Rosacea: Pathogenesis and Therapeutic Correlates

Abstract

Rosacea is a chronic inflammatory condition of which there is no cure. The pathogenesis of rosacea is likely multifactorial, involving genetic and environmental contributions. Current understanding suggests that pro-inflammatory pathways involving cathelicidins and inflammasome complexes are central to rosacea pathogenesis. Common rosacea triggers modulate these pathways in a complex manner, which may contribute to the varying severity and clinical presentations of rosacea. Established and emerging rosacea treatments may owe their efficacy to their ability to target different players in these pro-inflammatory pathways. Improving our molecular understanding of rosacea will guide the development of new therapies and the use of combination therapies.

Keywords: pathogenesis; rosacea; treatment.

Figure 1.

Schema of the risk factors, triggers, and pathogenesis pathways of rosacea. The pathogenesis of rosacea likely involves a complex interplay between several factors and pathways, including neurovascular dysregulation and innate immune system dysregulation involving cathelicidins and inflammasomes. These processes then give rise to the symptoms and clinical features of rosacea, depicted in blue. Known targets of medications currently used in treating rosacea are indicated.

Figure 2.

(A) Proposed cathelicidins pathway believed to be implicated in the pathogenesis of rosacea. Production of LL-37 leads to several physiological effects including angiogenesis, vasodilation, inflammation, and matrix degradation. (i) High densities of Demodex folliculorum upregulates the expression of TLR2 in sebocytes. Enhanced TLR2 activity leads to increased KLK5 activity and production of LL-37. (ii) CagA+ and VacA+ Helicobacter pylori strains stimulate mast cell activation and subsequent increase in histamines and prostaglandins, promoting inflammation. (iii) Through MMP2 upregulation and TLR2 signalling, ROS promote matrix degeneration and increase LL-37 production. (iv) UV promotes expression of CAMP in keratinocytes via vitamin D-dependent and ER stress-induced pathways. CAMP can then be cleaved into the bioactive LL-37 fragments. (B) Proposed inflammasome pathway believed to be implicated in the pathogenesis of rosacea. Inflammasome activation results in several physiological effects including chemotaxis of neutrophils, angiogenesis, and inflammation. The cathelicidins and inflammasome pathways are intricately linked. TLR2, toll-like receptor 2; KLK5, kallikrein-5; CagA+, cytotoxin-associated gene A positive; VacA+, vacuolating cytotoxin A positive; MMP2, matrix metalloprotease 2; ROS, reactive oxygen species; UV, ultraviolet; CAMP, cathelicidin antimicrobial peptide; ER, endoplasmic reticulum.