title: Endoplasmic reticulum stress: key promoter of rosacea pathogenesis.
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 signalling 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 signalling. 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 antirosacea drugs are proposed to attenuate the ER stress signalling cascade at some point. Overstimulated ER stress signalling 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.
authors.affiliation: Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Osnabrück, Germany.
authors.forename: Bodo C
authors.initials: BC
authors.lastname: Melnik
mesh_terms: D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D006967:Hypersensitivity / Q000209:etiology; D007113:Immunity, Innate; D042583:Lymphangiogenesis; D009389:Neovascularization, Pathologic; D012393:Rosacea / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D012627:Sebaceous Glands / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2
keywords: ER stress; TLR2; UPR; cathelicidin; rosacea; vitamin D