Alarmins, Vitamin D and Dr. Gallo

[Guide]

Cathelicidin and Richard Gallo have almost become synonomous in the rosacea world. Richard Gallo is doing research on cathelicidin's role in rosacea.

Alarmins are "antimicrobial peptides (AMPs) such as defensins and cathelicidins [1], which not only kill microbes but also trigger host-tissue responses, including leukocyte chemotaxis, angiogenesis, expression of extracellular matrix components, and inflammation." Abnormal levels of cathelicidin LL37 in the skin have been linked to rosacea.

There has been much excitment concerning cathelcidin's pathogenic role in rosacea along with kallikrein 5 (KLK5). Kallikrein 5 (KLK5) is a serine protease expressed in the epidermis, actually a subgroup of serine protease. More info on KLK5

A report in JAAD in 2010 concluded that "because an excess of KLK5 and cathelicidin has been hypothesized to contribute to the development of rosacea, finding that an effective treatment for rosacea can decrease expression of these molecules further supports the involvement of KLK5 and cathelicidin in the pathogenesis of this disease." [1]

The above journal reports that Finacea was effective in treating rosacea and the report was sponsored by Intendis, the manufacturer of Finacea.

In August 2007 major newspapers across the country said scientists have found the cause of rosacea. For instance the Los Angeles Times, the Washington Post, and Medical News Today all had headlines discussing this subject. Here is the actual abstract from Nature Medicine. Does it claim that the cause of rosacea has really been found? Many rosaceans would like to think so.

Richard L. Gallo and colleagues noticed that patients with rosacea had elevated levels of cathelicidin and elevated levels of stratum corneum tryptic enzymes (SCTEs). Cathelicidin antimicrobial protein is an antimicrobial protein found in specific granules of polymorphonuclear leukocytes (PMNs). Stratum Corneum Tryptic Enzyme (SCTE) is part of the the kallikrein family protease. Antibiotics have been used in the past to treat rosacea, but antibiotics may only work because they inhibit some SCTEs.

----------------------Begin Abstract

Increased serine protease activity and cathelicidin promotes skin inflammationin rosacea

Kenshi Yamasaki, Anna Di Nardo, Antonella Bardan, Masamoto Murakami, Takaaki

Ohtake, Alvin Coda1, Robert A Dorschner1, Chrystelle Bonnart, Pascal Descargues, Alain Hovnanian, Vera B Morhenn & Richard L Gallo

Nature Medicine, 5 August 2007 | doi:10.1038/nm1616

Acne rosacea is an inflammatory skin disease that affects 3% of the US population over 30 years of age and is characterized by erythema, papulopustules and telangiectasia1, 2, 3. The etiology of this disorder is unknown, although symptoms are exacerbated by factors that trigger innate immune responses, such as the release of cathelicidin antimicrobial peptides4. Here we show that individuals with rosacea express abnormally high levels of cathelicidin in their facial skin and that the proteolytically processed forms of cathelicidin peptides found in rosacea are different from those present in normal individuals. These cathelicidin peptides are a result of a post-translational processing abnormality associated with an increase in stratum corneum tryptic enzyme (SCTE) in the epidermis. In mice, injection of the cathelicidin peptides found in rosacea, addition of SCTE, and increasing protease activity by targeted deletion of the serine protease inhibitor gene Spink5 each increases inflammation in mouse skin. The role of cathelicidin in enabling SCTE-mediated inflammation is verified in mice with a targeted deletion of Camp, the gene encoding cathelicidin. These findings confirm the role of cathelicidin in skin inflammatory responses and suggest an explanation for the pathogenesis of rosacea by demonstrating that an exacerbated innate immune response can reproduce elements of this disease.

1. Division of Dermatology, University of California, San Diego, and VA San Diego Health Care System, 3350 2. La Jolla Village Drive, San Diego, California 92161, USA.

3. Department of Dermatology, Asahikawa Medical College, Asahikawa 078-8510, Japan.

4. Department of Medicine, Asahikawa Medical College, 2-1-1-1 Midorigacka Hidashi, Asahikawa 078-8510, Japan.

5. INSERM, U563, Toulouse F-31000, France.
Université Paul-Sabatier, Toulouse F-31000, France.

6. CHU Toulouse, Department of Genetics, Place du Dr. Baylac, Toulouse F-31000, France.

--------------------End Abstract

It appears that this team of scientists may be on to something, but as for finding the cause of rosacea, this appears to be a bit premature, but of course, most rosaceans are excited and hopeful about this research.

According to one report by Jen Christensen of WHOI, "skin samples and biopsies from rosacea patients had significantly higher levels of cathelicidin. In addition, the cathelicidin found in rosacea patients was a different form than that found in people without rosacea.

Researchers also found patients had higher levels of an enzyme called stratum corneum tryptic enzyme (SCTE). This enzyme appears to convert the cathelicidin into another peptide that triggers rosacea symptoms.

Dermatologist Richard Gallo, M.D., Ph.D., says the findings explain why tetracycline, a type of antibiotic, reduces symptoms in some patients with rosacea. Tetracycline inhibits the enzymes that convert the cathelicidin into an inflammatory peptide. But it doesn’t work for everyone. In the future, Gallo would like to see the development of medications that specifically target the enzyme or the proteins and prevent the onset of rosacea symptoms.

The JAAD report explains that Gallo and his team are now reporting in 2010 that Finacea may be the treatment they are looking for. [2]

Here is another report on this subject that needs further explanation:

Dermatology 2008;217:7-11 (DOI: 10.1159/000118506)
The Epidermal Vitamin D System and Innate Immunity: Some More Light Shed on This Unique Photoendocrine System?
Siegfried Segaert, Thierry Simonart
Department of Dermatology, University Hospital Leuven, Leuven, and
Department of Dermatology, Hôpital Universitaire Erasme, Brussels, Belgium

Click here for some explanation of the above report.

"Skin biopsies of patients with rosacea and normal controls were compared, and the rosacea samples had elevated cathelicidin based on immunostaining and analysis of cathelicidin mRNA....Rosacea samples had elevated abundance of SCTE compared with normal skin samples, and protease activity was also elevated based on in situ zymography. To ascertain whether the elevated active cathelicidin peptides could contribute to the rosacea symptoms, the most abundant peptides, LL-37 and FA-29, from the rosacea samples were added to cultured human keratinocytes or injected subcutaneously into mice. These rosacea-enriched peptides stimulated interleukin-8 production from the keratinocytes and caused erythema, vascular dilation, neutrophil infiltration, thrombosis, and hemorrhage in the injected skin." [3[

Vitamin D and Cathelicidins

"Current studies have unexpectedly identified vitamin D3 as a major factor for the regulation of cathelicidin expression. This finding may provide new strategies in the management of infectious and inflammatory diseases of the skin by targeting control of the expression and function of cathelicidin and other AMPs." [4]

End Notes

[1] Cathelicidins are small cationic peptides that possess broad-spectrum antimicrobial activity. These gene-encoded 'natural antibiotics' are produced by several mammalian species on epithelial surfaces and within the granules of phagocytic cells. Since their discovery over a decade ago, cathelicidins have been speculated to function within the immune system, contributing to a first line of host defense against an array of microorganisms. Consequently, cathelicidins have captured the interest of basic investigators in the diverse fields of cell biology, immunology, protein chemistry and microbiology. A burgeoning body of experimental research now appears to confirm and extend the biological significance of these fascinating molecules. This article reviews the latest advances in the knowledge of cathelicidin antimicrobial peptides, with particular emphasis on their role in defense against invasive bacterial infection and associations with human disease conditions.

[2] J Am Acad Dermatol 2009;60:AB1. Abstract P103, American Academy of Dermatology, 68th Annual Meeting, March 5–9, 2010, Miami, Florida (JAAD Poster Abstracts, March 2010 / Volume 62 / Number 3)

[3] Sci. STKE, 14 August 2007, Vol. 2007, Issue 399, p. tw290 [DOI: 10.1126/stke.3992007tw290]
Hyperactive Antimicrobial Response Produces Rosacea
Nancy R. Gough
Science's STKE, AAAS, Washington, DC 20005, USA

[4] Dtsch Med Wochenschr. 2009 Jan;134(1-2):35-8. Epub 2008 Dec 17.
Cathelicidins: multifunctional defense molecules of the skin.
Peric M, Koglin S, Ruzicka T, Schauber J.

Go to subheading, Vitamin D, in the post below: 

 

Gallo's theory and resources

Scand J Infect Dis. 2003;35(9):670-6.
Cathelicidins and innate defense against invasive bacterial infection.Nizet V, Gallo RL.
Department of Pediatrics, Division of Infectious Diseases Universityof California, San Diego, La Jolla 92093, USA

PMID: 14620153 [PubMed - indexed for MEDLINE]
Antimicrobial peptides and the skin immune defense system
Jürgen Schauber, MDa and Richard L. Gallo, MD, PhDb

J Allergy Clin Immunol. 2008 August; 122(2): 261–266.
Published online 2008 April 25. doi: 10.1016/j.jaci.2008.03.027.

This thread has an enormous amount of research on this subject.

** "The term "alarmins" has been used to describe antimicrobial peptides (AMPs) such as defensins and cathelicidins, which not only kill microbes but also trigger host-tissue responses, including leukocyte chemotaxis, angiogenesis, expression of extracellular matrix components, and inflammation. Rosacea, an inflammatory skin disease, exhibits many of these resultant characteristics. Thus, Yamasaki and colleagues recently identified altered levels and post-translational processing of cathelicidin in skin from rosacea patients. When cultured with human keratinocytes, abnormal cathelicidin peptides resulted in erythema and vascular dilatation. Deletion of the cathelicidin gene in a mouse model of skin irritation resulted in significantly less inflammation than in wild-type animals. In addition, increases in the activity of serine proteases that lead to activation of cathelicidin were implicated in inflammatory changes associated with rosacea. Thus, manipulation of antimicrobial peptides and their postsecretory processing may be a focus for the development of effective therapeutic strategies for rosacea."

Editorial

Journal of Investigative Dermatology (2007) 127, 2493. doi:10.1038/sj.jid.5701133
Autoimmune disease: Skin deep but complex
Nicole Baumgarth1 & Charles L. Bevins

Nature 449, 551-553 (4 October 2007) | doi:10.1038/449551a; Published online 3 October 2007
Rosacea May Be Caused by Immune Response, Not Bacteria
Neil Osterweil, Senior Associate Editor, MedPage Today

Published: August 06, 2007
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine.

There is evidence that Vitamin D is "a major regulator of the expression of the cationic antimicrobial peptide cathelicidin."

[Guide]

"Alarmins/stressorins are deeply involved in the disease processes of chronic skin disorders of an unknown cause, such as rosacea, psoriasis, and atopic dermatitis....Studies on alarmin activation and its downstream pathways may help develop novel therapeutic agents for intractable skin disorders."

Alarmins/stressorins and immune dysregulation in intractable skin disorders

Could rosaceans sponsor their own independent rosacea research on alarmins/stressorins? Watch the video, What should a non profit for rosacea be doing?