Why Is Rosacea Considered to Be an Inflammatory Disorder?
The Primary Role, Clinical Relevance, and Therapeutic Correlations of Abnormal Innate Immune Response in Rosacea-Prone Skin
June 2012 | Volume 11 | Issue 6 | Original Article | 694 | Copyright © June 2012
Overall, the threshold for inducing symptoms of skin sensitivity
tends to be lower in patients with ETR as compared to those with
PPR.1-3,8-11 However, both clinical experience and controlled clinical
studies have shown that many patients with PPR exhibit the same
symptoms and signs that are characteristic of sensitive skin and
are commonly associated with rosacea-prone skin.12-16
Much has been studied and written about the pathophysiological
mechanisms of rosacea. However, it has been difficult to uncover
all the relevant pieces of the puzzle or to accurately connect the
comment elements of cogent evidence.1-3,8-11,17-22
Although more research is needed to further define the pathogenesis
of rosacea, the most recent body of scientific data provides
strong support that patients with the common presenting manifestations
of rosacea innately exhibit rosacea-prone skin. Based
on a collection of studies and analyses, a predominant and fundamental
property of rosacea-prone skin is an abnormal innate
immune detection and response system. A hyper-responsive innate
immune system has been reported to be operative early in
the pathogenesis of rosacea, and in the three common cutaneous
subtypes of rosacea (ie, ETR, PPR, phymatous).8,18,19,22-24 As a result,
certain triggers can incite an exaggerated immune response that
is facilitated by the inherent properties of facial skin in the rosacea-
prone individual. In such patients, this facilitated triggering
of the innate immune response system induces the signaling of
cascades of inflammation that influence patterns of inflammation
and alter vascular biology.8,18,19,22,24,25-28 The clinical consequences
of this inflammatory process includes acute changes associated
with rosacea flares (ie, vasodilation with increased blood flow,
central facial erythema, and possibly inflammatory lesions) as
well as some responses that correlate with chronic changes of rosacea
(chronic vascular and perivascular inflammation, enlarged
cutaneous vasculature, persistent diffuse erythema, telangiectasias).
1-3,5,8-11,14,17-20,25-28 Importantly, vasodilation is recognized as a
central pathophysiologic finding in rosacea, with enlarged caliber
and dilation of cutaneous vasculature noted as compared to normal
facial skin and in the facial skin of patients with seborrheic
dermatitis, another very common inflammatory dermatosis associated
with erythema.1,2,8,18,20,25
Other published research findings support neurovascular dysregulation
and other neural-related physiochemical and structural
changes noted within rosacea-prone skin. These include colocalization
patterns of some sensory nerves and vessels; increased
density of certain neuroregulatory/vasoregulatory receptors in
ETR as compared to normal skin; increased expression of specific
vasoregulatory receptor-positive nerve fibers in skin from biopsies
of patients with rosacea; potential for activation by protease
enzymes of transient receptor potential (TRP) channels involved in
pain-temperature sensation and inflammation; and upregulation
of some neuropeptides that are likely to be operative in neurovascular
response and neurogenic inflammation in rosacea.1,8,9,11,20,29
Current evidence supports neurovascular dysregulation and
altered immune response as integral components of vasodilatory
reactivity and "neurogenic" symptoms such as stinging and
burning.8,9,11,18,29 Upregulation of several matrix metalloproteinase
enzymes (MMPs), such as collagenases, gelatinase, and elastase,
has also been noted in facial skin of rosacea patients and has been
correlated with dermal matrix degradation, vascular effects, and
activation of SC serine protease enzymes involved in innate immune
and inflammatory pathways in rosacea.1,8,30
Physiochemical characteristics have been identified in facial skin
of patients affected by PPR as compared to normal skin. It is important
to note that the recognition receptor system (ie, Toll-like
receptors [TLRs]), antimicrobial peptides (AMPs), and SC serine
protease enzymes function in normal skin primarily as the first line
of defense (innate immune response) against invasion by pathogens,
however, this innate immune response system has been
shown to be abnormal in facial skin affected by rosacea.18,19,22-24
How does innate immune response function in normal skin? In
normal skin, TLRs (such as TLR-2) serve to detect the proliferation
of microbes (ie, bacterial, fungal, viral), which are perceived as a
threat to invade and cause infection.18,19,31 The triggering of specific
TLRs activates an immediate host response to combat microbial
proliferation and invasion. Antimicrobial peptides (AMPs) such
as cathelicidin are a major component of this innate defense.
Cathelicidin exists as an inactive precursor form within the SC
of the epidermis.18,19,22 Upon activation by a triggering agent (ie,
bacteria, virus), conversion and degradation of cathelicidin by
a SC serine protease enzyme called kallikrein-5 (KLK-5) results
in the formation of pro-inflammatory peptides.18,22,32-35 The major
cathelicidin-derived peptide in skin is LL-37 which exhibits antimicrobial
properties and promotes vasodilation, angiogenesis,
and inflammation locally at the affected cutaneous site.18,22-24,26-
28 Without the innate immune system, microbial organisms that
find the opportunity to proliferate and invade compromised skin
would remain unchecked as the acquired immunity system takes
days to elicit and mount a directed antimicrobial immunologic
response. Importantly, the innate immune response system is
capable of being activated by certain ligands that have the capacity
to bind to specific TLRs, although these ligands are not
microbial in origin.31 Examples include ligands produced by
physical injury or damage from ultraviolet light, and exogenously
applied imiquimod, which binds to TLR-7.31
In patients with cutaneous rosacea, the innate immunity system
is abnormal leading to dysregulation of immune detection
and response. A large body of research has demonstrated
that the overall innate immune system in rosacea-prone facial