The role of neuroinflammation in rosacea

Rosacea is one of the most common chronic inflammatory skin diseases, and although it is frequently diagnosed, its pathophysiology is still poorly understood. Continued research has shed some light on the pathophysiology of rosacea and has brought neuroinflammation and neurogenic inflammation to the forefront as an important factor in the development of the disease. The hope is that therapies possibly targeting these pathways could prove effective, offering a beacon of hope for this often challenging to treat skin disease.

Recognized as a complex disease, rosacea can be characterized by a mosaic of symptoms including facial erythema (sometimes burning and painful) and telangiectasias, papules and pustules, as well as facial edema, typically occurring first on the central face around the nose, cheeks, forehead, and chin.

According to the presentation of symptoms, rosacea can be further divided into four subgroups, namely, erythematotelangiectatic rosacea (erythema, flushing, telangiectasias), papulopustular rosacea (erythema, edema, acne-like lesions), phymatous rosacea (rhinophymatous changes), and ocular rosacea (red, itchy, irritated eyes, swollen eyelids).

Rosacea is also associated with several different factors that can quickly trigger and exacerbate symptoms including spicy foods, alcohol, particularly red wine, exercising, stress, as well as exposure to ultraviolet light. These trigger factors can contribute to the development of facial erythema and flushing, sometimes perceived as a painful and burning sensation, all of which can lead to a significantly diminished quality of life in the affected individual.

“These changes in the face cannot only be disfiguring, but they can have a significant psychological impact on the affected patient, further underscoring the psychosocial impact of the disease and begging the need for more effective therapeutic solutions for this patient population,” said Professor Martin Steinhoff, M.D., Ph.D., M.Sc., F.R.C.P.I., professorial chair of dermatology and director UCD Charles Institute of Dermatology, University College Dublin (UCD), Dublin, Ireland.

Neurgenic inflammation

Most of the progress in respect to elucidating the pathophysiology of rosacea on a molecular basis has begun over the last decade or so. In this time, Dr. Steinhoff and colleagues have homed in on neurogenic inflammation as one of the pivotal factors involved in the development of rosacea and as such, perhaps the key to more effective treatment solutions for the skin disease.

Rosacea typically starts with flushing and erythema, Dr. Steinhoff says, and these symptoms are closely associated with neurogenic inflammation. If one applies the capsaicin that is contained in chili peppers, these patients will also get the erythema, flushing, as well as a stinging or pain sensation in the face, very similar to those patients who suffer from rosacea exhibiting these symptoms.

“This analogy reminds us very much of the same situation, so you can then drive the hypothesis that also there is a kind of burning and flushing, which is very rare in many other inflammatory diseases such as atopic dermatitis or psoriasis, that can stay for hours or days. Basically, this is explained by the activation of sensory nerves that then release neuropeptides into the environment, which, in turn, activate blood vessels and immune cells that then drive an inflammatory process, defined as neurogenic inflammation,” Dr. Steinhoff explains. He recently spoke at the 46^th annual meeting of the European Society for Dermatological Research in Munich.

Nerve cell communication

According to Dr. Steinhoff, understanding the mechanism of how the nerve cells communicate with the new cells and with the vascular system and knowing which kinds of mediators and receptors are responsible can help lead to treatment solutions targeting specific mediators or receptors.

In 2011, Dr. Steinhoff and his team published the transcriptome analysis of the rosacea subtypes¹, and found that several neuro-mediators and neuro-receptors are upregulated in rosacea, opening up the possibility for a targeted therapy.

For instance, neuro-peptide receptors for Calcitonin Gene-Related Peptide (CGRP), Substance P, or Transient Receptor Potential (TRP) ion channels, can all be activated by the typical trigger factors of rosacea such as exposure to sunlight, spicy foods, and temperature changes. According to Dr. Steinhoff, this gives a good indication that probably TRP channels are involved in the neurogenic inflammation, which further leads to the development of rosacea symptoms. Current research efforts are in part aimed at trying to block one of these TRP receptors, which could hopefully lead to an effective targeted therapy.

The possibility of a more effective therapy for rosacea would be very welcome for rosacea sufferers. According to Dr. Steinhoff, facial erythema remains one of the biggest issues among rosacea sufferers, while the papulopustular aspect of the disease can be largely controlled pharmacologically with different agents such as topical ivermectin or metronidazole, or with systemic anti-inflammatory antibiotics. Most patients will come back to their physician and are happy that the papulopustular is under control, but are often dissatisfied with the erythematous aspect of their disease, which can have a far-reaching impact on their psychosocial health and wellbeing. As such, therapies that can better address the neurogenic inflammation and subsequent erythema would be much desired.

“It is really worthwhile and very promising to perform translational research, trying to understand the mechanisms and pathophysiology from the beginning. This information must then be translated and brought into the clinic to establish proof of principle and concept with human studies. Moreover, it is crucial to have good academic industry partnerships where all the fields of industry and academia come together because although both have limited capacities, both have their skillsets that in these partnerships can often help towards the road for success which ultimately can help the patient with improved therapies,” Dr. Steinhoff says.

Disclosures: Dr. Steinhoff reports no relevant dislosures.

Reference:

¹ Steinhoff M, et al. Clinical, cellular, and molecular aspects in the pathophysiology of rosacea. J Investig Dermatol Symp Proc. 2011 Dec;15(1):2-11. doi: 10.1038/jidsymp.2011.7.