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

Inflammatory Mechanisms and the Pathophysiology of Rosacea

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

Innate Immune Response in Normal Skin

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

Innate Immune Response in Rosacea-Prone Facial Skin

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