New insights into rosacea pathophysiology: A review

of recent findings
Martin Steinhoff, MD, PhD,a J
urgen Schauber, MD,b and James J. Leyden, MDc
San Francisco, California; Munich, Germany; and Philadelphia, Pennsylvania

Rosacea is a common, chronic inflammatory skin disease of poorly understood origin. Based on its clinical
features (flushing, chronic inflammation, fibrosis) and trigger factors, a complex pathobiology involving
different regulatory systems can be anticipated. Although a wealth of research has shed new light over recent
years on its pathophysiology, the precise interplay of the various dysregulated systems (immune, vascular,
nervous) is still poorly understood. Most authors agree on 4 major clinical subtypes of rosacea: erythemato-
telangiectatic rosacea, papulopustular rosacea, phymatous rosacea, and ocular rosacea. Still, it needs to be
elucidated whether these subtypes develop in a consecutive serial fashion or if any subtypes may occur
individually as part of a syndrome. Because rosacea often affects multiple family members, a genetic component
is also suspected, but the genetic basis of rosacea remains unclear. During disease manifestation and early stage,
the innate immune system and neurovascular dysregulation seem to be driving forces in rosacea pathophys-
iology. Dissection of major players for disease progression and in advanced stages is severely hampered by the
complex activation of the innate and adaptive immune systems, enhanced neuroimmune communication,
profound blood vessel and possibly lymphatic vessel changes, and activation of almost every resident cell in the
skin. This review discusses some of the recent findings and aims to build unifying hypotheses for a modern
understanding of rosacea pathophysiology. ( J Am Acad Dermatol 2013;69:S15-26.)

Key words: adaptive immunity; antimicrobial peptides; cytokines; fibrosis; innate immunity; mast cells;
neurovascular system.

R osacea is a common chronic inflammatory or symptoms of rosacea include transient to

skin disease that almost exclusively affects
the central facial skin. Whether the dense
presence of sebaceous glands in this area (cheeks,
nose, chin, and forehead) or a specific physiology of
the nerve innervation and vascular composition is
crucial for this aspect is still a matter of debate. Many
authors currently regard this disease as a syndrome
or typology with 4 distinct clinical subtypes: eryth-
ematotelangiectatic rosacea (ETR), papulopustular
rosacea (PPR), phymatous rosacea (PhR), and ocular
rosacea.1 These subtypes may be discrete variants or
may be progressive from one to another.2 Besides
these subtypes, several additional variants have been
described with conflicting reception within the der-
matologic community.1,3 Characteristic clinical signs
persistent facial erythema, telangiectasia, papules,
pustules, edema, or a combination of these; some
individuals with rosacea also experience pain,
stinging or burning, and, albeit rarely, pruritus.1,4
Many triggers are associated with the initiation
or aggravation of rosacea including ultraviolet
(UV) radiation, heat (rarely noxious cold), spicy
food, alcohol, stress, and microbial infestation on
the face or in the gut (bacterial overgrowth).5
Demodex mites are particularly found in association
with several papulopustular lesions.6 His-
tologically, rosacea findings include dilated blood
and lymphatic vessels leading to erythema and
edema; a perivascular infiltrate consisting of in-
creased T cells, macrophages, and mast cells; and

From the Department of Dermatology, University of California, San
Franciscoa; Department of Dermatology and Allergy, Ludwig
Maximilian University, Munichb; and Department of Dermatol-
ogy, University of Pennsylvania School of Medicine.c
Publication of this article was supported by a grant from
Galderma International. Editorial support provided by
Galderma International.
Disclosure: Dr Steinhoff has served on an advisory board and as
speaker for Galderma, and as a consultant for Leo and Galderma
and received grants and equipment in compensation.
Dr Schauber has served as a speaker for Galderma, Astellas,
and La Roche Posay, and as a consultant for Leo and received
honoraria as compensation. Dr Leyden has served as consultant
for Galderma, Allergan, and Medicis and received honoraria in
compensation.
Accepted for publication April 21, 2013.
Reprint requests: Martin Steinhoff, MD, PhD, Department of Der-
matology, University of California, San Francisco, 1701 Divisadero
St, Third Floor, San Francisco, CA 94115. E-mail: SteinhoffM@
derm.ucsf.edu.
0190-9622/$36.00
2013 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2013.04.045

S15
S16 Steinhoff, Schauber, and Leyden J AM ACAD DERMATOL
DECEMBER 2013

often but not exclusively solar elastosis, edema, and patients does not initially develop ETR subtype, but
tortuous, dilated vessels.7-9 Of note, the dense in- present at disease onset with PPR or PhR. Therefore, it
flammatory infiltrate can be already found in the ETR actually remains unclear whether initial clinical pre-
subtype and even in patients with transient ery- sentation of an advanced subtype indicates a de novo
thema.2 The PPR subtype may also have a dense manifestation instead of development of the disease
follicular infiltrate with neutrophils and macro- from prior subclinical formation and progression from
phages near the follicle.7,8 Treatment currently fo- earlier subtypes.2,4 The latter view is supported by the
cuses on alleviating finding that an obvious dis-
symptoms because no cura- crepancy exists between the
tive therapy is available.10 CAPSULE SUMMARY clinical diagnosis of an inflam-
Evidence indicates a role of matory process and the
dRosacea pathophysiology is very complex,
Demodex mites in certain histopathological correlate:
involving various cell types and molecules
subtypes of rosacea; the already patients with
in the skin, and various subtypes.
pathogenic mechanism in transient flushing in early
early transient rosacea, how- dDespite progress in understanding ETR present a chronic inflam-
ever, remains unclear since pathophysiology of rosacea, much work matory process that is clini-
mites are not usually found at remains to more fully understand the cally not visible because of the
this stage.9 complex dysregulation of cells and absence of papules or pus-
It is becoming increas- mechanisms of disease onset. tules. Thus, a more detailed
ingly clear that the patho- dFuture studies should address analysis of different phases of
physiology of rosacea is communication between the skins rosacea is needed to deter-
quite complex, involving a vasculature, nervous system and innate mine whether the defined
large variety of cell types and adaptive immune systems (ie, subtypes of rosacea are re-
and molecules in the skin. activation and inhibition). lated stages of a single contin-
Recent studies suggest that uously worsening disease
rosacea initially occurs in in- consisting of multiple patho-
dividuals when inappropriate innate immune physiological pathways, or if different manifestations
responses to environmental stimuli lead to inflam- of rosacea represent a collection of several distinct and
mation and vascular abnormalities. However, based possibly nonconnected disease processes with a
on transcriptome along with immunohistochemical common phenotypic feature (syndrome).1,2,14
analysis a contribution of the adaptive immune So far, transcriptome along with quantitative
system can also be anticipated at an early stage of reverse transcription polymerase chain reaction
rosacea (M. S., unpublished data). analysis has shown that the clinical subtypes of
rosacea have different gene profiles that are
ROSACEA PATHOPHYSIOLOGY: A characteristic for each subform and more than 500
COMPLEX TAPESTRY genes differ from healthy skin. Interestingly, patients
Recently, an integrated theory about the patho- with PhR exhibit up-regulation of many inflammatory
physiology of rosacea has emerged as a result of genes indicating the existence of a more subclinical
various murine or human studies (Fig 1).2,5,11 but still relevant inflammatory process also in patients
with PhR. Thus, aside from these fundamental ques-
Findings from transcriptome analysis in tions on rosacea origin still remaining, novel molecular
rosacea data provided new insights in the pathophysiology of
Epidemiologic data comparing disease prevalence rosacea from patients with early flushing to fibrotic
and skin phenotype in different geographic regions changes and support for several more detailed lines of
suggest that rosacea has a genetic component, but research in rosacea (summarized in Steinhoff et al2). In
1 or more rosacea gene(s) have yet to be addition, those data also substantiate the activation of
identified.2,12,13 Recent transcriptome profiling several neurovascular and neuroimmune regulatory
analysis in patients with rosacea and subtypes pathways along with inflammatory and immune
ETR, PPR, and PhR has verified the existence of changes characterizing the pathophysiological pro-
distinct gene profiles for each disease subtype, cesses in early rosacea.2,5,15-17 Immunohistochemical
2
although with certain genes overlapping. This combined with morphometric analyses of ETR, PPR,
suggests that a developmental march from an earlier and PhR indicate that CD41 type 1 helper T cells (Th1),
inflammatory rosacea subtype to a more advanced macrophages, and mast cells are the predominant
fibrotic form can be assumed in most patients. activated immune cells in rosacea. Already early stages
Nevertheless, a smaller, but significant number of of rosacea (eg, ETR) present as a Th1-cell-mediated
J AM ACAD DERMATOL Steinhoff, Schauber, and Leyden S17
VOLUME 69, NUMBER 6

Abbreviations used:
AMP: antimicrobial peptide
CAMP: cathelicidin antimicrobial peptide
CCL2: cysteine-cysteine chemokine-2
CXCL8: cysteine-X-cysteine chemokine-8
ER: endoplasmic reticulum
ETR: erythematotelangiectatic rosacea
H2R: Histamine receptor-3
HTR3A: Serotonin receptor-3A
IL: interleukin
KLK: kallikrein
MMP: matrix metalloproteinases
NF-kB-C/EBPa: Nuclear factor-kappa-B-C/EBPa
NK: natural killer
PACAP: pituitary adenylate cyclase acti-
vating polypeptide
PhR: phymatous rosacea
PPR: papulopustular rosacea Fig 1. Schematic of proposed interactions among clinical,
SP: substance P immunologic, neurovascular, and molecular characteris-
TGF: transforming growth factor
Th1: type 1 helper T cell tics of rosacea. TLR, Toll-like receptor; TRPV1, transient
TLR: toll-like receptor receptor potential channel vanilloid receptor 1. Adapted
TRP: transient receptor potential from Steinhoff et al.2
channel
TRPA1: transient receptor potential
channel ankyrin receptor 1 because keratinocytes are equipped with sensors and
TRPV: transient receptor potential ion
channel vanilloid type are capable of communication with each other
TRPV1: transient receptor potential upon microbial challenge or encountering danger
channel vanilloid receptor 1 signals. The interaction of keratinocytes can trigger
UV: ultraviolet
VEGF-A: vascular endothelial growth immune-activating and/or proinflammatory cascades,
factor-A providing an adequate and coordinated immune
response. Antimicrobial peptides (AMPs) are among
the soluble defense factors, which are primarily
secreted by keratinocytes in the skin. Initially, AMPs
inflammatory skin disease with recruitment of macro-
were identified as endogenous antibiotics because of
phages and mast cells, but without increased numbers
their potential to kill various pathogens such as
of Langerhans cells, eosinophils, or natural killer (NK)
gram-positive and gram-negative bacteria, viruses,
cells. Those cells also represent the cell infiltrate of the
and fungi.15 Keratinocytes and other resident cells in
papules present in PPR, but, as stated, are already
the skinesuch as eccrine gland cells, mast cells, and
present in high numbers in ETR. In the PPR subtype,
sebocyteseproduce and secrete AMPs. In addition,
interleukin (IL)-8 messenger RNA is dramatically
invading immune cells (eg, neutrophils, NK cells)
up-regulated resulting in the recruitment of neutro-
contribute to the pool of AMPs in the skin.15,19-22
phils clinically observed as pustules. B cells are
Notably, the production of AMPs in the skin is a
activated in PhR and sometimes in PPR, but the
dynamic defense mechanism: although some AMPs
trigger for this remains unknown.2,5,10 However, this
are expressed constitutively in the skin, the production
result indicates that the adaptive immune system,
of others is highly increased in dangerous situations
represented by Th1 cells at a very early phase and
such as skin injury or infections.11,23-25 Furthermore,
throughout all subtypes, along with B cells or plasma
the expression and functions of AMPs are regulated on
cells, present only in the PhR and occasionally PPR,
the transcriptional and posttranscriptional level. Most
also plays a significant role in the pathophysiology of
AMPs are synthesized as propeptides and activated
rosacea. How the adaptive and the innate immune
after proteolytic cleavage from their precursor
system are connected in the pathobiology of rosacea is
molecules.26,27 Consequently, induction of trans-
an exciting question for future research.
cription and increased processing are needed to
provide the skin with enhanced AMP activity.
Antimicrobial peptides: Cutaneous innate Important and well-studied groups of AMPs in
defense effectors human skin are the families of defensins and of
To form an efficient barrier against the outside cathelicidins. Although there are several gene-
environment, our skin possesses multiple physical, encoded defensins (eg, a- and b-defensins), 1 single
biochemical, and cellular defense mechanisms.18 cathelicidin gene has been identified in man; it is
Here, the innate immune system plays a pivotal role, designated cathelicidin AMP (CAMP).28,29 Like many
S18 Steinhoff, Schauber, and Leyden
Fig 2. Schematic of proposed role of cathelicidin antimicrobial peptides in pathophysiology of
rosacea. ER, Endoplasmic reticulum; TLR, toll-like receptor; UV, ultraviolet.
AMP genes, CAMP encodes for a propeptide that is
composed of an N-terminal cathelin domain and a
C-terminal peptide with antimicrobial activity.30
The first active cathelicidin identified was LL-37,
a 37-amino-acid-long peptide with broad anti-
microbial activity. LL-37 forms a-helix in aqueous
solution, which enables the peptide to disrupt both
bacterial membranes and viral envelopes.31 On the
skin surface, active cathelicidin peptides such as
LL-37 are cleaved from the inactive precursor by
serine proteases of the kallikrein (KLK) family.26,32,33
Because LL-37 gains antimicrobial activity after
cleavage from the proform, processing of cathelici-
din by skin proteases is an important regulatory
mechanism of cathelicidin-mediated antimicrobial
activity.
Apart from antimicrobial activity, LL-37 has
additional functions in the activation and the control
of immune responses: LL-37 increases cytokine and
chemokine liberation from local cells and leukocytes
and has chemotactic effects on a large number of
immune cells.15 In addition, chemokine and
cytokine release in mast cells or keratinocytes is
also induced by LL-37.34 In cooperation with these
cytokines, LL-37 enhances innate immune responses
by multiple pathways.15,35 On top of all these effects,
LL-37 enhances the proliferation of endothelial
cells and seems to induce functionally important
angiogenesis.36 These attributes complement the
antimicrobial functions of LL-37 and have led to the
J AM ACAD DERMATOL
DECEMBER 2013
perception of LL-37 as not only an antimicrobial but
an alarmin peptide.37 The multiple roles of
cathelicidineespecially the antimicrobial actions
and the alarmin functionesuggest a central role for
this peptide in cutaneous innate immunity.
Consequently, dysfunction of the alarmin function of
cathelicidin LL-37 could play a role of in the pathogen-
esis of inflammatory skin disease to the same extent as
impaired antimicrobial activity.10,38,39 In the tran-
scriptome analysis, cathelicidin was found to be
up-regulated in all rosacea subtypes, although
modestly (approximately 2.5-fold). Thus, the role of
cathelicidin as a particular aggravating factor in rosacea
in human beings still needs further clarification.10,38,39
Dysfunction of CAMP as a cause of rosacea
Because cathelicidin peptides have proinflamma-
tory alarmin functions and may affect vascular
growth, these peptides could be involved in
the pathophysiology of rosacea (Fig 2). Indeed,
cathelicidin messenger RNA transcription and
protein expression are strongly increased in lesional
skin in rosacea compared with the skin of
nonaffected individualsedespite the absence of an
obvious infectious trigger in rosacea.10,16
As mentioned above, processing of the proprotein
is a crucial step in activating the different functions of
cathelicidin peptides. In the skin, cathelicidin is
processed by serine proteases of the KLK family
(particularly KLK5 [also known as stratum corneum
J AM ACAD DERMATOL
VOLUME 69, NUMBER 6
tryptic enzyme] and KLK7 [also known as stratum
corneum chymotryptic enzyme]).26 The resulting
peptide responsible for most cathelicidin effects is
LL-37. However, in addition to LL-37, some other
cleavage products of the proprotein as well as LL-37
fragments can also exert immune functions, but may
differ in their antimicrobial and immune activating
capacities.40
In rosacea, the cutaneous protease activity is
enhanced in lesional skin compared with healthy
skin and increased expression of serine proteases
such as KLK5 can be observed.16 Furthermore,
variant cathelicidin peptides and smaller fragments
can be detected. Thus, increased levels of the vaso-
active and proinflammatory host-defense peptide
LL-37 and its proteolytic peptide fragments are found
in rosacea, which can be explained by an abnormal
cathelicidin production and pathologic protease
activity.16,41
Confirming a pathogenic role of cathelicidin in
rosacea, injection of these peptide fragments found
in skin of patients with rosacea into mouse skin leads
to a rosacea-like dermatitis.16 In contrast, isolated
increase of protease activity in cathelicidin knock-
out mice does not cause dermal inflammation.16
However, the mechanisms underlying the in-
creased cathelicidin production and the enhanced
protease activity in skin of patients with rosacea are
still not fully understood. Both seem to be regulated
by different signaling pathways with retinoid-,
vitamin De, and cytokine-activated cascades play-
ing important roles.39 However, how cathelicidin
activation and activation of the innate immune
system results in transient and persistent erythema
in patients with ETR still needs to be explored in the
future.
Cathelicidin LL-37 expression in human keratino-
cytes is strongly induced by the activation of the
vitamin D pathway.42 This could explain why
rosacea occurs mainly in the face, as exposure to
UV light triggers activation of vitamin D in keratino-
cytes and subsequent cathelicidin expression.42,43
Recently, a second (vitamin Deindependent)
pathway triggering the induction of cathelicidin
synthesis was identified: in keratinocytes, cathelici-
din expression increases upon exposure to several
external stimuli (eg, infection, injuries, UV radiation,
and permeability barrier disruption), which also
triggers endoplasmic reticulum (ER) stress. Indeed,
ER stress increases CAMP expression via NF-kB-C/
EBPa independent of vitamin D receptor activation,
demonstrating a novel role for ER stress in stimulat-
ing innate immunity.44 This again could explain why
patients with rosacea often report nonspecific
triggers of skin inflammation (eg, heat, cold, UVB),
Steinhoff, Schauber, and Leyden S19
which in this scenario would mediate their
proinflammatory activities through ER stress and
cathelicidin induction.
But why is cutaneous protease activity elevated in
lesional skin in rosacea? As mentioned earlier,
resident cells in the skin such as keratinocytes
express receptors that sense pathogen-associated
molecular patterns. Toll-like receptors (TLRs) are
one family of pathogen-associated molecular pattern
sensors triggering further immune responses. As an
example, ligands for TLR2 are microbial structure
molecules such as cell wall fragments but also
chitin.45,46 In lesional skin of patients with rosacea,
keratinocytes express elevated levels of TLR2.45
Furthermore, TLR2 activation in keratinocytes leads
to a higher expression of KLK proteases and higher
protease activity.45
And what is the trigger for TLR2 in rosacea? Most
authors establish direct and indirect links of TLR2
up-regulation and increased receptor sensitivity to
the significant association between development of
rosacea and density of D folliculorum infesta-
tion.41,47 Possibly, chitin released from these mites
could serve as the trigger for TLR2 on keratinocytes
and link Demodex with increased protease activity
and cathelicidin-induced inflammation in rosacea.48
Furthermore, Lacey et al49 isolated Bacillus oleronius
from D folliculorum and determined the antigens
reacting to sera from patients with rosacea, but not to
healthy control subjects. Of note, they identified
heat-shock proteins and a lipoprotein in the anti-
genic molecules of B oleronius. Because heat-shock
proteins and lipoproteins are known stimulators
of TLR2, this observation could be an additional
explanation for TLR2-mediated stimulation of innate
immunity.
In addition, transcriptome analysis demonstrates a
significant up-regulation of several KLKs including
KLK5 (M. S., unpublished data). KLK up-regulation
can be induced by injury, physical stimuli, and
microbial agents in high amounts, indicating that
KLKs, proteases, and protease-activated receptors
are an additional system of the innate immune
system to sense danger as induced by rosacea
trigger factors.2,10,16,50 The interaction between the
antimicrobial and protease systems generated by
residing skin and immune cells in the pathophysiol-
ogy of rosacea needs to be explored.
Together, these observations potentially identify
a complex proinflammatory cascade involving
Demodex or other microbes, TLRs, cathelicidin, and
possibly other AMPs, as well as proteases and
protease inhibitors in the pathogenesis of rosacea.
Interestingly, several of these mechanisms could also
be exploited for novel therapies.
S20 Steinhoff, Schauber, and Leyden
Cathelicidin as a novel target for therapeutic
approaches in inflammatory skin diseases
The increasing data on the role of cathelicidin in
rosacea have prompted the idea that targeting AMP
expression could ameliorate cutaneous inflamma-
tion. Restoring antimicrobial activity or balancing
alarming activities of AMPs could be novel goals of sensory nerve endings but also by skin cells such
topical or systemic treatments for this inflammatory
skin disease.51 Several approaches are imaginable.
As an example, chitin released from Demodex mites
possibly triggers TLR2 activation and subsequent
increased protease activity in the skin of patients
with rosacea. Thus, decreasing the load of Demodex
mites on the skin or blocking TLR2 could decrease
protease activity, cathelicidin dysfunction, and
cutaneous inflammation. Indeed, inhibition of
Demodex has been suggested in the treatment of
rosacea before and decreased mite density is associ-
ated with reduced inflammation in clinical studies.6
Furthermore, retinoids, which can be used in the
treatment of moderate to severe rosacea, block TLR2
activity and could mediate their effects through this
mechanism as well.52
Increased protease activity is central to the
proinflammatory effects of dysfunctional cathelicidin
peptides in rosacea.16 Hence, topical or systemic
therapies inhibiting pathologic protease activity
could exert anti-inflammatory effects in rosacea.
Indeed, some established and clinically effective
therapies probably exert their beneficial effect
through this mechanism. As an example, tetracy-
clines such as doxycycline can inhibit proteases and
ameliorate cutaneous inflammation in rosacea.37,53,54
Importantly, these anti-inflammatory effects are
independent of the antimicrobial effect of doxycy-
cline and the doses needed for clinical effect in
rosacea are probably lower than those needed to
treat infections.
Another way to interfere with the outlined
proinflammatory cascade could be to block
increased cathelicidin production in lesional skin.
As mentioned earlier, vitamin D controls the
expression of cathelicidin and UVB triggers
activation of vitamin D from precursor molecules.55
Thus, the advice to patients with rosacea to avoid
exposure to sunlight might find its scientific basis in
those observations.
Role of neuroimmune interactions in rosacea
Trigger factors of rosacea such as exposure to
sunlight (UV radiation), heat or cold, alcohol, spicy
foods, or exercising can activate peripheral sensory
nerve endings and are thus thought to be implicated
in the pathophysiology of rosacea (Fig 3).2,14 In
addition to the activation of highly susceptible
J AM ACAD DERMATOL
DECEMBER 2013
cutaneous nerves, impairment of the innate immune
system and epidermal barrier may lead to a
hypersensitive skin resulting in transient and, later,
persistent erythema as well as pain, burning, or
stinging. Of note, neuromediators inducing those
neuroimmune responses cannot only be released by
as keratinocytes, activated endothelial cells, or
fibroblasts. Moreover, sensory nerves also express
TLRs or protease-activated receptors building a link
between the innate immune system and the nervous
system.56 Induction of neurogenic inflammation can
lead to release of proinflammatory cytokines or
chemokines, resulting in vasodilation, edema, and
inflammation with both transient and persistent
erythema, burning, stinging, and even fibrosis via
activation of mast cells.4,57-59 However, the exact
relationship between the cutaneous nervous system
and the innate immune system in rosacea remains
undefined as of yet, but it appears that both systems
are associated with clinical characteristics that result
from 1 or more disease triggers.2
The recent discovery of a novel class of nonselec-
tive cation channels, the transient receptor potential
channels (TRPs), has increased our understanding of
how sensory nerve endings are activated to release
vasoactive neuropeptides, to control pain or inflam-
mation, and may thus have significant implications
for the pathophysiology of rosacea.60-62 The TRP
family is currently composed of 28 channels with 7
subfamilies.63 Of note, those receptors are widely
expressed on neuronal and nonneuronal tissues
including keratinocytes or endothelial cells.61 Recent
studies have focused on TRP vanilloid receptor
1 (TRPV1), also known as the capsaicin receptor,
and TRP ankyrin receptor 1 (TRPA1) in pain induction
and inflammation.63 They can be activated by heat,
ethanol, or spicy food (TRPV1) or cold, formalin, or
other chemicals (TRPA1), all trigger factors of rosacea.
Activation of TRPV1 and TRPA1 causes release of
substance P and calcitonin gene-related peptide,
important mediators of neurogenic inflammation and
pain.55 Notably, affected rosacea skin has been shown
to have a significantly lower threshold for temperature
and chemicals resulting in facial hypersensitivity
as compared with nonlesional skin.64 Release of
calcitonin gene-related peptide may be particularly
important in view of its potent microvascular dilating
effect on arterioles, whereas SP is critical for
producing edema via activation of the NK1 receptor
on postcapillary venules.65,66
Both induce neurogenic inflammation.50 Patients
with rosacea often report that their facial erythema
is intensified by various spices. Interestingly,
exogenous agonists for both TRPV1 and TRPA1 are
J AM ACAD DERMATOL
VOLUME 69, NUMBER 6
Fig 3. Schematic of interaction among trigger factors, sensory nerves, and rosacea symptoms
and histopathology. IL, Interleukin; UV, ultraviolet. Printed with permission from Steinhoff
et al.2
chemicals derived from vegetables, spices, or
cosmetics (eg, capsaicin from chili peppers,
cinnamaldehyde from cinnamon, formalin in various
cosmetics).16,63
The emerging concept behind these findings for
the pathophysiology of rosacea is as follows: patients
with rosacea may have a genetic predisposition or
gain-of-function mutation in a receptor that is
involved in neurovascular regulation, sensing of
rosacea trigger factors (either overexpression or
overstimulation of TRP), which results in neuropep-
tide release (characterized by flushing and edema),
followed by transient to persistent erythema, and
recruitment of inflammatory cells to the site of
inflammation. How this neurovascular dysregulation
is related to the innate and adaptive immune system,
Steinhoff, Schauber, and Leyden S21
however, still needs to be explored. The fact that
very early rosacea is clinically presented as transient
flushing indicates at least the involvement if not a
central role of the neurovascular system in the
initiation phase of rosacea.
Epidermal proteases and their inhibitors play
key roles in normal skin homeostasis.50 The
proteases matriptase and caspase-14 are key
enzymes for filaggrin processing (significant role
for intact skin barrier functions) and the proteases
KLK5 and KLK7 maintain physiological desquama-
tion processes.16 In rosacea, increased levels of
KLK5 are found as a consequence of increased
TLR2 and its activation.16 Increased KLK-mediated
processing of cathelicidin peptides may lead to
increased levels of peptides and fragments thereof,
S22 Steinhoff, Schauber, and Leyden
which can induce vasodilatation and promote
leukocyte chemotaxis. Furthermore, increased
amounts of serine proteases may result in activation
of TRP via up-regulation and/or activation of
protease-activated receptors.17 In addition, in-
creased serine protease activity in rosacea could
also be caused by impaired inhibition.16 In general,
proteases can induce vasodilation, inflammation,
pain, or itch, and control immune function. Thus,
future studies will have to dissect which pathophys-
iological mechanisms of proteases in rosacea derive
from a direct effect on nerves, vessels, and immune
cells, and which derive from the interaction with
TLRs, AMPs, or TRP, respectively.
Neurovascular changes in rosacea
Neurovascular dysfunction (Fig 4) is yet another
aspect of the neural interactions and cutaneous
vascular alterations that are thought to have a key
role in rosacea pathophysiology, and is activated by
trigger factors.10 Here, we have to differentiate
between different critical roles of the blood and
lymphatic vessel system. The increased vasculature
response and persistent facial erythema in rosacea is
of particular interest because of the increasing
evidence that blood vessels and possibly lymphatic
vessels have significant roles in the control of acute
and chronic inflammatory disorders.67 In inflamed
skin, vessels remodel or change their phenotype
and become hyperpermeable, enlarged networks
with increased blood flow and facilitate influx of
inflammatory cells from chronic inflammation sites.
Activated blood vessel endothelial cells express
a large variety of different receptors, adhesion
molecules, and cytokines, and they enable leukocyte
attachment for migration into the skin to the major
sites of inflammation.
In rosacea, activation of precapillary arterioles
results in vasodilation (flushing, erythema), whereas
activation of postcapillary venules leads to protein
leakage (edema) and recruitment of leukocytes
through up-regulation of selectins and cell adhesion
molecules. In contrast, upon stimulation by growth
factors or external stimuli, blood vessels can grow in
numbers (angiogenesis). The role of angiogenesis in
rosacea is a matter of considerable debate; although
some groups argue that their data support a significant
role for angiogenesis in rosacea pathophysiology,68,69
more recent reports emphasize that the increase in
vascular tissue in patient samples primarily reflects
vasodilatation.10 For example, increased VEGF-A
levels as well as enhanced angiogenesis and/or
lymphangiogenesis have been reported in lesional
skin of rosacea.67,68 Others have found increased
size/volume of blood and lymphatic vessels while
J AM ACAD DERMATOL
DECEMBER 2013
Fig 4. Factors involved in skin vasoregulation and angi-
ogenesis in chronic inflammatory skin diseases. Adapted
with permission from Macmillan Publishers Ltd: J Investig
Dermatol Symp Proc,67 copyright 2011.
blood vessel angiogenesis was limited to PhR.10
Accordingly, lymphatic vessel expansion was
observed in all 3 rosacea subtypes, but no lymphan-
giogenesis. This is also supported by transcriptome
analysis demonstrating no or very limited
up-regulation of genes that are involved in angiogen-
esis.10 In contrast, various pathways involved in
vasodilation have been found to be significantly up-
regulated such as neuropeptides, tryptophan metab-
olites, lipids, or radical oxygen species2 (M. S. et al., in
preparation). The early involvement of lymphatic
vascular dilation even in subtypes with clinically
unrecognizable edema, and not only in clinically
relevant lymphedema as observed in Morbihahn
disease70, is intriguing. Until today, no convincing
pathophysiology seems to be capable of explaining
these lymphatic vessel changes in rosacea. Further
research in this area is highly warranted, because
many patients with rosacea significantly experience
the disfigurement induced by the lymphedema.
Schwab et al10 also revealed an enhanced
co-localization of mast cells with unmyelinated
sensory nerves, blood vessels, and myofibroblasts
already present in early rosacea. As found in other
skin diseases, a functional link between mast cells
with nerves and blood vessels can also be anticipated
in all skin rosacea subtypes.10,71 The increased
presence of mast cells alone despite the unrespon-
siveness of patients with rosacea to antihistamines
suggests the involvement of other mast cell
mediators in rosacea including lipid metabolites
J AM ACAD DERMATOL
VOLUME 69, NUMBER 6
or proteases, for example. Whether the classic
symptoms of early rosacea such as flushing and
pain sensations (pain, burning, stinging) occur as a
result of an inflammatory infiltrate, by activation of
skin resident cells, or as a result of a merely
neurovascular dysregulation by trigger factors is an
important question for future research in this field.
Whether mast cells are also involved in the
dysregulation of lymphatic vessels is unclear.
Because inhibition of blood vessel activation has
been shown to exert anti-inflammatory effects,67 and
vasoconstriction via activation of b2-adrenerigic
receptors (eg, brimonidine, oxymetazoline) of arte-
rial and arteriolar smooth-muscle cells results
in alleviation of flushing in rosacea, a beneficial
therapeutic effect by controlling vasodilation and
vessel activation can be anticipated.72 Whether these
drugs also have an intrinsic anti-inflammatory capacity
is currently unclear.
Together, both vasodilation of blood vessels and
lymphatic vessels as well as activation of vasoregu-
latory mediators and receptors play a significant role
in ETR, PPR, and PhR. Whether the trigger factors
directly control the dysregulation of the vessels or
indirectly stimulate vasodilation via activation of
sensory and/or autonomic nerves, immune cells, or
resident skin cells still needs to be explored.10
New molecular pathways in rosacea
Recent transcriptome analysis combined with
immunohistochemistry and morphometric analysis
of the cellular infiltrate and activated skin cells
revealed the induction of several so-far neglected
or underrecognized pathways in the pathophysiol-
ogy of rosacea. In a condensed form, these studies
showed that several cytokines and chemokines are
involved that are important for the recruitment of
Th1 cells and macrophages or activation of mast
cells, keratinocytes, and myofibroblasts including
tumor necrosis factor-alfa, interferon gamma, IL-26,
and various chemokines and chemokine receptors5
(M. S., manuscript in preparation). Further gene
analysis of classic neuromediators and receptors
revealed that several neuropeptides, vasoactive
amines, or TRPs involved in vasoregulation and
pain can also be expressed by resident skin cells
and/or immune cells. For example, PACAP is
increased in all subtypes of rosacea up to more
than 20-fold, can be released by activated endothe-
lial cells, degranulates mast cells, and is one of the
most potent vasodilators in human beings.66 Other
neuroreceptors up-regulated are the serotonin
receptor HTR3A, histamine receptors H2R or H3R, or
the receptor for adrenomedullin. Of note, the NK1
receptor was not found to be up-regulated,9 and the
Steinhoff, Schauber, and Leyden S23
expression levels of TRPV ion channels varied
extensively.56 The important inflammatory and neu-
rosensory mediator serotonin (5-hydroxytryptamine)
is released by mast cells, platelets, and others, and its
role has been investigated in several inflammatory
skin diseases.10,73,74 The precise role of the above-
mentioned mediators and receptors in the pathophys-
iology of all rosacea subtypes including ocular rosacea
still warrants further clarification.
Chronic UV radiation and rosacea
Although acute UV exposure is an undisputed
trigger factor for rosacea, it remains unclear how
much chronic photodamage contributes to the path-
ophysiology of the disease, especially because
photodamage is not a characteristic sign in patients
presenting with the early transient flushing type of
rosacea. Thus, although UV exposure is definitely a
trigger factor for the exacerbation of rosacea flush-
ing, and many patients during rosacea development
present with signs of chronic photodamage, it still
needs to be explored whether this characteristic is a
primary cause or secondary symptom in many
patients with rosacea.10,38,39 Rosacea and photo-
damage are more common in fair-skinned individ-
uals who have chronic facial erythema and may have
telangiectasias, and only prolonged or intense
flushing may identify affected persons from healthy
individuals in early disease stages.4 A recent clinical
study comprising 1000 Irish individuals who were
arranged in groups according to their different
lifetime UV exposure failed to establish a clinical
effect of chronic UV exposure to the prevalence of
PPR.75 However, from a histopathologic perspective,
besides the typical, angulated telangiectasias and
mild perivascular lymphocytic infiltrate in ETR, solar
elastosis is also a typical histologic finding even if not
clinically apparent.76 Furthermore, significantly ele-
vated levels of reactive oxygen species have been
observed in the skin samples of patients with
rosacea, which is mainly produced in the skin after
UV radiation.77,78 Because reactive oxygen species
is responsible for initiation of several proinflamma-
tory effects in the skin including expression of
the leukocyte-attracting chemokines CCL2 and
CXCL8,5,79 more research is needed for clarification
of an association of chronic UV damage with rosacea
pathophysiology.
Phymatous changes in rosacea
Late-stage PhR occurs more frequently in male
patients (despite a rosacea overall gender predilec-
tion for women) and is characterized by skin fibrosis
and phymatous changes. Thickened skin, particu-
larly on the nose (rhinophyma), can develop without
S24 Steinhoff, Schauber, and Leyden
obvious clinical signs of erythema or inflammatory
papules and pustules. However, as stated above,
recent transcriptome analyses combined with immu-
nohistochemistry indicate that clinically noninflam-
matory skin presents already with significant changes
of the lymphomonocytic infiltrate on the microscopic
level. In accordance with that, the majority of patients
report former symptoms of earlier-stage rosacea such
as flushing, erythema, papules, and pustules in their
history. From studies in other skin diseases and
animal models, it appears that several receptors for
cytokines, chemokines, growth factors, and/or pro-
teases are generally involved in a switch from an
inflammatory to a fibrotic disease stage.80 Various
mechanisms are discussed with some of them being
supported by experimental data, but definite clarifi-
cation of the crucial steps involved in triggering
fibrosis is still pending. In rosacea, activation of
fibroblasts seems to be characteristic, especially in
comparison with other inflammatory skin diseases,
and it already occurs in ETR and PPR.10 Interestingly,
the observed higher number of fibroblasts correlates
closely with the increased number of mast cells,
which are well known for their potentially fibrosis-
driving and fibroblast-modulating properties.81 The
striking up-regulation of tissue-destructing and
fibrosis-promoting matrix metalloproteinases (MMPs)
(especially MMP-9 and MMP-2) and serine proteases
in PPR and PhR may be the result of increased mast
cell numbers as well as keratinocyte and macrophage
activation, and thereby regulate fibroblast numbers
and activity.82,83 In addition, fibrogenic TGF-B iso-
forms TGF-B1 and TGF-B2 along with the TGF-B
receptor are overexpressed in PhR and may contrib-
ute to the development of rhinophyma by fibroblast
activation.84 Besides additional involvement of T cells
and macrophages, the view on keratinocytes has
changed over the recent years from rather inactive
bystanders to more and more actively involved cells in
inflammation and fibrosis by secretion of cytokines,
chemokines, growth-factors, MMPs, and serine pro-
teases.41,67 Future molecular and cellular characteri-
zation of fibroblast activation as well as secretion and
inhibition of MMP and serine protease release will be
needed to shed light on this vexing clinical problem.
CONCLUSIONS AND FUTURE DIRECTIONS
Despite impressive findings in recent studies on the
pathophysiologic principles in rosacea, much more
work needs to be done to understand the complex
dysregulated network of cells and mediators in this
frequent and complex disease. Current research
focusing on the underlying causes of rosacea points
toward a genetic predisposition and certain trigger
factors that help to establish the symptom of transient
J AM ACAD DERMATOL
DECEMBER 2013
flushing, the usual initial clinical manifestation of
rosacea. Induction of the innate immune system and
overstimulation of the sensory and/or autonomic
nervous system associated with vascular dysregulation
of arterioles, and later venules, may be the initial
pathologic processes behind the flushing and
ultimately result in chronic inflammation and fibrosis.
Future research needs to address the communica-
tion between the skin nervous system and innate
immune system (regarding activation and inhibi-
tion), the active and passive contribution of the
adaptive immune system to this disease, the regula-
tion of blood and lymph vessel dilatation and their
interaction with the skin nervous system as well as
their communication with immune cells, and the
control of fibroblast activation, as well as the con-
sequences of keratinocyte activation. Moreover,
transcriptome analysis provides evidence for a
significant up-regulation of genes involved in the
alcohol and lipid metabolism as well as sebaceous
gland regulation (M. S., unpublished observation).
Growing understanding of these pathophysiologic
principles behind this disease will enable us to
develop novel targets for a medical intervention
and eventually add new and improved treatments
to the actually rather limited armamentarium of
therapeutic options in rosacea.
REFERENCES
1. Wilkin J, Dahl M, Detmar M, Drake L, Feinstein A, Odom R,
et al. Standard classification of rosacea: report of the National
Rosacea Society expert committee on the classification and
staging of rosacea. J Am Acad Dermatol 2002;46:584-7.
2. Steinhoff M, Buddenkotte J, Aubert J, Sulk M, Novak P,
Schwab VD, et al. Clinical, cellular, and molecular aspects in
the pathophysiology of rosacea. J Investig Dermatol Symp
Proc 2011;15:2-11.
3. Wilkin J, Dahl M, Detmar M, Drake L, Liang MH, Odom R, et al.
Standard grading system for rosacea: report of the National
Rosacea Society expert committee on the classification and
staging of rosacea. J Am Acad Dermatol 2004;50:907-12.
4. Powell FC. Clinical practice: Rosacea. N Engl J Med 2005;352:
793-803.
5. Gerber PA, Buhren BA, Steinhoff M, Homey B. Rosacea: the
cytokine and chemokine network. J Investig Dermatol Symp
Proc 2011;15:40-7.
6. Lazaridou E, Giannopoulou C, Fotiadou C, Vakirlis E, Trigoni A,
Ioannides D. The potential role of microorganisms in
the development of rosacea. J Dtsch Dermatol Ges 2011;9:
21-5.
7. Cribier B. Pathophysiology of rosacea: redness, telangiec-
tasia, and rosacea. Ann Dermatol Venereol 2011;138(Suppl):
S184-91.
8. Cribier B. Physiopathology of rosacea: redness, telangiectasia,
and rosacea [in French]. Ann Dermatol Venereol 2011;
138(Suppl):S129-37.
9. Powell FC. The histopathology of rosacea: wheres the beef?.
Dermatology 2004;209:173-4.
10. Schwab VD, Sulk M, Seeliger S, Nowak P, Aubert J, Mess C,
et al. Neurovascular and neuroimmune aspects in the
J AM ACAD DERMATOL
VOLUME 69, NUMBER 6
pathophysiology of rosacea. J Investig Dermatol Symp Proc
2011;15:53-62.
11. Schauber J, Dorschner RA, Coda AB, Buchau AS, Liu PT, Kiken D,
et al. Injury enhances TLR2 function and antimicrobial peptide
expression through a vitamin D-dependent mechanism. J Clin
Invest 2007;117:803-11.
12. Abram K, Silm H, Maaroos HI, Oona M. Risk factors associated
with rosacea. J Eur Acad Dermatol Venereol 2010;24:565-71.
13. Chosidow O, Cribier B. Epidemiology of rosacea: updated
data [in French]. Ann Dermatol Venereol 2011;138(Suppl):
S124-8.
14. Steinhoff M, Bergstresser PR. Pathophysiology of rosacea:
introduction. J Investig Dermatol Symp Proc 2011;15:1.
15. Schauber J, Gallo RL. Expanding the roles of antimicrobial
peptides in skin: alarming and arming keratinocytes. J Invest
Dermatol 2007;127:510-2.
16. Yamasaki K, Di Nardo A, Bardan A, Murakami M, Ohtake T, Coda A,
et al. Increased serine protease activity and cathelicidin promotes
skin inflammation in rosacea. Nat Med 2007;13:975-80.
17. Steinhoff M, Buddenkotte J, Shpacovitch V, Rattenholl A,
Moormann C, Vergnolle N, et al. Proteinase-activated recep-
tors: transducers of proteinase-mediated signaling in inflam-
mation and immune response. Endocr Rev 2005;26:1-43.
18. Nestle FO, Di Meglio P, Qin JZ, Nickoloff BJ. Skin immune
sentinels in health and disease. Nat Rev Immunol 2009;9:
679-91.
19. Braff MH, Zaiou M, Fierer J, Nizet V, Gallo RL. Keratinocyte
production of cathelicidin provides direct activity against
bacterial skin pathogens. Infect Immun 2005;73:6771-81.
20. Murakami M, Ohtake T, Dorschner RA, Schittek B, Garbe C,
Gallo RL. Cathelicidin anti-microbial peptide expression in
sweat, an innate defense system for the skin. J Invest
Dermatol 2002;119:1090-5.
21. Dorschner RA, Pestonjamasp VK, Tamakuwala S, Ohtake T,
Rudisill J, Nizet V, et al. Cutaneous injury induces the release
of cathelicidin anti-microbial peptides active against group A
streptococcus. J Invest Dermatol 2001;117:91-7.
22. Antal AS, Dombrowski Y, Koglin S, Ruzicka T, Schauber J.
Impact of vitamin D3 on cutaneous immunity and anti-
microbial peptide expression. Dermatoendocrinol 2011;3:
18-22.
23. Peric M, Koglin S, Kim SM, Morizane S, Besch R, Prinz JC, et al.
IL-17A enhances vitamin D3-induced expression of cathelici-
din antimicrobial peptide in human keratinocytes. J Immunol
2008;181:8504-12.
24. Harder J, Bartels J, Christophers E, Schroder JM. Isolation
and characterization of human beta-defensin-3, a novel
human inducible peptide antibiotic. J Biol Chem 2001;276:
5707-13.
25. Wolk K, Witte E, Wallace E, Docke WD, Kunz S, Asadullah K,
et al. IL-22 regulates the expression of genes responsible for
antimicrobial defense, cellular differentiation, and mobility in
keratinocytes: a potential role in psoriasis. Eur J Immunol
2006;36:1309-23.
26. Yamasaki K, Schauber J, Coda A, Lin H, Dorschner RA,
Schechter NM, et al. Kallikrein-mediated proteolysis regulates
the antimicrobial effects of cathelicidins in skin. FASEB J
2006;20:2068-80.
27. Michaelson D, Rayner J, Couto M, Ganz T. Cationic defensins
arise from charge-neutralized propeptides: a mechanism for
avoiding leukocyte autocytotoxicity? J Leukoc Biol 1992;51:
634-9.
28. Cowland JB, Johnsen AH, Borregaard N. hCAP-18, a cathelin/
pro-bactenecin-like protein of human neutrophil specific
granules. FEBS Lett 1995;368:173-6.
Steinhoff, Schauber, and Leyden S25
29. Larrick JW, Hirata M, Zhong J, Wright SC. Anti-microbial
activity of human CAP18 peptides. Immunotechnology 1995;
1:65-72.
30. Gudmundsson GH, Agerberth B, Odeberg J, Bergman T, Olsson B,
Salcedo R. The human gene FALL39 and processing of the
cathelin precursor to the antibacterial peptide LL-37 in granulo-
cytes. Eur J Biochem 1996;238:325-32.
31. Braff MH, Gallo RL. Antimicrobial peptides: an essential
component of the skin defensive barrier. Curr Top Microbiol
Immunol 2006;306:91-110.
32. Zaiou M, Gallo RL. Cathelicidins, essential gene-encoded
mammalian antibiotics. J Mol Med (Berl) 2002;80:549-61.
33. Braff MH, Hawkins MA, Di Nardo A, Lopez-Garcia B, Howell MD,
Wong C, et al. Structure-function relationships among human
cathelicidin peptides: dissociation of antimicrobial properties
from host immunostimulatory activities. J Immunol 2005;174:
4271-8.
34. Zheng Y, Niyonsaba F, Ushio H, Nagaoka I, Ikeda S, Okumura
K, et al. Cathelicidin LL-37 induces the generation of reactive
oxygen species and release of human alpha-defensins from
neutrophils. Br J Dermatol 2007;157:1124-31.
35. Yu J, Mookherjee N, Wee K, Bowdish DM, Pistolic J, Li Y, et al.
Host defense peptide LL-37, in synergy with inflammatory
mediator IL-1beta, augments immune responses by multiple
pathways. J Immunol 2007;179:7684-91.
36. Koczulla R, von Degenfeld G, Kupatt C, Krotz F, Zahler S, Gloe
T, et al. An angiogenic role for the human peptide antibiotic
LL-37/hCAP-18. J Clin Invest 2003;111:1665-72.
37. Schauber J, Gallo RL. Antimicrobial peptides and the skin
immune defense system. J Allergy Clin Immunol 2008;122:261-6.
38. Yamasaki K, Gallo RL. Rosacea as a disease of cathelicidins
and skin innate immunity. J Investig Dermatol Symp Proc
2011;15:12-5.
39. Morizane S, Yamasaki K, Kabigting FD, Gallo RL. Kallikrein
expression and cathelicidin processing are independently
controlled in keratinocytes by calcium, vitamin D(3), and
retinoic acid. J Invest Dermatol 2010;130:1297-306.
40. Murakami M, Lopez-Garcia B, Braff M, Dorschner RA, Gallo RL.
Postsecretory processing generates multiple cathelicidins for
enhanced topical antimicrobial defense. J Immunol 2004;172:
3070-7.
41. Meyer-Hoffert U, Schroder JM. Epidermal proteases in the
pathogenesis of rosacea. J Investig Dermatol Symp Proc
2011;15:16-23.
42. Schauber J, Gallo RL. The vitamin D pathway: a new target for
control of the skins immune response? Exp Dermatol 2008;
17:633-9.
43. Peric M, Lehmann B, Vashina G, Dombrowski Y, Koglin S,
Meurer M, et al. UV-B-triggered induction of vitamin D3
metabolism differentially affects antimicrobial peptide expres-
sion in keratinocytes. J Allergy Clin Immunol 2010;125:746-9.
44. Park K, Elias PM, Oda Y, Mackenzie D, Mauro T, Holleran WM,
et al. Regulation of cathelicidin antimicrobial peptide expres-
sion by an endoplasmic reticulum (ER) stress signaling,
vitamin D receptor-independent pathway. J Biol Chem
2011;286:34121-30.
45. Yamasaki K, Kanada K, Macleod DT, Borkowski AW, Morizane
S, Nakatsuji T, et al. TLR2 expression is increased in rosacea
and stimulates enhanced serine protease production by
keratinocytes. J Invest Dermatol 2011;131:688-97.
46. Da Silva CA, Hartl D, Liu W, Lee CG, Elias JA. TLR-2 and IL-17A
in chitin-induced macrophage activation and acute inflam-
mation. J Immunol 2008;181:4279-86.
47. Georgala S, Katoulis AC, Kylafis GD, Koumantaki-Mathioudaki E,
Georgala C, Aroni K. Increased density of Demodex folliculorum
S26 Steinhoff, Schauber, and Leyden
and evidence of delayed hypersensitivity reaction in subjects
with papulopustular rosacea. J Eur Acad Dermatol Venereol
2001;15:441-4.
48. Koller B, Muller-Wiefel AS, Rupec R, Korting HC, Ruzicka T.
Chitin modulates innate immune responses of keratinocytes.
PLoS One 2011;6:e16594.
49. Lacey N, Delaney S, Kavanagh K, Powell FC. Mite-related
bacterial antigens stimulate inflammatory cells in rosacea. Br
J Dermatol 2007;157:474-81.
50. Brain SD, Williams TJ. Inflammatory edema induced by
synergism between calcitonin gene-related peptide (CGRP)
and mediators of increased vascular permeability. Br J
Pharmacol 1985;86:855-60.
51. Peric M, Koglin S, Dombrowski Y, Gross K, Bradac E, Buchau A,
et al. Vitamin D analogs differentially control antimicrobial
peptide/alarmin expression in psoriasis. PLoS One 2009;4: 71.
e6340.
52. Liu PT, Krutzik SR, Kim J, Modlin RL. Cutting edge: all-trans
retinoic acid down-regulates TLR2 expression and function.
J Immunol 2005;174:2467-70.
53. van Zuuren EJ, Gupta AK, Gover MD, Graber M, Hollis S.
Systematic review of rosacea treatments. J Am Acad Derma-
tol 2007;56:107-15.
54. Del Rosso JQ, Webster GF, Jackson M, Rendon M, Rich P,
Torok H, et al. Two randomized phase III clinical trials
evaluating anti-inflammatory dose doxycycline (40-mg dox-
ycycline, USP capsules) administered once daily for treatment
of rosacea. J Am Acad Dermatol 2007;56:791-802.
55. Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J,
et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct
inducer of antimicrobial peptide gene expression. J Immunol
2004;173:2909-12.
56. Sulk M, Seeliger S, Aubert J, Schwab VD, Cevikbas F, Rivier M,
et al. Distribution and expression of non-neuronal transient
receptor potential (TRPV) ion channels in rosacea. J Invest
Dermatol 2012;132:1253-62.
57. Tore F, Tuncel N. Mast cells: target and source of neuropep-
tides. Curr Pharm Des 2009;15:3433-45.
58. Foreman JC, Jordan CC, Oehme P, Renner H. Structure-activ-
ity relationships for some substance P-related peptides that
cause wheal and flare reactions in human skin. J Physiol 1983;
335:449-65.
59. Siebenhaar F, Magerl M, Peters EM, Hendrix S, Metz M,
Maurer M. Mast cell-driven skin inflammation is impaired in
the absence of sensory nerves. J Allergy Clin Immunol 2008;
121:955-61.
60. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine
JD, Julius D. The capsaicin receptor: a heat-activated ion
channel in the pain pathway. Nature 1997;389:816-24.
61. Aubdool AA, Brain SD. Neurovascular aspects of skin neurogenic
inflammation. J Investig Dermatol Symp Proc 2011;15:33-9.
62. Roosterman D, Goerge T, Schneider SW, Bunnett NW,
Steinhoff M. Neuronal control of skin function: the skin as a
neuroimmunoendocrine organ. Physiol Rev 2006;86:1309-79.
63. Nilius B, Owsianik G, Voets T, Peters JA. Transient receptor
potential cation channels in disease. Physiol Rev 2007;87:165-217.
64. Guzman-Sanchez DA, Ishiuji Y, Patel T, Fountain J, Chan YH,
Yosipovitch G. Enhanced skin blood flow and sensitivity to
noxious heat stimuli in papulopustular rosacea. J Am Acad
Dermatol 2007;57:800-5.
65. Greeno EW, Mantyh P, Vercellotti GM, Moldow CF. Functional
neurokinin 1 receptors for substance P are expressed by human
vascular endothelium. J Exp Med 1993;177:1269-76.
66. Seeliger S, Buddenkotte J, Schmidt-Choudhury A, Rosignoli C,
Shpacovitch V, von Arnim U, et al. Pituitary adenylate cyclase
J AM ACAD DERMATOL
DECEMBER 2013
activating polypeptide: an important vascular regulator in
human skin in vivo. Am J Pathol 2010;177:2563-75.
67. Huggenberger R, Detmar M. The cutaneous vascular system
in chronic skin inflammation. J Investig Dermatol Symp Proc
2011;15:24-32.
68. Gomaa AH, Yaar M, Eyada MM, Bhawan J. Lymphangio-
genesis and angiogenesis in non-phymatous rosacea. J Cutan
Pathol 2007;34:748-53.
69. Simpson LO. Treatment of hypertension. N Z Med J 1992;105:
90-1.
70. Wohlrab J, Lueftl M, Marsch WC. Persistent erythema and
edema of the midthird and upper aspect of the face (morbus
morbihan): evidence of hidden immunologic contact urti-
caria and impaired lymphatic drainage. J Am Acad Dermatol
2005;52:595-602.
Steinhoff M, Stander S, Seeliger S, Ansel JC, Schmelz M, Luger
T. Modern aspects of cutaneous neurogenic inflammation.
Arch Dermatol 2003;139:1479-88.
72. Fowler J, Jarratt M, Moore A, Meadows K, Pollack A, Steinhoff M,
et al. Once-daily topical brimonidine tartrate gel 0.5% is a novel
treatment for moderate to severe facial erythema of rosacea:
results of two multicenter, randomized and vehicle-controlled
studies. Br J Dermatol 2012;166:633-41.
73. Nordlind K, Thorslund K, Lonne-Rahm S, Mohabbati S, Berki T,
Morales M, et al. Expression of serotonergic receptors in
psoriatic skin. Arch Dermatol Res 2006;298:99-106.
74. Oliveira MC, Pelegrini-da-Silva A, Parada CA, Tambeli CH.
5-HT acts on nociceptive primary afferents through an
indirect mechanism to induce hyperalgesia in the subcuta-
neous tissue. Neuroscience 2007;145:708-14.
75. McAleer MA, Fitzpatrick P, Powell FC. Papulopustular rosacea:
prevalence and relationship to photodamage. J Am Acad
Dermatol 2010;63:33-9.
76. Cribier B. Rosacea under the microscope: characteristic
histological findings. J Eur Acad Dermatol Venereol doi:
10.1111/jdv.12121. Published online March 4, 2013.
77. Bakar O, Demircay Z, Yuksel M, Haklar G, Sanisoglu Y. The
effect of azithromycin on reactive oxygen species in rosacea.
Clin Exp Dermatol 2007;32:197-200.
78. Jones D. Reactive oxygen species and rosacea. Cutis 2004;74:
17-20, 32-4.
79. Lee HM, Shin DM, Kim KK, Lee JS, Paik TH, Jo EK. Roles of
reactive oxygen species in CXCL8 and CCL2 expression in
response to the 30-kDa antigen of Mycobacterium tuberculo-
sis. J Clin Immunol 2009;29:46-56.
80. Meyer M, Muller AK, Yang J, Sulcova J, Werner S. The role of
chronic inflammation in cutaneous fibrosis: fibroblast growth
factor receptor deficiency in keratinocytes as an example.
J Investig Dermatol Symp Proc 2011;15:48-52.
81. Hermes B, Welker P, Feldmann-Boddeker I, Kruger-Krasagakis
S, Hartmann K, Zuberbier T, et al. Expression of mast cell
growth modulating and chemotactic factors and their re-
ceptors in human cutaneous scars. J Invest Dermatol 2001;
116:387-93.
82. Maatta M, Kari O, Tervahartiala T, Peltonen S, Kari M, Saari M,
et al. Tear fluid levels of MMP-8 are elevated in ocular
rosaceaetreatment effect of oral doxycycline. Graefes Arch
Clin Exp Ophthalmol 2006;244:957-62.
83. Amalinei C, Caruntu ID, Giusca SE, Balan RA. Matrix metal-
loproteinases involvement in pathologic conditions. Rom J
Morphol Embryol 2010;51:215-28.
84. Pu LL, Smith PD, Payne WG, Kuhn MA, Wang X, Ko F, et al.
Overexpression of transforming growth factor beta-2 and its
receptor in rhinophyma: an alternative mechanism of path-
obiology. Ann Plast Surg 2000;45:515-9.