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

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