The Effect of Capsaicin on Neuroinflammatory Mediators of Rosacea

Abstract

Background Rosacea is a chronic inflammatory skin disease with a pathophysiological mechanism that remains unclear. Recently, dysregulation of the sensory nerve system has been implicated in the development of this condition. Objective This study aimed to investigate the effect of capsaicin on neuroinflammatory mediators in rosacea. In addition, this study aimed to evaluate the attenuating effects of capsazepine, a transient receptor potential vanilloid type 1 (TRPV1) antagonist. Methods We obtained skin tissue from both rosacea patients and normal individuals for an in vivo study. In addition, normal human epidermal keratinocytes (NHEKs) were cultured, and treated with capsaicin and capsazepine for an in vitro study. Quantitative changes in neuroinflammatory mediators were evaluated by semi-quantitative reverse transcription-polymerase chain reaction (PCR), real-time PCR, enzyme-linked immunosorbent assay, and immunofluorescence staining. Results The data showed the increase of TRPV1, TRPV4, cathelicidin (LL37) and tumor necrosis factor-α (TNF-α) in skin tissue by real-time PCR. In addition, the data showed that cathelicidin (LL37), kallikrein-5 (KLK-5), TNF-α, vascular endothelial growth factor (VEGF), interleukin (IL)-1α, IL-1β, IL-8, and protease-activated receptor 2 (PAR2) increased in capsaicin-treated NHEKs. Capsazepine attenuated the expression of TRPV1 and other mediators, except for IL-8, in capsaicin-treated NHEKs. Conclusion We confirmed that TRPV1, TRPV4, cathelicidin (LL37) and TNF-α are increased in rosacea skin, and that capsaicin is associated with increase of neuroinflammatory mediators such as LL37, KLK-5, TNF-α, VEGF, IL-1α, IL-1β, IL-8, and PAR2. Modulators or inhibitors of neuroinflammatory mediators including TRPV1 could be potential therapeutic option in the treatment of patients with rosacea.

New Insights into the Mutual Promotion of Rosacea, Anxiety, and Depression from Neuroendocrine Immune Aspects

“…CXCL8 expression in KCs is thought to be a key event in neutrophil recruitment for pustule formation; CRH activates the cannabinoid and vanilloid pathways, advancing the disease progression of rosacea. 43 , 44 …”

“…The first wave of chemokines is subsequently produced, resulting in concentrated aggregation of T cells into the surrounding hair follicle space. 44 Conversely, T cell-derived cytokines, such as IL-17 or IL-22, may, together with UV radiation, activate KCs to produce CCL20, CXCL1, and CXCL8. CCL20 attracts additional Th17, while CXCL1 and CXCL8 absorb large numbers of neutrophils, leading to the formation of pustules.…”

“…Although Th17 cells preferentially express the chemokine receptor CCR6, their specific ligand, CCL20, upregulates in keratinocytes stimulated by UVB radiation or TNF-α/IL-1. 44 IL-17 not only directly promotes angiogenesis and expansion but also stimulates the production of TNF-α, IL-1β, and IL-6, and coordinates with IL-1β and TNF-α to upregulate other angiogenic factors, such as vascular endothelial growth factor and IL-8. 56 , 57 Previous studies have suggested that inflammation and angiogenesis may be mutually regulated through a positive feedback loop.…”

“…CXCL8 expression in KCs is thought to be a key event in neutrophil recruitment for pustule formation; CRH activates the cannabinoid and vanilloid pathways, advancing the disease progression of rosacea. 43,44 A large body of previous evidence suggests that dysfunction of the HPA axis is closely associated with the development of anxiety and depression disorders. Both anxiety disorders and depressive disorders are associated with abnormalities in the stress response system, where inhibition of the subgenual prefrontal cortex and activation of the amygdala stimulates the autonomic sympathetic axis and the HPA axis when the organism is exposed to a physical or psychological stressor.…”

Biomarkers in rosacea: A systematic review

“…11,17 Tumour necrosis factor Six studies reported on TNF-α, with all studies noting an increase. 11,17,19,20,23,24 T A B L E 1 T h 1 biomarkers in patients with rosacea.…”