The yin and yang of cathelicidins: how the innate immune system drives skin disease

Journal of Drugs in Dermatology, Nov, 2007 by Kendra Gail Bergstrom

Initially Described in the 1990s

Initially described in the early 1990s, cathelicidins are antimicrobial peptides found in vertebrates like mammals, birds, and fish. In humans, they are expressed by keratinocytes and neutrophils, as well as the spleen and bone marrow. Cathelicidins respond to tissue injury via damaged keratinocytes and neutrophil granules. The family includes human cathelicidins LL-37 and [beta]-defensin. In skin, they are found in the cornified and granular layers. New research tells us that too little or too much cathelicidin can cause skin disease.

Active Against a Broad Spectrum of Pathogens

Cathelicidins are active against Gram-positive and Gram-negative bacteria, enveloped viruses including HIV, and fungi including candida and Cryptococcus. They are amphipathic, hydrophobic, and hydrophilic peptides that create pores or holes in pathogen membranes. Others bind lipopolysaccharide or recruit the immune system. Others inhibit reactive oxygen species created by neutrophils to mitigate excess tissue damage. Another effect is to promote angiogenesis and vascular dilatation. Cathelicidins are effective antibiotics against resistant staphylococcus, enterococcus, and pseudomonas in animal models.

How They Work

Cathelicidins are produced as propeptides and are proteolytically cleaved by serine proteases into active forms. Serine proteases include stratum corneum tryptic enzyme (SCTE), also called kallikrein-5. These proteases can be inactivated, stopping cathelicidins via protease inhibitors including SPINK5. Interestingly, mutations in SPINK5 also mediate the rare autosomal recessive genodermatosis Netherton syndrome. Netherton syndrome is characterized by erythroderma, atopic diathesis, ichthyosis linearis circumflexa, and trichorrhexis invaginata, the so-called "bamboo hair."

I. Cathelicidins Drive Rosacea: Role for Tetracyclines and New Therapeutics

Rosacea is a common disease affecting almost 3% of the US population over 30 years of age. Symptoms range from flushing and telangiectasias to papules, pustules, and later phymatous changes, almost exclusively on the face. While not life-threatening, this disease can cause significant morbidity due to its prominent location and the inappropriate association of redness with alcohol use.

An August 2007 article in Nature Medicine revealed for the first time a molecular mechanism of rosacea based in the innate immune system. (1) A group at the University of California, San Diego led by Richard Gallo evaluated human skin biopsies to characterize cathelicidin profiles in normal and rosacea skin, and replicated these changes in a mouse model. This work was based on the observation that cathelicidins cause skin changes (ie, neutrophil recruitment, angiogenesis, and cytokine release) that are also seen in rosacea. Another clue for their involvement is that rosacea flares are mediated by proinflammatory signals that also cause the release of cathelicidins.

In the human part of the study, 3-mm skin biopsies were taken from 11 rosacea patients and 10 normal controls at the nasomalar fold. Rosacea patients showed 10-fold higher concentrations of the active cathelicidin LL-37. The serine protease that activates cathelidicins, SCTE, was also increased up to 1,000 times higher than normal throughout the epidermis of the affected skin. Cathelicidins were almost undetectable in the normal skin.

Replicating the physiologic changes seen in human skin, a transgenic mouse was made with a constitutive knockout of the mouse cathelicidin. Both transgenic and normal mice were injected with cathelicidins, and in another experiment with SCTE, to duplicate the changes found in human rosacea skin. The skin of normal and cathelidicin-deficient mice was irritated to determine response to external stimulus, mimicking human rosacea. Normal mouse skin showed a brisk reaction, with erythema, vascular dilatation, neutrophilic infiltrate, and increased IL-8 to cathelicidins, SCTE, and physical irritation. Cathelicidin-deficient mice produced significantly less inflammation. Mice deficient in the protease inhibitor LEKTI, which stops cathelidicin activation, showed proirritant changes as well.

A previous study (4) shows that human cathelicidin increases vascular permeability. Why the increased permeability is confined to the face in rosacea is unclear.

These new clues to rosacea pathogenesis point to new directions in treatment. Tetracyclines, in addition to their antimicrobial properties, are effective protease inhibitors. They inhibit matrix metalloproteases-2 and -9, (2) as well as the serine proteases that activate cathelidicins. In this way, tetracyclines are able to decrease cathelicidin levels. This property may account for the efficacy of subantimicrobial doxycycline. (3)

This new research underscores the mechanism and potential efficacy of newer nonantibiotic dose tetracyclines and non-antibiotic tetracyclines now in development such as dimethylaminotetracycline.

Another possible therapeutic approach is topical cathelicidin inhibition. Topical protease inhibitors that stop cathelicidin activation have been investigated for ocular use in allergic conjunctivitis. (5) In the future, topical protease inhibitors may be able to mitigate irritation in rosacea.