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 tolllike 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.Abbreviations: AGE, advanced glycation end product; AMP, antimicrobial peptide; ASK1, apoptosis signal regulating kinase-1; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; ATRA, all-trans-retinoic acid; AzA, azelaic acid; BiP, immunoglobulin heavy chain-binding protein (=heat-shock 70 kD protein 5); C/EBPa, CCAAT/enhancer-binding protein alpha; CAMP, cathelicidin antimicrobial peptide (hCAP18); CD14, monocyte differentiation antigen CD14; CHOP, C/EBP-homologous protein; COL1A1, collagen type 1; eIF2a, eukaryotic translation initiation factor 2-alpha; ER, endoplasmic reticulum; HSP70, heat-shock protein 70 kD; IRE1, inositol-requiring 1a; KLK5, kallikrein 5; LL-37, cathelicidin C-terminal fragment; mTORC1, mechanistic target of rapamycin complex 1; NFjKB, nuclear factor kappa B; PERK, doublestranded RNA-dependent protein kinase (PKR)-like ER kinase; RAGE, receptor for advanced glycation end products; ROS, reactive oxygen species; RXR, retinoid X receptor; S1P, sphingosine-1-phosphate; SPHK1, sphingosine kinase 1 isoform; SREBP, sterol regulatory element-binding transcription factor; TGFb1, transforming growth factor beta 1; TLR, tolllike receptor; TRPV, transient rece...

Friends or Foes? Host defense (antimicrobial) peptides and proteins in human skin diseases

“…To date, the mechanisms leading to overproduction of LL‐37 in rosacea have not been fully clarified, but studies have suggested that both the vitamin D and TLR2 pathways are involved. In fact, endoplasmic reticulum stress increases TLR2 expression, leading to overexpression of LL‐37 and kallikrein 5, which mediate rosacea inflammation . In addition, LL‐37 is induced by the vitamin D pathway, and notably, polymorphisms in the vitamin D receptor are associated with rosacea .…”

“…In fact, endoplasmic reticulum stress increases TLR2 expression, leading to overexpression of LL-37 and kallikrein 5, which mediate rosacea inflammation. [116] In addition, LL-37 is induced by the vitamin D pathway, [117] and notably, polymorphisms in the vitamin D receptor are associated with rosacea. [118] Therefore, rosacea predominantly affects the central portions of the face because these areas are permanently exposed to UVB radiation, which activates the vitamin D pathway, resulting in the induction of LL-37.…”

The role of cold‐inducible RNA binding protein in cell stress response

“…Then CIRP relocates to cytoplasm from the nucleus to facilitate the translation of several mRNAs, activating the ERK1/2/MAPK and NF‐κB mediated anti‐apoptotic processes as well as TRX‐mediated anti‐oxidation process. Meanwhile, intracellular unfolded protein response (UPR) is activated to resist the stress‐caused ER stress . As the stress continues, the harmful substrates including ROS and abnormal proteins accumulate in cytoplasm.…”

Overlaps in the Pathogenesis of Rosacea and Atherosclerosis

“…Paradoxically, rosacea is most prevalent in individuals with fair skin of European descent, in which vitamin D deficiency is common due to their geographical location. That is why an alternative vitamin D-independent mechanism to promote CAMP expression has been proposed (Melnik, 2014;Melnik, 2016). LL-37 is an important factor in battling infectious agents, including M. tuberculosis; therefore it is possible that these individuals through evolution have developed an alternative vitamin D-independent pathway that activates the CAMP gene promoter.…”

“…This causes phosphorylation of a transcription factor known as CCAAT/enhancer-binding protein alpha (C/EBPa). Phosphorylated C/EBPa binds to a corresponding CAMP promoter region and upregulates the expression of the CAMP gene (Melnik, 2014;2016). ER stress, in response to heat, can also stimulate TRP channels through S1P signaling, thus potentially causing transient erythema (Mair et al, 2011).…”