What is the role of antimicrobial peptides (AMP) in acne vulgaris?

Ju rgen Harder
1
, Daisuke Tsuruta
2
, Masamoto Murakami
3
and Ichiro Kurokawa
4,5
1
Department of Dermatology, University of Kiel, Kiel, Germany;
2
Department of Dermatology, Osaka City University, Graduate School of Medicine,
Osaka, Japan;
3
Department of Dermatology, Ehime University, Graduate School of Medicine, Toon, Japan;
4
Division of Dermatology and Acne
Clinical Research Center, Meiwa Hospital, Nishinomiya, Japan;
5
Department of Dermatology, Hyogo Medical College, Nishinomiya, Japan
Correspondence: Dr. Ichiro Kurokawa, Division of Dermatology, Meiwa Hospital, Agenaruo-cho, Nishinomiya, Hyogo 663-8186, Japan,
Tel.: +81 798 47 1767, Fax: +81 798 47 7613, e-mail: kurokawa.i@meiwa-hospital.com
Abstract: Acne vulgaris is the most common disorder of the
pilosebaceous unit leading to inamed skin characterized by the
formation of comedones, papules, pustules and scarring. There is
increasing evidence that the abundance of Propionibacterium acnes
(P. acnes) in the inamed acne lesions triggers inammation.
Therefore, in addition to treatment with retinoids, the use of
antimicrobial agents has been established as a treatment option
for acne. This indicates that antimicrobial mechanisms to control
the growth of P. acnes may have an important inuence on the
severity of inammatory acne. One import antimicrobial innate
defense system comprises the production of antimicrobial peptides
(AMP), small molecules with a broad spectrum of antimicrobial
activity as well as immunomodulatory properties. Although the
role of AMP in acne is still emerging, there is increasing evidence
that AMP may be of importance in acne. The aim of this
viewpoint is to provide some hypotheses about the potential
function of AMP in the pathogenesis of acne and to discuss
potential AMP-based therapies for the treatment of acne.
Key words: acne vulgaris antimicrobial peptides cathelicidin
defensin
Accepted for publication 23 April 2013
Introduction
Acne is a common chronic inammatory disease of the piloseba-
ceous unit and affects about 27% of early adolescents and up to
93% of late adolescents (13). Typical sites for acne include the
face, chest and upper back (4) with the appearance of comedones
(5). Inamed lesions are characterized by red papules, pustules
and often by a subcutaneous abscess (5,6). Scarring, sometimes
keloid formation, can occur even after the inammation settles
(5,7). The major pathogenetic mechanism of acne consists of four
major components: (i) activation of the androgen receptor in the
sebaceous gland cells; (ii) stimulation of the production of sebum;
(iii) hyperkeratinization of the outer root sheath cells at the follic-
ular infundibulum; and (iv) proliferation of bacteria, especially
Propionibacterium acnes (P. acnes) (5,8). This bacterium produces
lipase, hyaluronidase and proteases and activates immune cells
thereby triggering inammation (912). Thus, to reduce P. acnes-
mediated inammation, it is necessary to reduce the growth of
P. acnes. Therefore, common treatment options include antibiotics
together with retinoids such as adapalene (1214). However, long-
term treatment with antibiotics (oral/topical) is complicated by
the development of resistant strains of P. acnes (15). Therefore,
new antimicrobial strategies for the treatment of acne are
required.
There is increasing evidence that host antimicrobial peptides
(AMP) may play a role in the pathogenesis of acne (5,16). AMP
provide a rapid defense against infection by acting as natural anti-
biotics (17). Most AMP are cationic amphiphatic peptides of small
size (<20 kDa) and exhibit a broad spectrum of antimicrobial
activity (18). Human AMP are mainly produced by epithelial cells
and neutrophils and are expressed both constitutively and induc-
ibly by inammatory stimuli (17,19,20). Important skin-derived
AMP comprise the family of beta-defensins, S100 proteins, RNases
and the cathelicidin LL-37. Healthy skin is protected by constitu-
tively secreted AMP such as psoriasin (S100A7) (21), RNase 7
(2224) and calprotectin (heterodimer of S100A8/A9) (25). In
addition, sweat glands release the anionic AMP dermcidin (26).
Although already abundant on the healthy skin surface, the
expression and secretion of psoriasin and RNase 7 are further
induced in atopic dermatitis and psoriasis (27). Other AMP such
as the human beta-defensin (hBD)-2 and hBD-3 as well as the
cathelicidin LL-37 show a low expression in healthy skin but are
induced during skin inammation and infection (28).
Antimicrobial peptides may play a dual role in cutaneous
innate immunity: on the one hand, their potent antimicrobial
activity contributes to a fast direct killing of microbes. On the
other hand, many AMP have immunomodulatory functions: they
exhibit diverse chemotactic activities, promote angiogenesis,
induce expression of extracellular matrix components or stimulate
cytokine release (2931). There is evidence that a dysregulation of
the immune-stimulating activities of AMP may be detrimental for
the host. For example, increased levels of abnormal processed
cathelicidin peptides have been reported to promote skin inam-
mation in rosacea (32). It is also discussed that the increased level
of hBD-2 in psoriasis, which may contribute to the low infection
rate in this disease (33), may trigger psoriasis due to its chemotac-
tic effects (34,35). In contrast to inammation-stimulating effects,
some AMP exhibit also anti-inammatory effects (3642).
Several AMP are induced in acne which makes it likely that
they may have an inuence on acne pathogenesis. Similarly, as
discussed for psoriasis, the induction of AMP in acne brings up
the question whether increased level of AMP in acne is an essen-
tial and benecial part of a concerted defense reaction against
P. acnes or whether this defense reaction triggers inammation in
acne. Thus, in the following we will discuss two hypotheses (see
386
2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Experimental Dermatology, 2013, 22, 386391
DOI: 10.1111/exd.12159
www.wileyonlinelibrary.com/journal/EXD
Viewpoint
also Fig. 1 and Table 1): (i.) AMP are needed as antimicrobial
defense molecules to control the growth of P. acnes in acne; (ii.)
The immunomodulatory properties of AMP worsen the disease.
We will end this viewpoint with a discussion of potential thera-
peutic approaches to use or inuence the expression of AMP for
the treatment of acne.
Upregulation of endogenous AMP in acne vulgaris:
benecial or detrimental?
First hypothesis: AMP are important defense mediators to
dampen clinical symptoms of acne
Chronnell et al. detected a constitutive expression of hBD-1 and
hBD-2 in the distal part of the outer root sheath, hair follicle stem
cell compartments and the pilosebaceous ducts, whereas inner hair
follicle compartments such as the proximal outer and inner root
sheath as well as the hair follicle bulb showed only very weak
expression. This expression pattern is in line with the expectation
that high concentrations of AMP are needed in the regions
exposed to a high microbial density (43,44). Compared with
healthy samples, hBD-2 expression was markedly increased in the
majority of acne biopsies with highest expression in pustules,
whereas hBD-1 was less induced (43,44). This is in concordance
with the expression pattern of hBD-1/hBD-2 in previous reports
showing that hBD-1 is rather constitutively expressed in epithelial
cells, whereas hBD-2 is an inducibly expressed peptide (20). The
authors speculate that the induction of beta-defensin expression in
acne lesions points to a potential involvement of beta-defensins in
the pathogenesis of acne vulgaris (43,44). Trivedi et al. (45)
reported microarray data from skin lesions of 6 acne patients and
conrmed a signicant upregulation of hBD-2 in acne lesions. In
addition, it has been reported that gene expression of hBD-2 as
well as LL-37 was induced in HaCaT keratinocytes by P. acnes cul-
ture supernatants (46). Whether the induced expression of hBD-2
in acne is mediated directly through P. acnes is not clear. How-
ever, the observation that P. acnes induced the in vitro expression
of hBD-2 in keratinocytes and sebocytes suggests that the
enhanced expression of hBD-2 in acne lesions may be triggered by
P. acnes (46,47). There is evidence that this induction may be
mediated by Toll-like receptors (TLRs) such as TLR-2 and TLR-4,
which are upregulated by P. acnes (47,48).
It is likely that the induced expression of hBD-2 in the acne
lesion is rst of all conceived as an antimicrobial defense response
against P. acnes. This is strengthened by a recent study reporting
that hBD-2 alone as well as in synergy with the free fatty acid
(FFA) lauric acid exhibits antimicrobial activity against P. acnes.
In addition, the antimicrobial activity of FFA-treated sebocytes
against P. acnes was inhibited by a hBD-2 neutralizing antibody
(49). This indicates that hBD-2 is active against P. acnes suggest-
ing that the upregulation of hBD-2 in acne lesions may restrict
the growth of P. acnes. Several reports provided evidence that
P. acnes promotes inammatory processes in acne through the
induction of inammatory mediators (47,5052). Thus, a growth
restriction of P. acnes by hBD-2 and perhaps by other AMP may
limit P. acnes-mediated inammation.
The cathelicidin LL-37 is another human AMP with in vitro
activity against P. acnes (53). The expression of LL-37 in seba-
ceous glands and its induction in HaCaT keratinocytes and sebo-
cytes by culture supernatants of P. acnes (46,53) suggest a
benecial role of LL-37 in acne by limiting growth of P. acnes.
Further evidence for a possible positive role of LL-37 in the path-
ogenesis of acne is provided by studies demonstrating anti-inam-
matory properties of LL-37. For example, LL-37 is able to reduce
the production of TNF-a by macrophages stimulated by bacterial
components (36,40) and is able to neutralize LPS (39). A recent
study has shown that LL-37 is able to bind to self-DNA present in
psoriasis. This blocks an excessive DNA-mediated activation of the
AIM2 inammasome (37).
Another host AMP which could play a role in limiting the
growth of P. acnes is RNase 7, an antimicrobial ribonuclease (24).
RNase 7 is highly expressed in healthy skin and is also present
throughout the entire hair follicle outer root sheath (23,24,54). Its
upregulation in inammatory skin diseases such as psoriasis and
atopic dermatitis (27) suggests that RNase 7 expression may
be also upregulated in acne lesions. As RNase 7 exhibits potent in
vitro activity against P. acnes (24), one may hypothesize that
RNase 7 may play a role in controlling the growth of P. acnes in
vivo. Further experiments are needed to assess the potential role of
RNase 7 in acne.
Psoriasin (S100A7) represents a major skin-derived AMP. It is
expressed in keratinocytes as well as in sebocytes (21). Although it
shows preferentially high activity against E. coli (21), a recent
report documented an antimicrobial activity of psoriasin against
Figure 1. Shown is the hypothetical role of antimicrobial peptides (AMP) in the
pathogenesis of acne. Propionibacterium acnes is sensed by the host leading to an
induced expression of AMP to limit the growth of P. acnes. On the other hand, the
increased amounts of AMP may contribute to recruit and activate effector cells
thus propagating inammation. However, this is a very simplied view because as
mentioned in the text, there is increasing evidence that AMP also exert anti-
inammatory properties which in turn may inuence the severity of acne. If the
observed upregulation of AMP in acne contributes to improve the clinical
symptoms or may rather worsen the disease needs further investigation.
2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Experimental Dermatology, 2013, 22, 386391 387
What is the role of AMP in acne vulgaris?
P. acnes, and this activity was enhanced in synergy with LL-37
(53). Psoriasin is highly induced in the inammatory skin diseases
psoriasis and atopic dermatitis as well as in wounds (27,55). In
addition, Schlapbach et al. (56) reported that psoriasin is mark-
edly upregulated in keratinocytes in the lesions of acne inverse.
Thus, it seems not very surprising that psoriasin expression is also
highly induced in the epidermis and in the sebaceous duct in acne
skin samples (57). Interestingly, topical treatment of skin with all-
trans retinoic acid led to an upregulation of psoriasin gene expres-
sion (58). As all-trans retinoic acid is used as a therapeutic agent
in acne, one may speculate that this treatment results in an
increased psoriasin expression in acne. This in turn may lead to
an enhanced psoriasin-mediated killing of P. acnes resulting in less
P. acnes-induced inammation. However, the validity of this
hypothesis needs further investigations.
In addition to hBD-2, Trivedi et al. (45) found also an upregu-
lation of the granulysin gene in acne lesions. Granulysin is a cyto-
toxic peptide produced in the cytolytic granules of cytotoxic T
lymphocytes and natural killer cells and is active against bacteria,
viruses, parasites as well as against some tumor cells (59). The
in vitro killing activity of granulysin against P. acnes suggests that
granulysin may contribute to limit the growth of P. acnes in
infected acne lesions (60).
Increased levels of hBD-2, granulysin, HNP-1-3, psoriasin and
probably other AMP in the acne lesions may indicate that AMP
play an important role as defense mediators in acne. The main
question is whether the upregulation of AMP in acne lesions is
benecial due to their antimicrobial activities or detrimental
because of immunostimulatory effects which may trigger inam-
mation. A study reporting successful treatment of acne with anti-
biotics and a decreased efciency of such treatments when
antibiotic-resistant propionibacteria were present indicates that
the growth control of acne-associated propionibacteria is an
important option to treat acne (15). This in turn suggests that the
antimicrobial activity of AMP may be benecial to limit diseases
severity of acne. Nevertheless, there is also some evidence that
increased levels of AMP may worsen inammation in acne. This
hypothesis is discussed in the next part.
Second hypothesis: induction of AMP worsens the clinical
symptoms of acne
Originally, many AMP have been discovered due to their antimi-
crobial activity. There is increasing evidence that several AMP are
more than just microbicidal: they interfere also with the host
through immunomodulatory activities. As many of these activities
have a pro-inammatory characteristic, it is possible that increased
AMP level may trigger inammation in acne. For example, the
upregulation of hBD-2 in acne lesions may be accompanied with
an increased inammatory scenario due to the inammatory
properties of hBD-2. Such properties include chemotactic activities
as well as induction of various chemokines and cytokines (6166).
In addition, the stimulation of keratinocytes migration and prolif-
eration by beta-defensins such as hBD-2 may contribute to forma-
tion of comedones (63). It has been reported that the induction
of hBD-2 gene expression in keratinocytes stimulated with pro-
inammatory cytokines, phorbol-myristate-acetate (PMA) and
bacteria was inhibited by all-trans retinoic acid (67). Interestingly,
all-trans retinoic acid (tretinoin) has been successfully used in the
treatment of acne because of its comedolytic and anti-inammatory
properties (68). It remains to be shown whether the inhibition of
hBD-2 induction in acne contributes to the anti-inammatory
properties of tretinoin.
Assuming that increased levels of hBD-2 and other AMP may
trigger inammatory processes in acne, it could be a therapeutic
option to interfere with the P. acnes-induced upregulation of
AMP. As mentioned above, TLRs are involved in the P. acnes-
mediated upregulation of hBD-2. Thus, blocking the function of
TLRs may represent a feasible approach to limit inammation in
acne. In line with this, Dispenza et al. (69) reported that a sys-
temic isotretinoin therapy of acne patients reduced the acne-
associated exaggerated TLR-2 level of monocytes. In addition, zinc
salts, which exhibit benecial effects on inammatory acne lesions
(13), inhibit the expression of TLRs in keratinocytes (70). In con-
cordance with these results, glucocorticoids enhance TLR-2
expression in human keratinocytes. This upregulation of TLR-2
was markedly increased in the presence of P. acnes and pro-
inammatory cytokines (71). TLR-2 mediated induction of pro-
inammatory cytokines and AMP may explain why glucocorticoid
treatment itself is able to provoke an acneiform reaction (71).
Human neutrophil peptide (HNP)-1-3 are members of the
alpha defensin family and are abundant in neutrophils where they
contribute to the killing of microbes (20). HNP-1-3 have been
detected in the perivascular and interstitial neutrophils in inam-
matory acne, and HNP-1-3 levels were higher in pustular lesions
as compared with uninvolved skin (72). Beside their antimicrobial
activities, HNP-1-3 exhibit chemotactic activities, promote the
production of pro-inammatory cytokines, activate immune cells
and induce histamine secretion from mast cells (7375). Intratrac-
heal instillation of HNPs in the mouse lung led to induction of a
strong inammatory response and lung dysfunction (76). This
gives rise to the speculation that HNPs may contribute to inam-
mation in acne. In line with this hypothesis, acne treatment with
isotretinoin revealed a perivascular and interstitial reduction in
HNP-1-3 expression of pustular lesions (72).
As mentioned above, an induction of granulysin gene expres-
sion in acne lesions has been reported. Beside its antimicrobial
activity, granulysin exhibits also chemotactic activity towards T
cells and monocytes and is able to activate the expression of
several pro-inammatory cytokines (77). Thus, one may speculate
that these immune-activating properties of granulysin may
contribute to inammation in acne lesions.
The cathelicidin LL-37 represents an AMP with various immu-
nomodulatory activities. It mediates angiogenesis, displays chemo-
tactic properties and induces the expression of several
pro-inammatory mediators (31,78). As LL-37 is able to recruit
and activate several immune cells, it is also allocated to the group
of alarmin peptides (79). LL-37 induces also the release of alpha-
defensins HNP-1-3 from neutrophils (80). Propionibacterium acnes
releases factor(s) that induce the gene expression of LL-37 in
keratinocytes (46) and in sebocytes (53) indicating that LL-37
may play a role in acne. An upregulation of LL-37 in acne lesions
by P. acnes may activate its alarmin function leading to enhanced
recruitment and activation of host immune cells and release of
pro-inammatory mediators. Such scenario may enhance the
severity of inammation in acne. However, as described above,
LL-37 exhibits also anti-inammatory activities which may also
compensate its pro-inammatory actives.
388
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Experimental Dermatology, 2013, 22, 386391
Harder et al.
The use or manipulation of AMP: potential
therapeutic options?
In the following part, we will discuss two potential therapeutical
options dealing with AMP: (i) Direct application of AMP to treat
acne and (ii) interference with AMP expression in acne.
Therapeutical option 1: the use of human and other AMP to
treat acne
Given the abundance of P. acnes, which much likely promotes and
maintains inammation in acne lesions, the use of antibiotics to
control the growth of P. acnes has been established as common
treatment option in acne (5,13). The antibiotics currently available
to treat acne have two major weaknesses. First, P. acnes is a multi-
drug resistant bacterial strain (81), and second, currently available
antibiotics against acne, such as tetracycline or clindamycin, are
bacteriostatic agents (82). AMP exert rapid and broad spectrum
antimicrobial effects and therefore may represent a novel future
class of antimicrobial agents (83). The advantage of AMP is that
they often target the microbial cell membrane and cell wall which
makes it hard for the microbes to develop complete resistance
against AMP. It is known that several bacteria developed strategies
to reduce their susceptibility to AMP, but this normally results
not in complete resistance against AMP (84). In addition, natural
AMP are still active against their natural microbial opponents
indicating that complete resistance to AMP is hard to achieve in
vivo. However, in vitro experiments using a synthetic frog-derived
AMP suggest that the possibility to acquire complete resistance
cannot be ruled out (85). Nevertheless, the potent bactericidal
activity of AMP together with potential benecial immunomodu-
latory roles suggests that some selected AMP could be the target
for the development of promising treatment options for acne
(17,38,60,86).
Given the assumption that the presence of P. acnes triggers
inammation in acne, it might be a feasible strategy to use AMP
with both, bactericidal activity against P. acnes and anti-inamma-
tory properties. As mentioned above, Deng et al. (77) have
reported that the AMP granulysin induced several cytokines and
chemokines suggesting that granulysin may trigger inammation.
However, McInturff et al. have generated modied granulysin-
based peptides that were highly effective in killing P. acnes but
also suppressed P. acnes-stimulated cytokine release. Thus, these
modied granulysin peptides may be useful therapeutic
agents because they are able to kill P. acnes and they may reduce
P. acnes-mediated inammation (60).
In contrast to the use of human-derived AMP, another prom-
ising approach would be to develop synthetic AMP based on
natural AMP found in animals and plants. Indeed, there are
some approaches to design synthetic AMP as drugs for the treat-
ment of acne. For example, a very promising AMP to treat acne
is omiganan, a synthetic derivative of the bovine AMP indolici-
dine (87). This molecule exhibits a very potent antimicrobial
activity and showed positive results in ve clinical trials as a
topical solution for the treatment of acne. Omiganan reduced
the disease severity and inammatory lesion in mild to moderate
acne (88).
Table 1. Expression and potential role of antimicrobial peptides (AMP) in acne
AMP Expression studies Support for a potential positive role in acne
Support for a potential negative role in
acne
hBD-2 Induced in acne lesions (4345)
Induced by Propionibacterium acnes
supernatant in keratinocytes (46) and by
living P. acnes in sebocytes (47)
hBD-2 alone and in synergy with free lauric acid
(FFA) kills P. acnes. The P. acnes-killing activity of
FFA-treated sebocytes was neutralized by anti-
hBD-2 IgG (49)
Potential promotion of inammation due to
chemotactic effects and induction of various
chemokines/cytokines (6166). Stimulation of
keratinocytes migration and proliferation may
contribute to formation of comedones (63).
The acne therapeutic agent all-trans retinoic
acid decreased hBD-2 expression in
keratinocytes (67)
LL-37 Induced by P. acnes supernatant in HaCaT
keratinocytes (46) and in sebocytes (53)
Active against P. acnes, synergistic activity together
with psoriasin (53). Binding of LPS (39), reduction
in bacteria-stimulated TNF-a production by
macrophages (36, 40) and inhibition of the
activity of the AIM2 inammasome (37) may
exert anti-inammatory activities
Possible inammatory reactions due to
recruitment and activation of immune cells;
induction of pro-inammatory cytokines
(78,79)
HNP-1-3 Present in neutrophils in inammatory acne;
increased level in pustular lesions (72)
Exhibit antimicrobial activity (20) May trigger inammation by chemotactic
activities and induction of pro-inammatory
cytokines (74,75). Intratracheal instillation of
HNPs in the mouse lung provoked
inammation (76)
Acne treatment with isotretinoin revealed a
perivascular and interstitial reduction in HNP-
1-3 expression of pustular lesions (72)
RNase 7 Expressed in outer epidermis and hair follicle
outer root sheath (23,54)
Active against P. acnes (24)
Psoriasin Upregulated in the epidermis and sebaceous
duct in acne samples (57)
Active against P. acnes, enhanced activity in
synergy with LL-37 (53)
Topical skin treatment with the acne therapeutic
agent all-trans retinoic acid increased psoriasin
expression (53,58)
Granulysin Induced in acne lesions (49) Active against bacteria (59)
Modied granulysin-based peptides are effective
against P. acnes but also suppress P. acnes-
stimulated cytokine release (77)
Chemotactic activity against T cells and
monocytes as well as induction of
pro-inammatory cytokines may trigger
inammation (77)
Adrenomedullin Expressed in the hair follicle but not markedly
upregulated in acne lesions (97)
Antimicrobial activity against P. acnes (96)
2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Experimental Dermatology, 2013, 22, 386391 389
What is the role of AMP in acne vulgaris?
As mentioned above, it would be a promising approach to use
AMP with both, anti-P. acnes and anti-inammatory activity. In
this regard, it has been reported that some frog skin-derived AMP
inhibited the growth of P. acnes, inhibited the release of
pro-inammatory cytokines and stimulated the release of anti-
inammatory cytokines making them attractive candidates for the
treatment of acne (89).
Another promising class of antibiotic molecules to treat acne
comprises bacterial AMP, termed bacteriocins (90). Several studies
reported high activity of various bacteriocins against P. acnes sug-
gesting that they may represent an alternative class of antibiotics
to control the growth of P. acnes (9193). Indeed, a lotion con-
taining an Enterococcus faecalis-derived bacteriocin signicantly
reduced the inammatory acne lesions compared with the placebo
lotion (91).
Therapeutical option 2: interference with AMP expression in
acne
Following the hypothesis that an increased expression of host AMP
in lesional acne would improve the clinical picture, it could be an
attractive strategy to develop and apply substances that induce the
expression of AMP. A promising approach in this regard could be
the application of FFAs as suggested by the studies of Nakatsuji and
co-workers. They showed that FFAs combine two benecial proper-
ties: they exhibit antimicrobial activity, and they enhance the
expression of hBD-2 and probably other AMP (49).
Several reports document that the expression of the human
cathelicidin LL-37 is induced by vitamin D (78). LL-37 is
expressed and induced by vitamin D in sebocytes and exhibits
antimicrobial activities against P. acnes which can be increased in
synergy with other AMP such as psoriasin (53). This leads to the
hypothesis that induction of LL-37 by vitamin D could be of
advantage in the treatment of acne patients. However, this would
be only successful if the antimicrobial and anti-inammatory
properties of LL-37 outweigh its pro-inammatory properties
(78). Nevertheless, the successful treatment of psoriasis with
vitamin D reveals vitamin D as a promising drug to treat
inammatory skin diseases, and thus, it is intriguing to speculate
that vitamin D may also be a treatment option for acne patients
(94,95).
Adrenomedullin, a multifunctional peptide hormone, exhibits a
high antimicrobial activity against P. acnes (96). Adrenomedullin
is expressed in the hair follicle, but its expression is not markedly
upregulated in acne lesions (97). As adrenomedullin has a strong
antimicrobial effect on P. acnes, one may speculate that a de-
ciency of adrenomedullin may promote the growth of P. acnes in
acne. Thus, application and/or specic induction of adrenomedul-
lin could be a treatment option to reduce P. acnes growth in acne.
Conclusion
Although the role of AMP in the pathogenesis of acne is still
emerging, there is some evidence that they may have relevance in
acne. However, whether AMP exert either a benecial or a detri-
mental inuence in the pathogenesis of acne is still unclear.
Undoubtedly, the antibacterial activity of AMP in acne will exert
benecial effects as shown by the use of classical antibiotics and
other bactericidal agents in the treatment of acne. The question
remains open whether the use of AMP may promote inamma-
tory effects. However, it is likely that epithelial-derived AMP,
which have been optimized during evolution to protect epithelia
from potential harmful microbial threats, are attractive candidates
as a drug for topical acne treatment. Even more promising might
be the development and application of modied AMP that on the
one hand are active against P. acnes and on the other hand are
able to inhibit P. acnes-induced inammation. As mentioned
above, the report of granulysin-derived AMP with such character-
istics indicates that the generation of such AMP is a feasible goal.
Clinical trials are necessary to assess the potential benet of such
optimized AMP in the treatment of acne.
Acknowledgements
JH was supported by a Heisenberg program of the German Research Foun-
dation.
Conict of interests
The authors have declared no conicting interests.
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