Therapeutic strategies focusing on immune dysregulation and neuroinflammation in rosacea

Abstract

Rosacea is a complex inflammatory condition characterized by papulopustular lesions and erythema on the central face for which there is no cure. The development of rosacea is influenced by both external triggers and genetics, but the common pathophysiology is overactivation of the immune system. Here, we review the current data on proinflammatory cytokines and dysregulation of the neurovascular system as targetable components of rosacea. Amelioration of cutaneous and gastrointestinal dysbiosis and other external factors impacts the immune state and has been observed to improve rosacea. While multiple treatments exist, many patients do not achieve their goals for rosacea control and highlights an unmet need for dermatologic care. Current interventions encompass topical/oral drugs, light devices, and avoidance of triggers management. Additional understanding of the underlying pathogenesis may help us develop novel targeted therapeutic strategies to improve rosacea.

Keywords: immune dysregulation; microbiota; neuroinflammation; rosacea; therapeutics.

Figure 1

A diagram illustrating potential pathogenic mechanisms of rosacea categorized into four major categories and interaction with immune system. Rosacea, a multifactorial condition, involves external triggers (orange box), genetic predisposition (purple box), immune dysregulation (blue box), and neurovascular dysregulation (red box). Treatment modalities correspond to these mechanisms, as shown outside of the boxes in the diagram. Only drugs aligned with Swiss S1 and National Rosacea Society guidelines are indicated. UV, ultraviolet; CAMP, cathelicidin antimicrobial peptide; KLK-5, Kallikrein 5; TLR2, toll-like receptor 2; TRP-, transient receptor potential channel; CGRP, calcitonin gene related peptide; PACAP, pituitary adenylate cyclase-activating peptide; IL-, interleukin; IRF4, interferon regulatory factor-4; TNF, tumor necrosis factor; IFNG, Interferon gamma; PAR, protease-activated receptor; SP, substance P; CRH, corticotropin-releasing hormone; NO, Nitric oxide; VIP, vasoactive intestinal polypeptide; ATP, adenosine triphosphate.

Figure 2

A diagram showing the role of immune dysregulation in the pathogenesis of rosacea. Environmental factors activate toll-like receptor (TLR)2 on keratinocytes, leading to kallikrein (KLK) 5 expression in rosacea. KLK5 cleaves human cathelicidin (hCAP), producing LL-37 (also known as hCAP18), triggering pathways like NLR family pyrin domain containing (NLRP)3 inflammasome, Janus protein tyrosine kinase/Signal Transducers and Activators of Transcription (JAK/STAT), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). LL-37 stimulates mast cells via Mas-related G-protein coupled receptor member (MRGPR) X2, inducing the production of inflammatory cytokines and matrix metalloproteinase (MMP)9. MMP-9 further enhances KLK5 production or releases LL-37, creating a positive feedback loop. LL-37 also stimulates Th-1 and Th-17 cells, with IL-17 contributing to angiogenesis. Production of hCAP is regulated by LL-37-induced mammalian target of rapamycin (mTORC) 1 signaling, again creating a positive feedback loop. Immune-targeted therapies for rosacea are shown in blue boxes. Only drugs aligned with Swiss S1 and National Rosacea Society guidelines are indicated. This figure was created with BioRender.com and obtained authorization on February 11, 2024. TLR2, toll-like receptor 2; KLK-5, Kallikrein 5; hCAP, human cathelicidin; mTOR, mammalian target of rapamycin; IL-, interleukin; TGF-β, Transforming growth factor beta; TNF-α, tumor necrosis factor; VEGF, vascular endothelial growth factor; MRGPRX2, Mas-related G-protein coupled receptor member X2; Th-, T helper cell; NLRP3, NLR family pyrin domain containing 3; JAK/STAT, Janus protein tyrosine kinase/Signal Transducers and Activators of Transcription; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; MMP, matrix metalloproteinase; ROS, reactive oxygen species; NO, Nitric oxide.

Figure 3

A diagram showing the pathophysiology of rosacea involving neurovascular dysregulation. External factors can activate sensory neurons via transient receptor potential cation channel (TRPV) receptors, leading to neuropeptide release. This activates mast cells through Mas-related G-protein coupled receptor member (MRGPR) X2, causing degranulation of histamine, serotonin, and chemokines, resulting in vasodilation, pain, and itch. Stress causes the autonomic nervous system to overstimulate vasodilator fibers, affecting the layer of smooth muscle enveloping the blood vessels, ultimately resulting in vasodilation. The figure includes medications recommended by Swiss S1 and National Rosacea Society guidelines (blue boxes) associated with this mechanism. This figure was created with BioRender.com and obtained authorization on July 03, 2024. UV, ultraviolet; TRP-, transient receptor potential channel; SP, substance P; VIP, vasoactive intestinal polypeptide; ATP, adenosine triphosphate; PACAP, pituitary adenylate cyclase-activating peptide; CGRP, calcitonin gene related peptide; ANS, autonomic nervous system.