Rosacea is an ancient disease that primarily involves the facial skin of northern Europeans. First described by French surgeon Guy de Chauliac in the 14th century, characters with rosacea have appeared in literature, such as Shakespeare's Henry V, and in art, like Ghirlandaio's painting, The Old Man and His Grandson.1 In the past 125 years of the British Journal of Dermatology (BJD), many papers have appeared that describe the diagnosis, clinical associations and therapy of this common skin disease. A search of the U.S. National Library of Medicine reveals 102 publications in the BJD on rosacea since 1953. However, despite much attention in the dermatology literature of the 20th century, not much headway was made in understanding the pathophysiology of this common disease until the modern revolution in our understanding of how the skin detects and responds to danger in the environment. This field has become known as the ‘innate immune system’. Our lab has been fortunate to be a part of this ongoing revolution in immunology and to be in the right place at the right time to apply this knowledge to rosacea. In fact, understanding how and why this system explains rosacea is a perfect way to understand the fundamentals of the innate immune system in human biology.

Rosacea is quite common, with some studies estimating the prevalence in certain populations as high as 22%, although most studies of northern European populations and the U.S.A. place this around 2–3%.2 The disease typically manifests with erythema and telangiectasias of the central face, often with a stinging/burning sensation associated with easy flushing. A diverse range of triggers for the disease has been reported, including sun, heat, emotional stress, exercise, caffeine, alcohol, spicy foods and certain microbes, among others. Similarly, diverse clinical presentations are recognized. In 2002, the National Rosacea Society Expert Committee developed a standard classification system for rosacea, codifying four subtypes: 1, erythematotelangiectatic rosacea, which demonstrates permanent erythema, easy flushing and telangiectasias; 2, papulopustular rosacea, which includes papules and pustules; 3, phymatous rosacea, which commonly has rhinophyma or other phymatous changes; and 4, ocular rosacea, which presents with dry, gritty‐feeling eyes.3 This diversity of symptoms, triggers and clinical presentations has made it difficult to elucidate the pathophysiology of this disease. This has changed with recent advances in our understanding of the innate immune system and the role it plays as an intermediary between our environment and host physiology. Other important work elucidating vascular and neuronal dysfunction has added to the complex tapestry of aberrant reactions to extrinsic and intrinsic factors that lead to the clinical disease of rosacea.

In 2007, we described for the first time the critical role that antimicrobial peptides (AMPs) and proteases play in the pathogenesis of rosacea. The cathelicidins form a family of peptides initially described for their ability to kill microbes, and were the first of the AMPs discovered in skin. However, we have since learned that alternative proteolytic processing of cathelicidin yields peptides with myriad biological effects, which include inducing chemotaxis, promotion of proinflammatory cytokines, angiogenesis and more.4-7 In rosacea, cathelicidins too are abundant in the epidermis and are processed into aberrant forms that drive both proinflammatory and proangiogenic processes.8

Key to understanding how the innate immune system is malfunctioning in rosacea is the realization that this system depends on diverse gene products. AMPs like cathelicidin depend on proteases for activation. The kallikrein (KLK) serine proteases, KLK5 and KLK7, are the major proteases responsible for cathelicidin processing in skin.4 KLK5 is also abnormally abundant in rosacea, and is responsible for processing the excess cathelicidins into aberrant forms that help drive the disease.8 Another important family of proteases in rosacea is the matrix metalloproteinases (MMPs). MMPs normally take part in tissue remodelling during wound healing, but have recently been found to activate KLK proteases, which in turn drive the overproduction of proinflammatory and proangiogenic cathelicidin fragments.9 Additionally, these proteases are induced in rosacea skin and promote dermal and vascular remodelling, as well as inflammatory damage, in this disease.10-12

The key roles of cathelicidin peptides and proteases in the pathogenesis of this disease are supported by the efficacy of a number of treatments. For years, azelaic acid and tetracycline antibiotics have been known to be effective therapies in some patients, although their mechanisms were unclear. In fact, tetracyclines are effective at subantimicrobial doses. Doxycycline, a member of the tetracycline family, was found to inhibit MMP activation in vitro.9 This limits the downstream activation of KLK and inhibits activation of cathelicidin. Azelaic acid is another effective therapy for rosacea. It was found in mice that azelaic acid decreases KLK activity and cathelicidin expression. Additionally, treatment with azelaic acid 15% was associated with decreased serine protease activity in human patients with rosacea.13 For decades it has been known that both of these therapies are clinically effective; however, elucidation of their mechanism supports the role of proteases and abnormal cathelicidin processing in the pathophysiology of rosacea.

Why are cathelicidin and KLK5 too high in rosacea? A definitive answer to this question is not yet clear, but this also serves to define the nature of innate immunity. The innate immune system depends on diverse pattern recognition receptors, such as the Toll‐like receptors (TLRs), to sense the environment. These molecules respond to extrinsic stimuli, such as microbial components, chemicals and physical trauma, as well as some intrinsic factors, such as tissue damage or ultraviolet‐induced apoptotic cells. They then orchestrate the release of cytokines and antimicrobial molecules, such as cathelicidins. Interestingly, many of the triggers of rosacea are also inducers of this system. One member of the TLR family, TLR2, is highly overexpressed in rosacea skin, which correlates with increased TLR2 activation to environmental stimuli. This results in increased production of KLK5 by keratinocytes and subsequently increased levels of the aberrant cathelicidin forms, which promote the disease.8, 14 Additionally, TLR2 indirectly increases cathelicidin production by stimulating conversion of vitamin D from the 25‐hydroxy form to the active 1,25‐dihydroxy form in keratinocytes, which promotes cathelicidin production.15 Together, these findings help link environmental triggers to the clinical disease.

These pathogen recognition receptors were first described for their ability to recognize microbial components, but the pattern recognition receptors are usually very promiscuous, and can respond to many different stimuli. This fits perfectly with clinical observations in rosacea.

Several microbes have been implicated in rosacea pathology, including Demodex folliculorum, Bacillus oleronius and Propionibacterium acnes. D. folliculorum is a common mite that inhabits sebaceous follicles. It has been implicated in rosacea exacerbations, as the mites are present in the patient's facial skin. One possibility is that chitin from the mite directly activates the overabundant TLR2 in patients with rosacea.16 In addition, B. oleronius has been isolated from D. folliculorum, and certain components from this microbe induce an inflammatory response. The implicated factors include lipoproteins and heat shock proteins, which are known agonists of certain TLRs, including TLR2. This provides a link between increased D. folliculorum, overabundant TLR2 and rosacea disease activity.14, 17 Finally, P. acnes, one of the most abundant commensal organisms on facial skin, has been shown to activate TLR2, leading to increased expression of cathelicidin and KLK5 in a dose‐dependent manner.14 Thus, these microbes implicated in rosacea have links through the aberrant expression of innate immune receptors in rosacea skin to the production of proinflammatory and proangiogenic factors, which drive the disease.

In addition to these innate immune receptors and molecules, mast cells have recently been shown to contribute to rosacea. Mast cells are prototypical cells of the innate immune system. They are found in increased numbers in rosacea skin and are capable of releasing various mediators that increase inflammation and promote angiogenesis.8, 18 In response to relatively low levels of cathelicidin, mast cells release MMP9, which is involved both directly in the pathophysiology of rosacea, and also in the activation of KLK5. Mast cells have also been shown to induce production of MMP9 and KLK in keratinocytes.19 In addition, mast cells are activated by various neuropeptides in skin. This is important, as neuronal dysregulation, including vasomotor instability, neuronal injury and release of proinflammatory neuropeptides, has been shown to be a significant contributor to rosacea pathology, and the mast cell may help link neuronal activity and stress with the pathogenesis of this disease.20

Neuropeptides, such as pituitary adenylate cyclase‐activating peptide (PACAP), have been associated with rosacea flairs and flushing.21 This may be due to the ability of PACAP, and other neuropeptides, to trigger activation of mast‐cell proteases and expression of proinflammatory cytokines.19 The role of mast cells in rosacea is supported by the findings that treatment with topical cromolyn in a small study decreased MMP activity and reduced erythema, with a mild decrease in KLK and cathelicidin protein.19 These findings support an important role for mast cells in the development and perpetuation of rosacea by providing a link between innate immunity and neuronal dysregulation.

Rosacea is a common disease with diverse triggers and clinical presentations, which have made its pathophysiology elusive. Fortunately, with the expansion of our understanding of innate immunity, a window has opened to help explain this disease. Aberrant expression of various factors, such as cathelicidins, proteases or TLR2, create a milieu that is both overly responsive to various triggers and capable of causing the inflammation and angiogenesis associated with rosacea. Additionally, the mast cells present in increased numbers seem to interact with both the innate immune system and the nervous system to bridge neural signals with the vascular and inflammatory effects that characterize this disease. Understanding these interactions also helps to elucidate why certain therapies work; tetracycline antibiotics or azelaic acid can suppress proteases and cathelicidin production; topical cromolyn suppresses mast‐cell activity and results in decreased erythema. It also illuminates areas to investigate for novel treatments, such as inhibitors of TLR2 or mast cells, or other protease inhibitors.

After 700 years of frustration trying to understand and treat this condition that affects millions of people worldwide, we are entering a time where our understanding of the pathophysiology of rosacea is accelerating, and novel therapeutic avenues are opening. We hope it will not take the next 125 years of the BJD to report how this knowledge will develop into a cure.