Advertisement

Rosacea Pathogenesis

  • Gerd Plewig
  • Bodo Melnik
  • WenChieh Chen
Chapter

Abstract

Multiple factors are involved in rosacea pathogenesis such as disturbed epidermal barrier function, cathelicidin antimicrobial peptide (CAMP)-mediated inflammation with inflammasome activation, aberrations of vascular reactivity, enhanced innate immunity, neurogenic inflammation, angiogenesis, fibrosis, and Demodex mite hypercolonization. The lack of appropriate animal models of rosacea underlines the importance of translational research approaching rosacea pathogenesis.

Bibliography

  1. Addor FA. Skin barrier in rosacea. An Bras Dermatol. 2016;91:59–63.PubMedPubMedCentralGoogle Scholar
  2. Binet F, Sapieha P. ER stress and angiogenesis. Cell Metab. 2015;22:560–75.PubMedGoogle Scholar
  3. Blumberg PM. To not be hot when TRPV1 is not. Temperature (Austin). 2015;2:166–7.Google Scholar
  4. Bronner DN, Abuaita BH, Chen X, et al. Endoplasmic reticulum stress activates the inflammasome via NLRP3- and caspase-2-driven mitochondrial damage. Immunity. 2015;43:451–62.PubMedPubMedCentralGoogle Scholar
  5. Buhl T, Sulk M, Nowak P, et al. Molecular and morphological characterization of inflammatory infiltrate in rosacea reveals activation of Th1/Th17 pathways. J Invest Dermatol. 2015;135:2198–208.PubMedGoogle Scholar
  6. Casas C, Paul C, Lahfa M, et al. Quantification of Demodex folliculorum by PCR in rosacea and its relationship to skin innate immune activation. Exp Dermatol. 2012;21:906–10.PubMedGoogle Scholar
  7. Chen W, Plewig G. Are Demodex mites principal, conspirator, accomplice, witness or bystander in the cause of rosacea? Am J Clin Dermatol. 2015;16:67–72.PubMedGoogle Scholar
  8. Chen X, Niyonsaba F, Ushio H, et al. Human cathelicidin LL-37 increases vascular permeability in the skin via mast cell activation, and phosphorylates MAP kinases p38 and ERK in mast cells. J Dermatol Sci. 2006;43:63–6.PubMedGoogle Scholar
  9. Chen X, Takai T, Xie Y, et al. Human antimicrobial peptide LL-37 modulates proinflammatory responses induced by cytokine milieus and double-stranded RNA in human keratinocytes. Biochem Biophys Res Commun. 2013;433:532–7.PubMedGoogle Scholar
  10. Chen Y, Moore CD, Zhang JY, et al. TRPV4 moves toward center-fold in rosacea pathogenesis. J Invest Dermatol. 2017;137:801–4.PubMedPubMedCentralGoogle Scholar
  11. Ci X, Li H, Yu Q, et al. Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase activation pathway. Fundam Clin Pharmacol. 2009;23:449–55.PubMedGoogle Scholar
  12. Dajnoki Z, Béke G, Kapitány A, et al. Sebaceous gland-rich skin is characterized by TSLP expression and distinct immune surveillance which is disturbed in rosacea. J Invest Dermatol. 2017;137:1114–25.PubMedGoogle Scholar
  13. Degouy A, Mengeaud V, Ginisty H, et al. Quantification of Demodex folliculorum by PCR in rosacea and its relationship to skin innate immune activation. Exp Dermatol. 2012;21:906–10.PubMedGoogle Scholar
  14. Gallo RL, Granstein RD, Kang S, et al. Standard classification and pathophysiology of rosacea: the 2017 update by the National Rosacea Society Expert Committee. J Am Acad Dermatol. 2018;78:148–55.PubMedGoogle Scholar
  15. Gerber PA, Buhren BA, Steinhoff M, Homey B. Rosacea: the cytokine and chemokine network. J Investig Dermatol Symp Proc. 2011;15:40–7.PubMedPubMedCentralGoogle Scholar
  16. Ghosh R, Lipson KL, Sargent KE, et al. Transcriptional regulation of VEGF-A by the unfolded protein response pathway. PLoS One. 2010;5:e9575.PubMedPubMedCentralGoogle Scholar
  17. Gomaa AH, Yaar M, Eyada MM, Bhawan J. Lymphangiogenesis in non-phymatous rosacea. J Cutan Pathol. 2007;34:748–53.PubMedGoogle Scholar
  18. Goodall JC, Wu C, Zhang Y, et al. Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression. Proc Natl Acad Sci U S A. 2010;107:17698–703.PubMedPubMedCentralGoogle Scholar
  19. Guzman-Sanchez DA, Ishiuji Y, Patel T, et al. Enhanced skin blood flow and sensitivity to noxious heat stimuli in papulopustular rosacea. J Am Acad Dermatol. 2007;57:800–5.PubMedGoogle Scholar
  20. Heindryckx F, Binet F, Ponticos M, et al. Endoplasmic reticulum stress enhances fibrosis through IRE1α-mediated degradation of miR-150 and XBP-1 splicing. EMBO Mol Med. 2016;8:729–44.PubMedPubMedCentralGoogle Scholar
  21. Helfrich YR, Maier LE, Cui Y, et al. Clinical, histologic, and molecular analysis of differences between erythematotelangiectatic rosacea and telangiectatic photoaging. JAMA Dermatol. 2015;151:825–36.PubMedGoogle Scholar
  22. Holmes AD, Steinhoff M. Integrative concepts of rosacea pathophysiology, clinical presentation and new therapeutics. Exp Dermatol. 2017;26:659–67.PubMedGoogle Scholar
  23. Igarashi J, Michel T. Sphingosine-1-phosphate and modulation of vascular tone. Cardiovasc Res. 2009;82:212–20.PubMedPubMedCentralGoogle Scholar
  24. Inceoglu B, Bettaieb A, Trindade da Silva CA, et al. Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain. Proc Natl Acad Sci U S A. 2015;112:9082–7.PubMedPubMedCentralGoogle Scholar
  25. Ivic I, Solymar M, Pakai E, et al. Transient receptor potential vanilloid-1 channels contribute to the regulation of acid- and base-induced vasomotor responses. J Vasc Res. 2016;53:279–90.PubMedGoogle Scholar
  26. Jeong SK, Kim YI, Shin KO, et al. Sphingosine kinase 1 activation enhances epidermal innate immunity through sphingosine-1-phosphate stimulation of cathelicidin production. J Dermatol Sci. 2015;79:229–34.PubMedPubMedCentralGoogle Scholar
  27. Keestra-Gounder AM, Byndloss MX, Seyffert N, et al. NOD1 and NOD2 signalling links ER stress with inflammation. Nature. 2016;532:394–7.PubMedPubMedCentralGoogle Scholar
  28. Kim JY, Kim YJ, Lim BJ, et al. Increased expression of cathelicidin by direct activation of protease-activated receptor 2: possible implications on the pathogenesis of rosacea. Yonsei Med J. 2014a;55:1648–55.PubMedPubMedCentralGoogle Scholar
  29. Kim S, Joe Y, Jeong SO, et al. Endoplasmic reticulum stress is sufficient for the induction of IL-1β production via activation of the NF-κB and inflammasome pathways. Innate Immun. 2014b;20:799–815.PubMedGoogle Scholar
  30. Kim SH, Yang IY, Kim J, et al. Antimicrobial peptide LL-37 promotes antigen-specific immune responses in mice by enhancing Th17-skewed mucosal and systemic immunities. Eur J Immunol. 2015;45:1402–13.PubMedGoogle Scholar
  31. Koczulla R, von Degenfeld G, Kupatt C, et al. An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J Clin Invest. 2003;111:1665–72.PubMedPubMedCentralGoogle Scholar
  32. Komori R, Taniguchi M, Ichikawa Y, et al. Ultraviolet A induces endoplasmic reticulum stress response in human dermal fibroblasts. Cell Struct Funct. 2012;37:49–53.PubMedGoogle Scholar
  33. Langeslag M, Quarta S, Leitner MG, et al. Sphingosine 1-phosphate to p38 signaling via S1P1 receptor and Gαi/o evokes augmentation of capsaicin-induced ionic currents in mouse sensory neurons. Mol Pain. 2014;10:74.PubMedPubMedCentralGoogle Scholar
  34. Lee YM, Kim YK, Chung JH. Increased expression of TRPV1 channel in intrinsically aged and photoaged human skin in vivo. Exp Dermatol. 2009;18:431–6.PubMedGoogle Scholar
  35. Lee YM, Kang SM, Chung JH. The role of TRPV1 channel in aged human skin. J Dermatol Sci. 2012;65:81–5.PubMedGoogle Scholar
  36. Lee SE, Takagi Y, Nishizaka T, et al. Subclinical cutaneous inflammation remained after permeability barrier disruption enhances UV sensitivity by altering ER stress responses and topical pseudoceramide prevents them. Arch Dermatol Res. 2017;309;541–50.PubMedGoogle Scholar
  37. Leichner TM, Satake A, Harrison VS, et al. Skin-derived TSLP systemically expands regulatory T cells. J Autoimmun. 2017;79:39–52.PubMedPubMedCentralGoogle Scholar
  38. Lumley EC, Osborn AR, Scott JE, et al. Moderate endoplasmic reticulum stress activates a PERK and p38-dependent apoptosis. Cell Stress Chaperones. 2017;22:43–54.PubMedGoogle Scholar
  39. Ma L, Lee BH, Mao R, et al. Nicotinic acid activates the capsaicin receptor TRPV1: potential mechanism for cutaneous flushing. Arterioscler Thromb Vasc Biol. 2014;34:1272–80.PubMedPubMedCentralGoogle Scholar
  40. Margalit A, Kowalczyk MJ, Żaba R, Kavanagh K. The role of altered cutaneous immune responses in the induction and persistence of rosacea. J Dermatol Sci. 2016;82:3–88.PubMedGoogle Scholar
  41. Mascarenhas NL, Wang Z, Chang YL, Di Nardo A. TRPV4 mediates mast cell activation in cathelicidin-induced rosacea inflammation. J Invest Dermatol. 2017;137:972–5.PubMedGoogle Scholar
  42. McMahon F, Banville N, Bergin DA, et al. Activation of neutrophils via IP3 pathway following exposure to Demodex-associated bacterial proteins. Inflammation. 2016;39:425–33.PubMedGoogle Scholar
  43. Melnik BC. Endoplasmic reticulum stress: key promoter of rosacea pathogenesis. Exp Dermatol. 2014;23:868–73.PubMedGoogle Scholar
  44. Melnik BC. Rosacea: the blessing of the Celts—an approach to pathogenesis through translational research. Acta Derm Venereol. 2016;96:147–56.PubMedGoogle Scholar
  45. Mera K, Kawahara K, Tada K, et al. ER signaling is activated to protect human HaCaT keratinocytes from ER stress induced by environmental doses of UVB. Biochem Biophys Res Commun. 2010;397:350–4.PubMedGoogle Scholar
  46. Meyer-Hoffert U, Schröder JM. Epidermal proteases in the pathogenesis of rosacea. J Investig Dermatol Symp Proc. 2011;15:16–23.PubMedGoogle Scholar
  47. Mrozkova P, Spicarova D, Palecek J. Hypersensitivity induced by activation of spinal cord PAR2 receptors is partially mediated by TRPV1 receptors. PLoS One. 2016;11:e0163991.PubMedPubMedCentralGoogle Scholar
  48. Murillo N, Aubert J, Raoult D. Microbiota of Demodex mites from rosacea patients and controls. Microb Pathog. 2014;71-72:37–40.PubMedGoogle Scholar
  49. Muto Y, Wang Z, Vanderberghe M, et al. Mast cells are key mediators of cathelicidin-initiated skin inflammation in rosacea. J Invest Dermatol. 2014;134:2728–36.PubMedPubMedCentralGoogle Scholar
  50. Ní Raghallaigh S, Bender K, Lacey N, et al. The fatty acid profile of the skin surface lipid layer in papulopustular rosacea. Br J Dermatol. 2012;166:279–87.PubMedGoogle Scholar
  51. O’Reilly N, Bergin D, Reeves EP, et al. Demodex-associated bacterial proteins induce neutrophil activation. Br J Dermatol. 2012;166:753–60.PubMedGoogle Scholar
  52. Palamar M, Degirmenci C, Ertam I, Yagci A. Morphological and functional evaluation of meibomian gland dysfunction in rosacea patients. Curr Eye Res. 2017;42:325.PubMedGoogle Scholar
  53. Park K, Elias PM, Shin KO, et al. A novel role of a lipid species, sphingosine-1-phosphate, in epithelial innate immunity. Mol Cell Biol. 2013a;33:752–62.PubMedPubMedCentralGoogle Scholar
  54. Park K, Elias PM, Hupe M, et al. Resveratrol stimulates sphingosine-1-phosphate signaling of cathelicidin production. J Invest Dermatol. 2013b;133:1942–9.PubMedPubMedCentralGoogle Scholar
  55. Park K, Ikushiro H, Seo HS, et al. ER stress stimulates production of the key antimicrobial peptide, cathelicidin, by forming a previously unidentified intracellular S1P signaling complex. Proc Natl Acad Sci U S A. 2016;113:E1334–42.PubMedPubMedCentralGoogle Scholar
  56. Park K, Lee SE, Shin KO, Uchida Y. Insight into the role of endoplasmic reticulum stress in skin function and associated diseases. FEBS J. 2019;286:413–25.PubMedGoogle Scholar
  57. Pereira ER, Frudd K, Awad W, Hendershot LM. Endoplasmic reticulum (ER) stress and hypoxia response pathways interact to potentiate hypoxia-inducible factor 1 (HIF-1) transcriptional activity on targets like vascular endothelial growth factor (VEGF). J Biol Chem. 2014;289:3352–64.PubMedGoogle Scholar
  58. Peric M, Koglin S, Kim SM, et al. IL-17A enhances vitamin D3-induced expression of cathelicidin antimicrobial peptide in human keratinocytes. J Immunol. 2008;181:8504–12.PubMedPubMedCentralGoogle Scholar
  59. Picardo M, Ottaviani M. Skin microbiome and skin disease: the example of rosacea. J Clin Gastroenterol. 2014;48(Suppl 1):S85–6.PubMedGoogle Scholar
  60. Powell FC. Rosacea and the pilosebaceous follicle. Cutis. 2004;74(3 Suppl):9–12, 32–34.PubMedGoogle Scholar
  61. Reinholz M, Ruzicka T, Steinhoff M, et al. Pathogenesis and clinical presentation of rosacea as a key for a symptom-oriented therapy. J Dtsch Dermatol Ges. 2016;14(Suppl 6):4–15.PubMedGoogle Scholar
  62. Rodríguez-Martínez S, Cancino-Diaz JC, Vargas-Zuñiga LM, Cancino-Diaz ME. LL-37 regulates the overexpression of vascular endothelial growth factor (VEGF) and c-IAP-2 in human keratinocytes. Int J Dermatol. 2008;47:457–62.PubMedGoogle Scholar
  63. Salzer S, Kresse S, Hirai Y, et al. Cathelicidin peptide LL-37 increases UVB-triggered inflammasome activation: possible implications for rosacea. J Dermatol Sci. 2014;76:173–9.PubMedGoogle Scholar
  64. Sattler EC, Hoffmann VS, Ruzicka T, et al. Reflectance confocal microscopy for monitoring the density of Demodex mites in patients with rosacea before and after treatment. Br J Dermatol. 2015;173:69–75.PubMedGoogle Scholar
  65. Schwab VD, Sulk M, Seeliger S, et al. Neurovascular and neuroimmune aspects in the pathophysiology of rosacea. J Investig Dermatol Symp Proc. 2011;15:53–62.PubMedPubMedCentralGoogle Scholar
  66. Shimasaki S, Koga T, Shuto T, et al. Endoplasmic reticulum stress increases the expression and function of toll-like receptor-2 in epithelial cells. Biochem Biophys Res Commun. 2010;402:235–40.PubMedGoogle Scholar
  67. Smith JR, Lanier VB, Braziel RM, et al. Expression of vascular endothelial growth factor and its receptors in rosacea. Br J Ophthalmol. 2007;91:226–9.PubMedPubMedCentralGoogle Scholar
  68. Steinhoff M, Buddenkotte J, Aubert J, et al. Clinical, cellular, and molecular aspects in the pathophysiology of rosacea. J Investig Dermatol Symp Proc. 2011;15:2–11.PubMedPubMedCentralGoogle Scholar
  69. Sukumaran P, Schaar A, Sun Y, Singh BB. Functional role of TRP channels in modulating ER stress and autophagy. Cell Calcium. 2016;60:123–32.PubMedPubMedCentralGoogle Scholar
  70. Sulk M, Seeliger S, Aubert J, et al. Distribution and expression of non-neuronal transient receptor potential (TRPV) ion channels in rosacea. J Invest Dermatol. 2012;132:1253–62.PubMedGoogle Scholar
  71. Suurmond J, Habets KL, Dorjée AL, et al. Expansion of Th17 cells by human mast cells is driven by inflammasome-independent IL-1β. J Immunol. 2016;197:4473–81.PubMedGoogle Scholar
  72. Takahashi T, Asano Y, Nakamura K, et al. A potential contribution of antimicrobial peptide LL-37 to tissue fibrosis and vasculopathy in systemic sclerosis. Br J Dermatol. 2016;175:1195–203.PubMedGoogle Scholar
  73. Tam AB, Mercado EL, Hoffmann A, Niwa M. ER stress activates NF-κB by integrating functions of basal IKK activity, IRE1 and PERK. PLoS One. 2012;7:e45078.PubMedPubMedCentralGoogle Scholar
  74. Thibaut de Ménonville S, Rosignoli C, Soares E, et al. Topical treatment of rosacea with ivermectin inhibits gene expression of cathelicidin innate immune mediators, LL-37 and KLK5, in reconstructed and ex vivo skin models. Dermatol Ther (Heidelb). 2017;7:213–25.Google Scholar
  75. Tjabringa GS, Ninaber DK, Drijfhout JW, et al. Human cathelicidin LL-37 is a chemoattractant for eosinophils and neutrophils that acts via formyl-peptide receptors. Int Arch Allergy Immunol. 2006;140:103–12.PubMedGoogle Scholar
  76. Turgut Erdemir A, Gurel MS, Koku Aksu AE, et al. Demodex mites in acne rosacea: reflectance confocal microscopic study. Australas J Dermatol. 2017;58:e26–30.PubMedGoogle Scholar
  77. van Zuuren EJ. Rosacea. N Engl J Med. 2017;377:1754–64.PubMedGoogle Scholar
  78. Yamasaki K, Gallo RL. Rosacea as a disease of cathelicidins and skin innate immunity. J Investig Dermatol Symp Proc. 2011;15:12–5.PubMedGoogle Scholar
  79. Yamasaki K, Schauber J, Coda A, et al. Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin. FASEB J. 2006;20:2068–80.PubMedGoogle Scholar
  80. Yamasaki K, Di Nardo A, Bardan A, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007;13:975–80.PubMedGoogle Scholar
  81. Yazici AC, Tamer L, Ikizoglu G, et al. GSTM1 and GSTT1 null genotypes as possible heritable factors of rosacea. Photodermatol Photoimmunol Photomed. 2006;22:208–10.PubMedGoogle Scholar
  82. Zhang X, Song Y, Xiong H, et al. Inhibitory effects of ivermectin on nitric oxide and prostaglandin E2 production in LPS-stimulated RAW 264.7 macrophages. Int Immunopharmacol. 2009;9:354–9.PubMedGoogle Scholar
  83. Zhang YY, Yu YY, Zhang YR, et al. The modulatory effect of TLR2 on LL-37-induced human mast cells activation. Biochem Biophys Res Commun. 2016;470:368–74.PubMedGoogle Scholar
  84. Zheng Y, Niyonsaba F, Ushio H, et al. Cathelicidin LL-37 induces the generation of reactive oxygen species and release of human alpha-defensins from neutrophils. Br J Dermatol. 2007;157:1124–31.PubMedGoogle Scholar
  85. Zhou M, Xie H, Cheng L, Li J. Clinical characteristics and epidermal barrier function of papulopustular rosacea: a comparison study with acne vulgaris. Pak J Med Sci. 2016;32:1344–8.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Gerd Plewig
    • 1
  • Bodo Melnik
    • 2
  • WenChieh Chen
    • 3
  1. 1.Department of Dermatology and AllergyLudwig-Maximilian-University MunichMunichGermany
  2. 2.Department of Dermatology, Environmental Medicine and Health TheoryUniversity of OsnabrückOsnabrückGermany
  3. 3.Department of Dermatology and AllergyTechnical University of MunichMunichGermany

Personalised recommendations