Neurovascular and Neuroimmune Aspects in the Pathophysiology of Rosacea

Abstract

Rosacea is a common skin disease with a high impact on quality of life. Characterized by erythema, edema, burning pain, immune infiltration, and facial skin fibrosis, rosacea has all the characteristics of neurogenic inflammation, a condition induced by sensory nerves via antidromically released neuromediators. To investigate the hypothesis of a central role of neural interactions in the pathophysiology, we analyzed molecular and morphological characteristics in the different subtypes of rosacea by immunohistochemistry, double immunofluorescence, morphometry, real-time PCR, and gene array analysis, and compared the findings with those for lupus erythematosus or healthy skin. Our results showed significantly dilated blood and lymphatic vessels. Signs of angiogenesis were only evident in phymatous rosacea. The number of mast cells and fibroblasts was increased in rosacea, already in subtypes in which fibrosis is not clinically apparent, indicating early activation. Sensory nerves were closely associated with blood vessels and mast cells, and were increased in erythematous rosacea. Gene array studies and qRT-PCR confirmed upregulation of genes involved in vasoregulation and neurogenic inflammation. Thus, dysregulation of mediators and receptors implicated in neurovascular and neuroimmune communication may be crucial at early stages of rosacea. Drugs that function on neurovascular and/or neuroimmune communication may be beneficial for the treatment of rosacea.

Ocular rosacea: a review

“…These forms of cathelicidin peptides are known for its role in natural host defense against infections and in promoting leukocyte chemotaxis, angiogenesis, and extracellular matrix component expression (27) . Supporting this theory, gene array studies found that mRNA expression levels of cathelicidin were found to be significantly increased in all subtypes of rosacea (29) . Additionally, local proteases (serine protease KLK5) that control the production of cathelicidin in epidermis were also abnormally expressed in rosacea patients (25,27) .…”

“…Studies have demonstrated increased blood flow in the face and larger and more numerous vessels in the face than in other areas of the body (31) . Significantly dilated blood and lymphatic vessels were reported in all subtypes of rosacea (29) . Studies further demonstrated an up-regulation of genes involved in vasoregulation and neurogenic inflammation and suggested that dysregulation of mediators and receptors implicated in neurovascular and neuroimmune communication may be crucial at early stages of rosacea (26,29,32) .…”

“…Significantly dilated blood and lymphatic vessels were reported in all subtypes of rosacea (29) . Studies further demonstrated an up-regulation of genes involved in vasoregulation and neurogenic inflammation and suggested that dysregulation of mediators and receptors implicated in neurovascular and neuroimmune communication may be crucial at early stages of rosacea (26,29,32) . Improvement of erythema and flushing in rosacea by topical administration of a-adrenergic receptor agonists, oxymetazoline and xylometazoline, helps support this theory (25,33,34) .…”

Ocular Rosacea—a Review

“…Significantly dilated blood vessels have been reported in all subtypes of rosacea. 9 • Neurovascular component-this has been suggested to be an underlying mechanism on the basis of exaggerated skin sensitivity to noxious heat stimuli, which may be seen in these patients. 10 DOI: https://doi.org/10.17925/USOR.2017.…”

Antibiotic Resistance Considerations of Importance to Clinical Dermatologists

“…[30][31][32][33][34] As a result, many of the studies of therapies used to treat rosacea (eg tetracyclines, azelaic acid, ivermectin) especially with presence of papulopustular lesions, appear to affect inflammatory pathways/modes of action unrelated to an underlying bacterial trigger that appear to be operative in rosacea pathophysiology (eg inhibition of matrix metalloproteinases, downregulation of cathelicidin pathway, reduction in number of Demodex mites). [35][36][37][38][39][40][41][42][43] The large body of evidence supporting an inflammatory pathogenesis of rosacea that is not triggered by a bacterial etiology has led globally to rosacea management recommendations supporting that avoidance of an antibiotic effect whenever possible is favorable in order to reduce the emergence of antibiotic-resistant bacteria.…”