TLR2 Expression Is Increased in Rosacea and Stimulates Enhanced Serine Protease Production by Keratinocytes

Abstract

A diverse environment challenges skin to maintain temperature, hydration, and electrolyte balance while also maintaining normal immunological function. Rosacea is a common skin disease that manifests unique inflammatory responses to normal environmental stimuli. We hypothesized that abnormal function of innate immune pattern recognition could explain the enhanced sensitivity of patients with rosacea, and observed that the epidermis of patients with rosacea expressed higher amounts of Toll-like receptor 2 (TLR2) than normal patients. Increased expression of TLR2 was not seen in other inflammatory skin disorders such as atopic dermatitis or psoriasis. Overexpression of TLR2 on keratinocytes, treatment with TLR2 ligands, and analysis of TLR2-deficient mice resulted in a calcium-dependent release of kallikrein 5 from keratinocytes, a critical protease involved in the pathogenesis of rosacea. These observations show that abnormal TLR2 function may explain enhanced inflammatory responses to environmental stimuli and can act as a critical element in the pathogenesis of rosacea.

Blushing in rosacea sufferers

“…Yamasaki and Gallo [25] proposed recently that the innate immune system triggers an abnormal inflammatory reaction that mediates the symptoms of rosacea [26,27]. If so, erythema may be due to chronic inflammation.…”

Ocular rosacea: a review

“…Doxycycline, used in the treatment of cutaneous and ocular rosacea, decreases both MMP-8 and MMP-9 activity (21,22) . Tumor necrosis factor (TNF-alfa) was also elevated in rosacea (23) . Significant overexpression of ICAM-1 (intercellular adhesion molecule 1) and HLA-DR, inflammatory markers, was observed in conjunctival epithelial cells of patients with rosacea (24) .…”

“…Microbial organisms such as Helicobacter pylori, Demodex folliculorum, Demodex brevis and Staphylococcus epidermidis have been appointed as other possible causative factors in exacerbation of the disease; however this remains a controversy (23,26,31,(38)(39)(40)(41)(42)(43) . The prevalence of H. pylori infection was found higher in patients with rosacea when compared to the general population, and its eradication has been shown to influence the clinical outcome of this disease (31,39,(44)(45)(46) .…”

“…To further test their hypothesis, researchers injected abnormal cathelicidin or protease that produce these peptides in the skin of mice and observed similar inflammatory features of the disease found in humans (27) . Observation of higher amounts of receptors of the recognition system, Toll-like receptor 2 (TLR2), in the epidermis of patients with rosacea explained the overreaction of these patients to environmental stimuli, since enhanced action of TLR2 in keratinocytes leads to an increase in serine protease KLK5 and cathelicidin production (23,25) . Interestingly, tetracyclines, which improve signs and symptoms of rosacea, are known to inhibit expression and activity of several matrix metalloproteinases (21) , as well as a class of proteases that activate cathelicidin, sustaining this theory (26,27) .…”

“…Recently, studies have shown that disease exacerbation is stimulated by normal external environmental factors, leading to unique activation of pro-inflammatory systems as well as innate immune responses (23,25,26) . Molecular studies propose that the enhanced sensitivity of patients with rosacea may be caused by abnormal recognition of common environmental stimuli.…”