant differences among have to be explored for the specific processes of sebocyte
women with differing acne severity with other androgenic growth and development. Such two families are divided into
hormones (testosterone, progesterone, and testosterone/ three isotypes: a, b, and c; and have distinct binding affin-
estrogen ratios) [26]. ities to the ligand.
Keratinocyte and sebocyte androgen receptors mediate The RARA gene is located on chromosome 17 and con-
hyperkeratinisation, sebaceous gland growth, sebogenesis sists of 10 exons and two promoters resulting in the two
and adult sebum duction. As a consequence of their func- RARa1 and RARa2 isoforms [32]. RARa1 has a wide distribu-
tions in sebum production and follicular formation, andro- tion of tissue, including liver, spleen, intestine, spine, spinal
gens also have an indirect effect on inflammation [25]. cord, cerebral cortex, vagina, ovary, testis and breast, and is
believed to be a canonical isoform [33].
In comparison, RARa2 is found in a limited number of tis-
Receptors and transcription factors involved in acne sues, such as the stomach, lung and liver, and tends to be a
Histamine receptors more potent cell differentiation blocker than RARa1 in the
absence of ligand. Its function in holding cells in an undiffer-
Histamine and, conversely, antihistamines can also signifi- entiated state of stem cells is seen in multiple myeloma
cantly alter sebaceous activity. Edward et al. [27] have done where RARa2 expression is associated with multiple primary
experimentation on the identification of Histamine Receptors myeloma and drug resistance [34].
as well as squalene levels diminution by an antihistamine in
Sebocytes. They explored the sebocytes produced response
to antihistamines by investigating the H-1 receptor presence Retinoic receptor b
and by assessing the outcome of DPH at levels of cellular It is located on chromosome 3. This consists of 13 exons and
squalene. Diphenhydramine (DPH), an antagonist of hista- 4 promoter regions resulting in five different isoforms [35]. In
mine 1 receptor decreases significantly the concentrations of comparison to RARa, RARb’s tissue distribution is more lim-
squalene in human sebaceous gland cells [28]. ited and widespread in epithelial tissues [36] and neural tis-
Squalene synthesis can affect DPH through transcriptional sue and hardly visible in the skin. RARb1 is considered an
regulatory pathways through expression of squalene syn- isoform of the fetus and plays a crucial role in development.
thase. Sterol response element-binding protein-1 plays a key Although RARb1 in adult tissues is largely undetectable,
role in lipogenesis in the promoter region of squalene syn- aberrant expression has been identified in several cell lines
thase. IGF-1 receptor stimulates the sterol reaction element- derived from lung cancer [37].
binding squerol synthase protein-1 [29]. Nonetheless, squa-
lene rates intonation can require control at many different
levels. In addition, through the G-Protein coupling route that Retinoic receptor c
can complement cAMP levels, the H-1 receptor can intermin- Location of the gene RARc is chromosome 12. The key com-
gle with adenyl cyclase directly [30]. Because insulin ponent of the RAR protein, including the binding domains of
decreases fat metabolism by reducing adipocyte cAMP rates, DNA and ligand, is encoded by seven exons [38].
it is possible, if the cAMP production is mediated by an H-1 In both the human and the mouse epidermis, RARa
receptor antagonist, this contributes to a decrease in lipid accounts for 90% of the RARs, and is thus the main RAR,
lipid cells like a sebocyte. cAMP measurements in sebocytes while the other 10% are RARa and RARb. Study on mice skin
treated with DPH will lead to clarifying the pathways. epidermis with selective retinoids as well as RARa by induc-
In addition to the reduction of squalene levels and squa- ing conditional somatic mutagenesis has shown that the
lene synthase expression, the proposed hypothesis for DPH complete absence of RARs in basal keratinocytes has no
anti acne potential is reduction of sebum production, mini- impact on their homeostatic growth [32]. Thus, epidermal
mization of pore blockage thus inhibiting the inflammation. keratinocyte self-renewal does not seem to entail a signaling
Then, further test is carried out for the confirmation of mechanism based on RAR [39]. However, RARc present in
potential clinical relevance, by analyzing the human seba- supra basal keratinocytes was found to be involved in the
ceous glands for H-1 receptors presence. The discovery of basal layer hyperproliferation induced by RA through a para-
histamine 1 receptors in human sebaceous glands further crine signal. Therefore, this effect was attributable to reti-
convinced the beneficial role of antihistamines in the treat- noids’ defensive behavior during wound healing [40].
ment of acne [28]. The pathogenesis of acne includes RAR/RXR-mediated
transactivation or transrepression. Transactivation is expected
to take place in several steps: (i) ligand binding (e.g. retinoic
Retinoic receptor a
acid), (ii) dimerization (e.g. RAR/RXR), (iii) DNA interaction, (iv)
Retinoids put forth their pleiotropic effects on the cell devel- coactivator induction, and (v) RNA elongation [41].
opment via specific nuclear receptors, like the retinoic acid So, retinoids act by increasing the proliferation of kerati-
receptors (RAR) and retinoid X receptors (RXR) belonging to nocytes and encouraging differentiation to normalize
4 S. BHARTI AND H. C. VADLAMUDI

desquamation. Topical retinoids also inhibit many essential Toll like receptor
acne-activated inflammatory pathways: toll-like receptors,
Human Toll-like receptors are a category of glycoproteins
leukocyte migration, and AP-1 pathway [42].
involved in the innate immune response to exogenous
Apparently, however, isotretinoin, tretinoin, and tazaro-
pathogenic microorganisms acting on the surface as trans-
tene also inhibit the activation of Toll-like receptors. Blocking
membrane receptors [54]. Prior to the discovery of TLRs, the
these pathways decreases the release of nitric oxide and
body’s inborn immune system was established as the first
inflammatory cytokines and prevents cellular inflamma-
pro-inflammatory defense line responsible for mobilizing,
tion [40,42].
accumulating phagocytic cells, and activating the micro-
organism-entry cascade complement process [55].
TLR signals are carried out through two distinct paths:
Fibroblast growth factor receptors (FGFR) one dependent on and independent of the standard adap-
The fibroblast growth factor (FGF) receptors form a family of tor protein, myeloid differentiation factor 88(MyD88). The
related, but independently separate, tyrosine kinase recep- MyD88-dependent pathway activates other kinases such as
tors. Four FGFR types are available–FGFR1 to FGFR4 [43,44]. cJun-NH2-terminal kinase, extracellular signal-regulated kin-
The FGFR family’s important feature is that alternative splic- ase (ERK) 1 and 2, and p38 mitogen-activated kinase
ing creates a number of FGFR isoforms. Two forms of FGFR2 enzyme [56]. NF-pB translocates into the nucleus after acti-
vation and acts as a transcription factor, while MAPK phos-
are FGFR2b and FGFR2c. FGFR2b is found primarily in epithe-
phorylation tends to translocate different transcription
lial cells and associates FGF7 and FGF10, but not FGF2 [45].
factors into the nucleus. These transcription factors cause
FGFR2b is found primarily in the supra-basal spinal layer of
coding of inflammatory cytokines to stimulate proinflamma-
the epidermis and sebocyte and plays a key role in control-
tory genes [57].
ling epithelial proliferation and differentiation [46]. The
MyD88-independent pathways include 1) Alternative NF-
FGFR2c isoform which is primarily expressed in mesenchymal
kB and MAPK activation, bypassing the MyD88 protein com-
binds to FGF2, FGF4, FGF6, FGF9, FGF17, FGF18, but not
plex by downstream TNF-receptor-associated factor (TRAF)-6
FGF7 and FGF10.
activation by TRIF (Toll-IL-1 receptor [TIR] comprising IFN-
Specific lineage expression of the isoforms FGFR2b and
b-inducing adapter); and 2) Type 1 interferon (IFN) gene
FGFR2c allows mutual association during growth between
induction, in particular IFN-a and IFN-b, by activation of the
epithelial and mesenchymal layers [47]. Dimerization of the
IFN regulatory factor (IRF)-3 and IRF-7 by TRIF, ultimately
receptor results in autophosphorylation of seven retained
leading to development [57,58].
residues of intracellular tyrosine that are used as recruiting
TLRs are found in the human skin in various types of cells
domain-containing SH2 protein sites for downstream signal- like the epidermis, adipose tissue, etc. with significant differ-
ing activation [48]. The fibroblast growth factor of the recep- ences in expression and usability depending on the type of
tor substratum 2 acts as a docking site for a number of cell. The most important epidermal cells expressing TLRs are
intracellular proteins, including Grb2, SHP2, and c-Cbl [43,49]. keratinocytes, expressing TLRs 1–6 and 9, and Langerhans
The receptor complex is ubiquitinylated and degraded cells (LCs), expressing all TLRs, particularly TLRs 1, 2, 3, 5, 6
after binding FGF7 to FGFR2b, whereas FGF10 binds the and 10. It has also been shown that LCs produceIL-10, a Th-2
receptor to the endosomes for recycling [50]. Under physio- cytokine, which means that immunotolerance can include
logical circumstances, intracellular vesicles and FGFR2 lyso- LCs. Many TLR cells comprise monocytes/macrophages, lym-
somal degradation by FGFR2-ubiqitination terminate FGFR2 phocytes DCs, T and B, mast cells, endothelial cells, fibro-
and FRS2 transient ligand-dependent endocytosis [51]. blasts, and adipocytes [59–61].
Androgen-producing overexpression of FGFR2b-signaling A very distinctive peptidoglycan, an exogenous ligand for
in acne skin emerged as a potential reason that is respon- TLR-2, is one of the major components of P. acnes’ cell wall.
sible for acne vulgaris. In addition, FGFR2b-signaling pathway It has been found that large amounts of TLR-2 are expressed
in dermal-epithelial interaction in the process of comedogen- in acne lesions on perifollicular and peribulbar macrophages.
esis, sebaceous gland proliferation, lipogenesis skin append- Furthermore, a strong link has been shown between the
age formation, and pilosebaceous follicle homeostasis might extent of acne lesions and the concentration of TLR-2
also be involved in the progression of acne [52]. expressing cells. The development of IL-6, IL-8, and IL12
Anti-androgens that decrease the signaling pathways of inflammatory cytokines is specifically dependent on P. acnes
androgen-responsive FGFR2b during puberty resulting in and TLR-2 interactions. Monocyte-secreted proinflammatory
decreased follicular differentiation and hypertrophy of the cytokines, in particular IL-8, are triggered by P. acnes activa-
sebaceous gland. The new insights in FGFR2b-signaling tion of TLR-2, resulting in the induction of neutrophils into
modulation in acne suggest a new therapeutic stratagem the pilosebaceous community [55,62].
that allows the formulator attempt to repress improved sig- Like TLR-2, the expression of TLR-4 in acne lesion kerati-
naling directly. Selective inhibition of tyrosine kinase recep- nocytes has been shown in in vivo and in vitro studies. There
tors interaction as well as overlapping downstream targets is a support for the activation of immune and inflammatory
such as PI3K/Akt could be a better alternative approach for responses in acne, including TLR-4 enhancement by P. acnes
the management of acne [53]. cell wall lipopolysaccharides [63].
 JOURNAL OF RECEPTORS AND SIGNAL TRANSDUCTION 5

The Forkhead Box O1 (FoxO1) transcription factor of them were memory/effectors in the CD4 þ T cell popula-
tion, with a same amount displaying a homing feature of the
FoxO1 was proposed as a key to understanding the relation-
skin indicating a particular inflammatory response from the
ship between the acne-related hereditary, physiological and
adaptive immune system [70].
environmental factors. It has also been shown that retinoids Apparently, the growth factor-like signaling mechanisms
are active inducers of FoxO proteins, and FoxO1 mediates of ectopeptidases are not fully understood, but the enzym-
adverse reactions such as hypertriglyceridemia caused by iso- atic behavior of APN and DP IV does not seem necessary for
tretinoin [64]. signal transduction [71]. Anti-CD3-mediated human lympho-
cyte activation enhanced Akt’s function. An inhibitor of DP IV
FoxO1 and endocrine abnormalities related to acne could dramatically suppress the triggering of an act.
Therefore, ectopeptidase inhibitor therapy can have positive
Polycystic ovary syndrome (PCOS) is a common endocrine anti-inflammatory effects on acne by down-regulating the
condition that affects 5–20% of women, based on their per- IL-1 signaling and down-regulating the proliferation of Akt-
sonal background. The pathogenesis of PCOS includes hyper- mediated T-cells by growing the rates of T-cells in nuclear
androgenemia, impaired gonadotropin production, as well as FoxO1 [72,73].
insulin resistance. Acne and hirsutism are often associated
with PCOS. Insulin tolerance to adipose tissue and muscle in
PCOS leads to increased insulin/IGF-1 signaling for epithelial Role of FoxO1 in acne caused by stress
targets such as pilosebaceous non-insulin resistant units [65]. The sebaceous gland is not only a passive target endocrine
Many endocrine diseases with elevated insulin and insulin organ that responds to sex hormones, but also plays an
resistance are often correlated with acne disease such as active role in multiple neuroendocrine/neuromediator axes
HAIR-AN (hyperandrogenism, resistance to insulin, nigric including corticotropin hormone release (CRH) and melano-
acanthosis). There is an increased incidence of acne in acro- cortin releasing peptides [74,75]. CRH is the main HPA axis
megaly, Laron syndrome with recombinant IGF1, early adre- neuroregulator and plays a key role in regulating endocrine,
narchy, and precocious pubarche. All of these endocrine flexibility and immune stress response. In human sebaceous
disorders with elevated levels of insulin/IGF-1 are expected glands and sebocytes SZ9578, CRH’s association with its
to be associated with lower levels of FoxO1, thus increasing receptors CRHR1 and CRHR2 is significant.
the production of acne [66,67]. CRH can induce neutral lipid synthesis in SZ95 sebocytes,
whereas antalarmine, a common CRHR1 inhibitor, can
Effects of FoxO1 and ectopeptidase on the role of acne decrease sebaceous neutral lipid synthesis [76]. In sebaceous
glands in acne-involved skin, a significant increase in CRHR
and immune
expression was found relative to sebaceous glands not
Ectopeptidases are broad functional transmembrane proteins affected in acne. Substantial evidence also supports the sig-
that can modulate the responses of bioactive peptides and nificant role of CRH/CRHR signaling in triggering lipogenesis
influence development, apoptosis, differentiation, cell adhe- and inflammation of acne. In human monocytic cells, CRH
sion and motility. Previously, acne activation was correlated has been shown to activate the PI3K/Akt pathway [77]. Thus,
with ectopeptidases dipeptidylpeptidase IV (DP IV) and ami- the acnegenic stress effects may reduce FoxO1 nuclear levels
nopeptidase N (APN). It can be shown that DP IV and APN through CRH/CRHR induced PI3K/Akt upregulation in seba-
antagonists in different disease models have significant ceous glands.
immunosuppressive and anti-inflammatory effects [68]. IL-1 is
an acne induction established cytokine [69]. Intriguingly, DP
Androgen receptor (AR)
IV and APN inhibitors have been shown to enhance IL-1
receptor antagonist expression that can mitigate IL-1’s acne- Endocrine mechanisms regulate the sebocyte functioning
promoting effect. such as lipid synthesis alteration, sebocyte proliferation and
DP IV and APN inhibitors in SZ95 sebocytes impaired rep- differentiation. Androgens shot up the active sebaceous
lication, improved terminal differentiation and decreased gland by connecting to the receptors of nuclear androgen
overall neutral lipid production slightly. Therefore, comedo- (ARs). Highest density of ARs has been seen in sebaceous
genesis, lipogenesis and inflammation can be reduced by glands [78].
metabolites of DP IV and APN [68]. Androgen receptors are one of the types of nuclear recep-
In reaction to nuclear FoxO activity, AMP genes are acti- tor superfamily and possess three domains like ligand-bind-
vated [70]. Increased growth factor signaling of puberty and ing domain, DNA-binding domain, and N-terminal regulatory
insulinotropic western diet that decrease nuclear FoxO1 and domain. Ligands for ARs are dihydroxytestosterone (DHT)
AMP development helps in promoting the growth of P. acnes and testosterone. Androgen receptors reallocate from the
and the formation of biofilms. As found in early acne lesions cytosol into the nucleus ahead binding to its ligand either
[69], P. acne induced TLR2-stimulation can then induce T-cell DHT or testosterone. Then the AR-ligand complex serves up
infiltration. In addition, large numbers of CD4 þ T cells in nor- as a transcriptional factor and initiates the androgen-depend-
mal skin above and beyond the constituent level of T cells ent activation that regulates the expression of their target
were found near uninvolved early acne lesion follicles. Most genes, such asprostate specific antigen (PSA). Apart from
6 S. BHARTI AND H. C. VADLAMUDI

this, ARs also interact with diverse coregulators via N-ter- regulates the sebum production [87]. Fourth, the involve-
minal domain binding [79]. ment of AR coregulators like transcriptional factors (viz. ERa
Androgens play very important role in acne, throughout and AP-1), kinases (viz. ERK and MAK), chaperones (viz.
sebaceous follicular hyperkeratinization, a characteristic HSP70 and HSP90), cytoskeletal proteins (viz. actin and fila-
observation in acne. Androgens induce an increase in sebum min), and histone modifiers (viz. HDAC and SRC) may com-
production in the sebaceous glands. It was proposed that pensate for the discrepancy in DHT synthesis [88]. Apart
the whole integument of patients with acne was dependent from these, persuasive androgens consequently control der-
on androgen levels [80]. mal physiology all the way through intracrine or para-
Sebaceous glands are considered as the androgen target crine manners.
tissues in acne pathophysiology. Castration might avert these The probable implication on the mechanism of androgen/
bum production, whilst testosterone replacement may pos- AR in the regulation of sebocyte activity was suggested des-
sibly rescind this circumstance [81]. Choudhry et al. [82] per- pite a clear idea is still unkown. The first hypothesis is andro-
form immunohistochemistry and biochemical attachment gen receptors might increase the activity of fibroblast
assays to test the localization of ARs in sebaceous gland epi- growth factor receptor 2 (FGFR2) which plays a very crucial
thelial cells. The skin is not the major resource of the produc- role in the development of sebaceous gland and maintaining
tion of androgen for cells such as sebocytes, sweat glands, homeostasis [89]. The second reason might be the escalated
and dermal papilla cells. Circulating androgenic hormones lipogenesis in the sebocytes owing to sterol regulatory elem-
such as dehydroepiandrosterone (DHEA) and androstene- ent binding proteins (SREBPs) expression [90]. Thirdly, the
dione, though, are the primary source of androgens that can cross-discussion of androgens with an insulin-like growth fac-
be transformed to testosterone and 5a-dihydrotestosterone tor-1 (IGF-1) that regulates the production of acne [91]. In
(DHT) following digestion. Sebaceous glands are enriched general, IGF-1 stimulates the expression of SREBP-1 that
with steroidogenic enzymes which play a key role in the con- enhances the lipogenesis in sebocytes [92,93]. IGF-1 also
version of androgenic pro-hormones like dehydroepiandros- affects the metabolism of androgens [94]. Besides, IGF-1 can
terone DHEA/DHEAS (DHEA sulfate) and androstenedione augment the AR activity all the way through multitude
into androgen hormones like testosterone and DHT [83]. mechanisms like FOXO1 (an AR co-repressor) activation by
Testosterone can be further metabolized by the enzyme phosphorylation that suppresses the ligand mediated AR
viz. 5a-reductases into a very potent androgen, 5a-dihydro- stimulation, AR transactivation as well as diminishes the
testosterone (DHT). Testosterone as well as DHT has the abil- expression of androgen-induced androgen receptor target
ity to bind with the AR; however, DHT exhibited 10-fold genes [95]. The fourth mechanism might be the ability of
greater affinity and binding ability to AR in comparison to androgens or androgen receptors to increase the inflamma-
testosterone. 5a-Reductase enzyme exists in three different tory reaction and response toward macrophages and neutro-
isoforms like type I, II and III with a varied expression pat- phils [96,97]. This supports that androgen/AR not only
terns in the tissues [84]. involved in the stimulation of sebocytes for sebum produc-
Type I 5a-reductase is predominantly expressed in sebo- tion but also increase the inflammatory response of macro-
cytes, dermal fibroblasts and keratinocytes, Type II 5a-reduc- phages and neutrophils that consequences in the acne
tase is found in adult seminal vesicles, epididididymis, formation as well as its progression.
prostate glands, and fibroblasts, while Type III 5a-reductase Isotretinoin is the recommended medication for recalci-
is found in prostate and sebocyte cell lines. Type III 5a-reduc- trant severe nodulocystic acne [98]. The role of AR in the
tase shows significant involvement in the N-linked glycosyla- skin in the nuclear compartment of the cell was established
tion in addition to the steroidogenic activity [85]. by a comprehensive literature review. Nuclear and cytoplas-
The sebocyte Type I 5a-reductase is responsible for the mic AR positivity was documented by few researchers.
accelerated development of sebum. Conversely, from the Cytoplasmic androgen receptors are the unbound AR recep-
in vitro and clinical studies, it was observed that the selective tors that only with their ligand are internalized or translo-
inhibitors of type I 5a-reductase neither show a remarkable cated into the nucleus [99]. However, some researchers
reduction in the production of sebum nor a significant believe that bound steroid receptors such as estrogen recep-
improvement in the acne vulgaris reduction thus suggesting tors, progesterone receptors and androgen receptors are
that restraint of 5a-reductase activity alone may not be satis- closely linked to nuclear chromatin, while unbound receptors
factory to improve acne [86]. are more readily accessible from the nucleus of cells [100].
The causes may be the suppression of a single type of Thus, regulating AR development by either treating with
5a-reductase, which may not be sufficient to block the entire antiandrogens alone or in combination with antibiotics to
development of DHT due to the consistency accompanied combat bacterial infection may be a prospective therapeutic
by various types of 5a-reductase, and the sebaceous glands perspective for more efficient and successful acne dis-
may be highly responsive and reactive, even at low DHT con- order care.
centrations. Secondly, in addition to type I 5a-reductase, the
other isoform type III 5a-reductase may also contribute a sig-
Liver X-Receptor (LXR)
nificant role in the regulation of sebum production. Thirdly,
androgen hormones, testosterone and DHT may not be Liver X-receptor (LXR) belongs to the nuclear receptor family
involved in the similar manner for AR activation which of transcription factors and closely associated to nuclear
 JOURNAL OF RECEPTORS AND SIGNAL TRANSDUCTION 7

receptors like peroxisome proliferator-activated receptors, Sebocyte differentiation is strongly linked to enhanced
retinoid X receptors. LXR is differentiated in two different iso- lipid synthesis and cell aggregation. Sebocytes express LXRa,
forms namely LXRa and LXRb. LXR-a is highly articulated in the use of natural 22(R)-hydroxycholesterol or LXRa synthetic
liver and is also present in several parts like adipose tissue, ligands greatly reduces proliferation, enhances lipogenesis
macrophages, intestine, and kidney. It is also found in the and strengthens sebocyte differentiation [106,107].
skin like sebaceous glands, sweat glands as well as hair The production of LXRa is synonymous with excess
follicles [101]. sebum and inflammation generally suspected of causing
LXRa plays a vital role in the regulation of genes impli- acne lesions, suggesting that LXRa may be one of the more
cated in innate immunity, inflammatory response and more- significant clinical strategies for acne treatment.
over lipid biosynthesis. While LXRb are involved in the
keratinocyte differentiation as well as epidermal permeability Melanocortin receptor
barrier function [102].
Stimulation of LXRs rouse the keratinocyte differentiation Melanocortin receptors act on sebaceous gland activity. MC1,
and develop permeability barrier homeostasis via numerous MC2, MC4 and MC5 receptor expression, but not MC3 recep-
mechanisms embracing the activation of epidermal lipid pro- tor expression, has been documented in human skin.
duction, intensifying lamellar body pattern and secretion, Melanocortin MC1 receptor plays a major role in skin homeo-
and enhancing the enzyme activity that is necessary for the stasis, including regulations on skin and hair pigmentation
extracellular synthesis of lipids in the stratum corneum layer [108,109], immune and inflammatory reactions, and extracel-
consequencing the development of lamellar membranes that lular matrix interactions. The presence of receptor melano-
arbitrate the epidermal permeability barrier function [103]. cortin MC1 was found in both undifferentiated and
LXRs are known to be involved in the regulation of lipid differentiated sebocytes in human sebaceous glands [110].
and cholesterol metabolism. All LXR isoforms i.e. LXRa and The immunoreactivity of the MC1 receptor was shown to be
LXRb can form retinoid X receptor (RXR) heterodimers and greater in patients with acne sebaceous glands than in usual
directly attach to the LXR response element (LXRE) which is skins [111].
DNA 52 sequence [104]. Melanocortin MC2 receptor was indicated to react to
While many experimental results suggest comparable use human skin stress and may regulate lipolysis of adipocytes.
of the mechanisms involved in adipogenesis for sebocyte dif- The human skin observed MC2 receptor mRNA and its pro-
tein was found in normal keratinocytes [75]. Signaling of
ferentiation, there was no explanation of the role of LXRs for
melanocortin MC4 receptors leads to pigmentation regula-
sebocytes. Activation of LXRa was found to cause lipid syn-
tion in cultivated cells [112], but its activity has not been
thesis in sebocytes followed by SREBP-1 and PPAR induc-
shown in vivo in human skin. MC4 receptors have been
tion [105].
found in both keratinocytes and melanocytes in the dermal
LXR ligands facilitated the development of all three PPAR
papillae cells [113] and human epidermis [112]. Receptors of
subtypes and downstream target genes, indicating that
melanocortin MC5 detected immunoreactivity in human skin
PPARs mediate the lipogenic function of LXRa in sebocytes,
in sebaceous glands, eccrine glands, hair follicles, and epider-
at least in part. A new independent report revealing that
mis. Melanocortin MC5 receptor is present only in the seba-
both isotypes of LXR are expressed in SZ95 sebocytes and
ceous gland in the differentiated cells in the middle of the
that these findings have been confirmed by LXRa agonists
glands, whereas this receptor is not expressed by the main,
mimic lipogenesis [106].
undifferentiated cells [110].
Throughout our understanding of the biochemical proc-
Melanocortins induce intracellular signaling by binding
esses that regulate lipogenesis throughout adipose tissue and activating G-protein together with melanocortin recep-
and liver, substantial progress has been made over the past tors, leading to an increase in cyclic adenosine monophos-
decade. A number of transcriptional factors have been identi- phate production. Cholera toxin irreversibly inhibits GS
fied that trigger lipogenesis measures in pre-adipocytes enzyme that, by activating adenylyl cyclase, induces the
cooperatively and sequentially. CCAAT/enhancer binding pro- development of cyclic adenosine monophosphate. For sebo-
teins, peroxisome proliferator activated receptors (PPARs) cyte differentiation, cholera toxin was required in response
and sterol regulatory element binding protein-1 (SREBP-1) to specific peroxisome proliferator-activated receptor-a and
are considered to play critical roles in adipogenesis among receptor-c agonists in the rat’s primary sebocyte culture and
them. LXRa is highly expressed in tissues such as liver, kid- without cholera toxin these agonists were ineffective [114].
ney, small intestine, spleen, skeletal muscle, and adipose tis- Only at the beginning of development and in completely
sue, studies have thus shown that both LXRa and LXRb are mature cells, melanocortin MC5 receptor mRNA and protein
found in SZ95 sebocytes and that LXRa plays a critical role in were detected, as shown by reverse transcription polymerase
sebaceous lipid production [105]. chain reaction and immunohistochemistry [110].
Therefore, studies were carried out to suggest the func- It was found that NDP-a-MSH induced moderate differen-
tion of LXR in sebaceous lipogenesis and cellular lipid accu- tiation and increased cyclic adenosine monophosphate syn-
mulation using the immortalized human sebaceous cell line thesis in sebocyte cultures, while cholera toxin induced
SZ95, showing the same features, morphology and pheno- higher levels of cyclic adenosine monophosphate growth
type as normal human sebocytes [104]. and increased sebocyte differentiation [115].
8 S. BHARTI AND H. C. VADLAMUDI

The rationale for sebum regulation melanocortin MC5 [125]. This effect is more noticeable when cells are handled
receptor antagonists is based on the following facts: (1) the concurrently with dihydrotestosterone or when there is an
melanocortin MC5 receptor in human sebaceous glands is agonist receptor X retinoid. Research in SZ95 sebocytes indi-
expressed at high levels and its expression is associated with cates that linoleic acid, but not other ligands of PPARa,
sebaceous cell differentiation [110]; (2) exogenous a-MSH improves lipid development [125]. Studies in isolated human
and sebaceous lipids controlled by testosterone; and (3) sebaceous glands, though, imply that PPAR ligands such as
selective melanocortin MC5 mice receptor disruption trig- linoleic acid decrease lipogenesis [126].
gered sebaceous lipid down-regulation and compromised It is unclear whether endogenous ligands are correctly
exocrine gland functions [116,117]. defined in the skin that act on PPARs. Potential ligands in
the skin and sebaceous glands contain fatty acids, eicosa-
noids, and other lipids. This theory is confirmed by pilot find-
Peroxisome proliferator-activated receptor(PPAR) ings in zileuton-treated patients of reduced sebum
PPARs type heterodimers with retinoid X receptors and func- development and acne, an enzyme lipoxygenase inhibitor
tion as transcriptional regulators for a number of genes, believed to result in eicosanoid formation that interacts with
including those involved in the processing of adipose tissue, PPARs [81]. Clearly, more clinical studies in different popula-
liver and skin lipids [118,119]. In comparison to retinoid tions of acne-impacted patients will help determine whether
receptors, three PPAR subclasses differ in tissue position and the production of sebum is decreased through agonism or
transcription activity [120,121]. Receptors of PPARa are found antagonism to particular PPAR subtypes and enhances
in many human tissues, including liver, kidney, back, skeletal acne [128,129].
muscle, fat, and endothelial cells. PPARa has been shown to
play a critical role in the control of cell uptake, activation
Epidermal growth factor receptors
and b-oxidation of fatty acids. Fibrates used exclusively for
the treatment of hyperlipidemia are the most commonly In 1962, in the salivary glands of the mouse, epidermal
used exogenous PPARa agonists [122]. Nevertheless, the pre- growth factor (EGF) was identified and was the first to be
cise lipid metabolism behavior of PPARa agonists is relatively described as growth factor. This associates with the EGF
complex and has been shown to vary in specific cellular sys- receptor (EGFR) on keratinocyte surfaces, hair follicle cells,
tems. It is usually expressed at relatively higher rates in a and eccrine and sebaceous glands [130]. EGF was developed
wide range of liver, adipose tissue, and skin tissues and cells. by platelets, macrophages and monocytes, and its primary
Within epidermal keratinocytes, substances that bind with role is to stimulate epithelial cell growth through a separ-
receptors have previously been shown to promote differenti- ation, although it also affects fibroblasts and smooth muscle
ation and lipogenesis [123]. cells [131]. There are currently two groups of EGFR antago-
Treatment with PPARc ligands of fibroblasts stimulates nists: monoclonal antibodies (cetuximab, panitumumab, and
adipogenesis and enhances the development of lipids; matuzumab) targeting the extracellular ligand-binding
results arising from activation of target adipogenic genes domain and small-molecule tyrosine kinase inhibitors (gefiti-
[124]. PPARs are also present in the immortalized human nib, erlotinib, lapatinib, and afatinib) targeting the intracellu-
sebocyte cell line (SZ95), and the intracellular lipid content is lar domain [132]. EGFR is important for the skin’s normal
enhanced by the treatment of these cells with linoleic acid, a development and physiology. Particularly in the basal cell
ligand for PPARc and PPARd [125]. layer, the outer root sheath of hair follicles and the seba-
In preputial sebocytes of rats, human sebocytes, human ceous epithelium, it is highly expressed in the epidermis. In
sebaceous glands, hair follicles, and human keratinocytes the eccrine epithelium and dendritic antigen-presenting cells
[125,126], each of the PPAR subtypes is identified. it is also moderately expressed [133]. In addition, by modify-
Localization tests were performed in whole specimens of ing the normal function of these systems, clinically distinct
human skin, demonstrating that all PPAR subtypes are found forms of cutaneous toxicity of EGFR inhibitors can be estab-
in stable and acne-involved sebaceous glands and piloseba- lished. It is known that cutaneous eruptions are unique to
ceous ducts [125,127]. The expression of PPAR was confirmed the drug class. It is possible to find wide range of dermato-
by immunohistochemistry in SEB-1. In the basal layer of the logical adverse events. Populopustules and xerosis are typ-
sebaceous gland, this subtype is expressed within separate ical findings.
cells within the gland with noted expression of PPARp. Such Throughout skin development and homeostasis, the EGFR
results are consistent with those of Alestas et al. [127] who signaling pathway plays a key role. Epidermal keratinocytes
express in healthy skin sebaceous gland and acne-involved are a rich source of EGFR ligands, including EGF, alpha (TGF-
and uninvolved skin of acne subjects each of the a), amphiregulin, heparin (HB-EGF) and growth factor epire-
PPAR subtypes. gulin [134]. EGF is well known to be active in cutaneous
PPARp ligands improve the aggregation of lipids in kerati- wound healing by activating, proliferating and migrating ker-
nocytes in murines [123]. Nevertheless, there have been con- atinocytes, endothelial cells and fibroblasts, thus promoting
flicting reports about the impact of PPAR ligands on the epidermal and dermal regeneration [135]. Furthermore, in
development of sebaceous lipids. Studies in preputial cells of ulcerative colitis cases, local administration of EGF mediated
rats show that PPAR ligands, including fibrates, linoleic acid, relief can be observed. Surprisingly, EGF was also active in
and thiazolidinediones, increase intracellular lipid droplets inflammatory downmodulation. In a study, EGFR signaling
 JOURNAL OF RECEPTORS AND SIGNAL TRANSDUCTION 9

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No potential conflict of interest was reported by the author(s). [21] Evgenia M, Ganceviciene r, Christos Z. An update on the role of
the sebaceous gland in the pathogenesis of acne.
Dermatoendocrinol. 2011;3:41–49.
[22] Zouboulis CC, Schagen S, Alestas T. The sebocyte culture: a
ORCID
model to study the pathophysiology of the sebaceous gland in
Harini Chowdary Vadlamudi http://orcid.org/0000-0003-0719-0903 sebostasis, seborrhoea and acne. Arch Dermatol Res. 2008;300:
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