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Endoplasmic reticulum stress: key promoter of rosacea pathogenesis.

Exp Dermatol. 2014 Jul 21;

Authors: Melnik BC

Abstract
Recent scientific interest in the pathogenesis of rosacea focuses on abnormally high facial skin levels of cathelicidin and the trypsin-like serine protease kallikrein 5 (KLK5) that cleaves the cathelicidin precursor protein into the bioactive fragment LL-37, which exerts crucial proinflammatory, angiogenic and antimicrobial activities. Furthermore, increased expression of Toll-like receptor-2 (TLR2) has been identified in rosacea skin supporting the participation of the innate immune system. Notably, TLRs are expressed on sensory neurons and increase neuronal excitability linking TLR signaling to the transmission of neuroinflammatory responses. It is the intention of this viewpoint to present a unifying concept that links all known clinical trigger factors of rosacea such as UV-irradiation, heat, skin irritants, and special foods to one converging point: enhanced endoplasmic reticulum (ER)-stress that activates the unfolded protein response (UPR). ER-stress via upregulation of transcription factor ATF4 increases TLR2 expression resulting in enhanced production of cathelicidin and KLK5 mediating downstream proinflammatory, angiogenic and antimicrobial signaling. The presented concept identifies rosacea trigger factors as environmental stressors that enhance the skin's ER-stress response. Exaggerated cutaneous ER-stress that stimulates the TLR2-driven inflammatory response may involve sebocytes, keratinocytes, monocyte-macrophages and sensory cutaneous neurons. Finally, all anti-rosacea drugs are proposed to attenuate the ER-stress signaling cascade at some point. Over-stimulated ER-stress signaling may have evolutionarily evolved as a compensatory mechanism to balance impaired vitamin D-driven LL-37-mediated antimicrobial defenses due to lower exposure of UV-B irradiation of the Northern Celtic population. This article is protected by copyright. All rights reserved.

PMID: 25047092 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/pubmed/25047092?dopt=Abstract = URL to article

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