Rosacea: Molecular Mechanisms and Management of a Chronic Cutaneous Inflammatory Condition

Abstract

Rosacea is a chronic cutaneous inflammatory disease that affects the facial skin. Clinically, rosacea can be categorized into papulopustular, erythematotelangiectatic, ocular, and phymatous rosacea. However, the phenotypic presentations of rosacea are more heterogeneous. Although the pathophysiology of rosacea remains to be elucidated, immunologic alterations and neurovascular dysregulation are thought to have important roles in initiating and strengthening the clinical manifestations of rosacea. In this article, we present the possible molecular mechanisms of rosacea based on recent laboratory and clinical studies. We describe the genetic predisposition for rosacea along with its associated diseases, triggering factors, and suggested management options in detail based on the underlying molecular biology. Understanding the molecular pathomechanisms of rosacea will likely aid toward better comprehending its complex pathogenesis.

Keywords: genetic; immune defect; inflammation; neurovascular dysregulation; rosacea; triggering factor.

Figure 1

Schematic view of the factors known to contribute to the molecular mechanisms of rosacea.

Figure 2

Primary pathogenic targets in rosacea with their respective treatment options. Blue lines indicate pathophysiological pathways involved in rosacea. Red lines illustrate major target pathways associated with the management options. Red words indicate management options in rosacea. Upward arrows indicate increased expression of certain protein.

Figure 3

Representation of proposed mechanisms for rosacea. Predisposing factors are associated with dysregulated immune responses and neurovascular dysregulation. Among the triggering factors, demodex proliferation directly disrupts the epidermal barrier. Demodex and ultraviolet radiation can cause the elevated expression of TLR-2. TLR-2 regulates the release of KLK-5, which disrupts the epidermal barrier and activates the cleavage of hCAP-18 into LL-37. LL-37 stimulates tissue inflammation, vasodilation, and angiogenesis in rosacea. LL-37 also facilitates the degranulation of mast cells, which further enhances the expression of MMP-1, MMP-9, and IL-6. Furthermore, Th1 and Th17-mediated immune reactions affect inflammation in rosacea. In addition, Erdr1 is related to the upregulation of IL-18 and angiogenesis. Heat and stress can induce the release of various neuromodulators, such as PACAP, VIP, substance P, CGRP, and the TRP family. These cause neurovascular dysregulation, which consequently results in inflammation, vasodilation, and angiogenesis in rosacea. Blue solid lines indicate pathophysiological pathways involved in rosacea. Dashed lines denote the proposed mechanisms for triggering factors and predisposing factors in rosacea. Upward arrows indicate increased expression of certain protein. Abbreviation: TLR, Toll-like receptor; KLK-5, Kallikrein-5; MMP, Matrix metalloproteinase; PACAP, Pituitary adenylate cyclase-activating polypeptide; VIP, Vasoactive intestinal peptide; CGRP, Calcitonin gene-related peptide; TRP, Transient receptor potential, VEGF, Vascular endothelial growth factor; FGF, Fibroblast growth factor; ROS, Reactive oxygen species.