skin is hyper-responsive leading to the signaling of inflammatory
pathways that correlate with commonly observed clinical
manifestations of rosacea.8,18,22-24 Findings noted in cutaneous
rosacea that correlate pathophysiologically with clinical
manifestations of rosacea include an increased expression of
TLR-2 (a recognition receptor), an increase in the precursor of
cathelicidin (hCap18), and an increase in the SC serine protease
enzyme KLK-5.8,18,22-24 In rosacea-prone skin, keratinocytes
with higher levels of TLR-2 promote an increase in KLK-5 activity.
18,22,24 As a result, the larger quantity of cathelicidin coupled
with the enhanced enzymatic activity of KLK-5 activates the
conversion of cathelicidin to multiple variant peptides. These
peptides promote the signaling of inflammatory cascades and
vascular responses that can lead to chemoattraction of inflammatory
cells, vasodilation with perivascular edema, and
downstream signaling which can promote alterations in vasculature
(ie, increase in vascular endothelial growth factor
[VGEF]).18,22,24,26,27 The marked inflammatory infiltrate shown to
be present in all three major subtypes of rosacea (ie, ETR, PPR,
phymatous) is diffuse, predominantly perivascular, and heavily
composed of Th1 cells and macrophages, even in the absence
of inflammatory lesions, further suggesting that an augmented
innate immune response plays a very active and early role in
rosacea.8 In cases where inflammatory lesions (ie, papules,
pustules) are present, both LL-37 and interleukin-8 (IL-8) are believed
to be operative in the chemoattraction of neutrophils.8,26
Importantly, unique to rosacea-prone skin as compared to normal
skin (based on studies of subjects with PPR) is the production
of varient cathelicidin-derived peptides in addition to LL-37. These
variant forms exhibit greater ability to precipitate inflammation
and induce changes in cutaneous vasculature as compared to
the shorter forms of LL-37 produced in normal skin.18,22
Ultimately, the collective biologic effects of the abnormal innate immune
response associated with rosacea correlate with both specific
pathophysiological responses and visible changes noted on clinical
examination. The pathophysiological responses include diffuse dermal
inflammatory cell infiltration, chemoattraction of neutrophils
in some cases, vasodilation with perivascular inflammation and
increased cutaneous blood flow, and structural changes in vasculature
including promotion of neovascularization.8,18-20,22-28 The visible
cutaneous manifestations include erythema, variable amounts of
edema, telangiectasias, and in some cases inflammatory lesions.
Potential Triggers and Innate Immune Response in Rosacea
Current evidence supports that a microbial source (ie, bacterium,
Demodex mites) is not a mandatory component of the pathogenesis
of rosacea, including both ETR and PPR.1,3,8,10,18,19,22,30
Thorough review of several published references coupled with
the most recent basic science and clinic research supports the
predominant pathogenic roles of abnormal innate immune
response and neurovascular dysregulation/neurogenic inflammation,
both early and later in the emergence and development
of cutaneous rosacea.8,18,19,23,24,36,37
With regard to the role of microbial organisms in the pathogenesis
of rosacea, especially patients presenting clinically as PPR,
it is currently believed that proliferation of organisms such as
Demodex folliculorum may serve as a pro-inflammatory trigger
that in selected cases interacts with the heightened innate
immune response of rosacea-prone skin.1,36 In other cases, the
trigger that incites the immunologic response in rosacea-prone
skin may prove to be exposure to ultraviolet light or increased
ambient heat, without any involvement of a microbial trigger.
8,37,38 However, as noted above, a microbe such as a bacterium
or mite is not believed to be a mandatory component of the
pathogenesis of rosacea but may in some cases be involved with
inciting a flare by triggering innate immunologic response which
is both dysregulated and augmented in cutaneous rosacea.
Correlation of Other Potential Pathophysiologic Factors and Innate Immune Response in Rosacea
With regard to the pathophysiologal mechanisms involved in rosacea,
several potential pathways have been reported that can
"cross talk" with and modulate innate immune response. These
include increases in several matrix metalloproteinase enzymes
(MMPs), which are most pronounced in PPR and phymatous rosacea;
upregulated epidermal and dermal expression of several
MMPs by reactive oxygen species (ROS); signaling of activation
of SC serine proteases (ie, KLK-5) by some MMPs; participation
of MMPs and cathelicidin-derived peptide (ie, LL-37) in modulating
dermal matrix degradation; increased magnitude of
depletion of cutaneous antioxidant reserve in rosacea as compared
to normal skin; and the direct correlation of cutaneous
antioxidant depletion with rosacea severity.8,9,18,21,22,29,37,39
Another pathophysiological connection with innate immune
response relates to status and function of the SC permeability
barrier in rosacea. An increase in transepidermal water loss
(TEWL) has been documented in central facial skin of patients
