Most individuals affected by rosacea are of northern European origin and up to 1/3 have a family history of the disorder [1]. The disease affects mostly facial skin and is characterized by flushing, nontransient erythema, papules, pustules, inflammatory nodules and telangiectasia. Secondary features that often occur include burning and stinging of the face, occasional dermatitis or scaling of the face, and edema. In many sufferers, rosacea can be worsened or triggered by factors that initiate flushing, such as exercise, emotion, menopause and alcohol [2]. In 2002, the National Rosacea Society Expert Committee created a standard classification system for rosacea [3] and grading system in 2004 [4]. The purpose of the committee is to develop a standard system that can serve as an instrument to investigate the manifestation of rosacea for both clinician and researchers.

We have proposed the hypothesis that a dysregulation of the innate immune system in patients with rosacea could unify current clinical observations. In innate immunity, the pattern recognition system, which includes the TLR (toll-like receptor) and NLR (nucleotide-binding domain and leucine-rich repeat-containing) families, respond to environmental stimuli such as UV, microbes, physical and chemical trauma. Triggering the innate immune system normally leads to a controlled increase in cytokines and antimicrobial molecules in the skin [5, 6]. One of these antimicrobial molecules is a peptide known as cathelicidin [7]. Some forms of cathelicidin peptides were known to have a unique capacity to be both vasoactive and proinflammatory. Therefore, given the potential for a single molecule to affect both of the events that describe rosacea, we began an analysis of cathelicidin in rosacea. Individuals with rosacea expressed abnormally high levels of cathelicidin [8]. Importantly, the cathelicidin peptide forms found in rosacea were not only more abundant but were different from those in normal individuals. These forms of cathelicidin peptides promote and regulate leukocyte chemotaxis [9], angiogenesis [10], and expression of extracellular matrix components [11]. The presence of the vasoactive and inflammatory cathelicidin peptides in rosacea was subsequently explained by abnormal production of local protease kallikrein 5 (KLK5), which controls the production of cathelicidin peptides in epidermis [8, 12]. To confirm the importance of these observations and test the hypothesis that abnormal cathelicidin could induce the signs of rosacea, we injected these peptides or the enzymes that produce cathelicidin into the skin of mice. This rapidly resulted in skin inflammation resembling pathological changes in rosacea, therefore confirming our hypothesis [8]. Combined, these findings indicated that an exacerbated innate immune response induces abnormal cathelicidin, and that this then leads to the clinical findings.

Much of the previous work on the pathophysiology of rosacea has focused on attempts to make sense of associations between triggers of the disease and its clinical manifestations. Most patients report flushing episodes, thus leading to a common hypothesis that vascular hyperreactivity and increased blood play a role in the susceptibility to this disease. A few studies have demonstrated a measurable increase in blood flow in skin lesions of patients with rosacea [21, 22]. Some factors that trigger flushing such as emotional stress, spicy food, hot beverages, high environmental temperatures and menopause worsen rosacea [23], thus supporting this hypothesis. Resolution of erythema and flushing by topical α1-adrenergic receptor agonist application also supports the hypothesis that vascular hyperreactivity is major factor of rosacea pathology [24].

ROS involvement in rosacea pathology has been discussed as explanation for the action of medicines for rosacea treatment. Inhibition of ROS generation in neutrophils by tetracyclins [30], azelaic acid [31], metronidazole [32], and retinoids [33], which are used for rosacea treatment, provokes the hypothesis of ROS involvement in rosacea pathology. Erythromycin and azithromycin, the other effective medicine for rosacea treatment, have been shown to have antioxidant effects [34, 35]. ROS levels were examined in skin biopsy samples from rosacea and healthy individuals, and confirmed higher ROS activity in rosacea lesional skin than healthy controls [36, 37]. The decrease of ROS in rosacea skin was also observed after azithromycin treatment [36], suggesting rosacea treatments affect ROS activity and supporting the hypothesis of ROS involvement in rosacea pathology. Although the precise localization of ROS activities is not determined in rosacea skin, the source of ROS would be infiltrated leukocytes and epidermal keratinocytes.

UV and sun exposure are known to cause a flushing response and appears to worsen the clinical symptoms of rosacea [23]. Mechanistically, in mice, UV-B induces cutaneous angiogenesis that is histologically similar to the telangiectasia seen in rosacea histopathology [43]. In skin, epidermal keratinocytes are a major source of angiogenic factor VEGF (vascular endothelial growth factor) and FGF2 (fibroblast growth factor 2, also know as basic FGF) [29, 44]. UV-B increases VEGF and FGF2 secretion from human keratinocytes and expression in mouse epidermis [26, 43, 45]. As discussed previously, UV irradiation also produces ROS, which cause vascular and dermal matrix damage via upregulation of matrix metalloproteinases [46-48]. The abnormal and damaged dermal matrix may permit leakage and accumulation of inflammatory mediators and prolonged retention of inflammatory cells, factors which could lead to inflammation in the disease. Thus UV irradiation could induce erythema in the skin by increasing expression of angiogenic factors and by degenerating extracellular matrix.

Although proteases involvements have not been discussed well in rosacea pathology, protease actions would be responsible for a part of rosacea histology. We identified serine protease kallikrein 5 (KLK5, also know as stratum corneum tryptic enzyme SCTE) as the processing enzyme of cathelicidin and found high KLK5 expression in rosacea skin [8, 12]. KLK5 expresses in upper epidermis (granular to cornfield cell layer) in normal skin, and rosacea skin expresses KLK5 in the entire epidermis. KLK5 digest corneodesmosome proteins desmocollin 1 and desmoglein 1 in epidermis, and suppose to affect desquamation of epidermal keratinocytes [50, 51]. KLK5 also efficiently digest the extracellular matrix components, collagens type I, II, III, and IV, fibronectin, and laminin [52]. Considering the high KLK5 expression in basal cells of rosacea epidermis, KLK5 could play a part of skin inflammatory reactions in rosacea by affecting dermal matrix and vascular remodeling.

Two microbes have been discussed in rosacea pathology: Demodex folliculorum and Helicobacter pylori. D. folliculorum, a mite that lives within sebaceous follicles, has been implicated as a trigger of rosacea since histological studies revealed inflammation of the pilosebaceous follicle units. Studies have shown increased density of the mites in patients with rosacea compared with control patients [57-59]. Lacey et al isolated Bacillus oleronius from D. folliculorum and identified the antigens reacting to sera from rosacea individuals but not from control individuals [60]. The extracts of the B. oleronius stimulate proliferation of mononuclear cells from patients with rosacea suggesting that rosacea individuals are exposed to the B. oleronius molecules and that B. oleronius from D. folliculorum induces inflammatory in rosacea. Interestingly, they identified heat shock proteins (HSP) and a lipoprotein in the antigenic molecules of B. oleronius. HSP and lipoproteins from microbes are also known to be stimulant for TLRs [61, 62]. This report supports the hypothesis of mite and pilosebaceaous unit involvement in rosacea. Further studies are required to examine if these B. oleronius molecules evokes innate immune reaction or if rosacea is caused by adaptive immune reaction against B. oleronius and D. folliculorum.