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
]. 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
]. 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.
Normally, the innate immune system of the skin is programmed to detect microbes, tissue damage such as UV-induced apoptosis, or damage of the extracellular matrix [13
]. As described above, sun exposure, dermal matrix changes and microbes have been shown to be triggers of rosacea. Our preliminary data showed that TLR2 expression is altered in rosacea skin, which enhances skin susceptiblity to innate immune stimuli and leads to increased cathelicidin and kallikrein production [15
]. Interestingly, TLR2 involvement in other disorders is also suggested by the clinical findings in glucocorticoid inducing rosacea-like dermatitis, so-called perioral dermatitis [16
]. Although the precise molecular mechanisms of the steroid-induced dermatitis is not determined, Shibata et al recently reported that glucocorticoid increases TLR2 expression in epidermal keratinocytes, and that P. acnes
enhanced glucocorticoid-dependent TLR2 induction [20
]. Thus, our new findings and accumulated knowledge on rosacea suggest the innate immune response in rosacea has gone awry. For a variety of reasons these patients are more susceptible to stimuli that do not cause inflammatory reactions in normal patients. Innate immunity is triggered by the events previously associated with worsening of the disease.