Cathelicidin Peptide LL-37 and Vitamin D3

[Guide]

In an article published in PLoS ONE [1] stated that “The cause of rosacea has been proposed as over-production of the cationic cathelicidin peptide LL-37.” This statement is without a doubt the result of the work of Gallo, et. al, at the University of San Diego that was initially published in Nature Magazine [2].

"This inflammatory antimicrobial peptide is known to complex nucleic acids and induce both inflammatory and interferon responses from keratinocytes." [12]

"Cathelicidins and defensins provide broad-spectrum protection against gram-positive and gram-negative bacteria....For example, the human cathelicidin LL-37 has potent direct antibacterial activity against bacteria such as Group A Streptococcus (GAS),..." [10]

So what is cationic cathelicidin peptide LL-37? It is an Antimicrobial peptide (AMP) which is part of our immune system that attack invading bacteria or other microbes to defend our body. There has been some evidence that rosacea may be a result of an immune system disorder. [3] Gallo, mentioned earlier, said in 2004, that rosacea may be an “abnormality in the innate immune system … caused by too much cathelicidin.” He is also quoted as saying “if we believe that the disease is caused by too much cathelicidin, we could develop a strategy to block the effects of the cathelicidins by making molecules that mimic that protein but don’t have the same effects.” [4]

When reading these articles, one might conclude that the theory of what causes rosacea is over and that cathelicidin is the culprit. However, the article only said that the “cause of rosacea has been proposed as over-production of the cationic cathelicidin peptide LL-37.” The jury is still out on what causes rosacea. [5]

However, it is important to note that as Dr. Gallo pointed out, “if we believe that the disease is caused by too much cathelicidin” then the treatment might be radically different. Antibiotics are regularly used to treat rosacea and may be treating the wrong target. [6] So this new article published in PloS One by Zhang, et. al, “tested a new class of non-anticoagulant sulfated anionic polysaccharides, semi-synthetic glycosaminoglycan ethers (SAGEs)” on mouse skin. The result:

“Topical application of a 1% (w/w) SAGE emollient to overlying injected skin also reduced erythema and PMN infiltration from intradermal LL-37.” [1]

Cathelicidin LL-37 Ignites Primed NLRP3 Inflammasomes in Rosacea

So we wait and see what will become of this new treatment for rosacea based on the theory that the cause is an overproduction of Cationic Cathelicidin Peptide LL-37.

LL-37 Suppression Treatments

"Coptis chinensis Franch (CC) has been used as a medicinal herb in traditional oriental medicine. However, little is known about the efficacy and mechanism of action of CC in rosacea. In this study, we evaluate the effect of CC and its molecular mechanism on rosacea in human epidermal keratinocytes. CC has the capacity to downregulate the expression of KLK5 and cathelicidin, and also inhibits KLK5 protease activity, which leads to reduced processing of inactive cathelicidin into active LL-37. It was determined that CC ameliorates the expression of pro-inflammatory cytokines through the inhibition of LL-37 processing. In addition, it was confirmed that chitin, an exoskeleton of Demodex mites, mediates an immune response through TLR2 activation, and CC inhibits TLR2 expression and downstream signal transduction. Furthermore, CC was shown to inhibit the proliferation of human microvascular endothelial cells induced by LL-37, the cause of erythematous rosacea. These results demonstrate that CC improved rosacea by regulating the immune response and angiogenesis, and revealed its mechanism of action, indicating that CC may be a useful therapeutic agent for rosacea." [13]

Botox Reduces LL-37-Induced Erythema

Hydroxychloroquine Suppresses LL37-induced Mast Cells

Cinnamtannin B1 (CB1)

Paeoniflorin

Vitamin D3 and Cathelicidin

"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." [7]

"Therapies targeting vitamin D3 signalling may provide novel approaches for the treatment of infectious and inflammatory skin diseases by affecting both innate and adaptive immune functions through AMP regulation." [8]

Low Serum Vitamin D in Rosacea Patients
"Serum vitamin D was lower in patients with rosacea, although serum cathelicidin was higher than that of the controls. This suggests that the role of vitamin D level in the pathogenesis of rosacea merits further investigation." [9]

High Serum Vitamin D in Rosacea Patients
"Patients with rosacea have relatively high serum vitamin D levels compared to control groups. The result of our study suggests that increased vitamin D levels may lead to the development of rosacea. To confirm status of vitamin D levels in patients with rosacea, larger epidemiological studies are needed." [11]

As the previous two paragraphs have indicated opposite Vitamin D serum levels in rosacea patients, the jury is still out on this as we await further developments in research on this. Wouldn't it be incredible of a non profit organization for rosacea patient advocacy like the RRDi could get it members to support independent research on Vitamin D and rosacea or fund more investigation into LL-37?  Just think if 10K members each donated one dollar and we sponsored such an infestation?  

More on Cathelicidin • More on Cytokines

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End Notes

[1] Novel Sulfated Polysaccharides Disrupt Cathelicidins, Inhibit RAGE and Reduce Cutaneous Inflammation in a Mouse Model of Rosacea.
Zhang J, Xu X, Rao NV, Argyle B, McCoard L, Rusho WJ, Kennedy TP, Prestwich GD, Krueger G.
PLoS One. 2011 Feb 9;6(2):e16658.

[2] Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea
Kenshi Yamasaki1, Anna Di Nardo1, Antonella Bardan1, Masamoto Murakami2, Takaaki Ohtake3, Alvin Coda1, Robert A Dorschner1, Chrystelle Bonnart4,5, Pascal Descargues4,5, Alain Hovnanian4,5,6, Vera B Morhenn1 & Richard L Gallo1
Nature Medicine 13, 975 – 980 (2007)
Published online: 5 August 2007 | doi:10.1038/nm1616

[3] Alarmins, Vitamin D, And Other Info
post by Brady Barrows, Director of the RRDi

[4] Innate immunity: Role in rosacea?
Michelle Stephenson
Dermatology Times, June 1, 2004
posted at Rosacea Support Group

[5] Theories Revisited

[6] Dr. Gallo is quoted as saying, “Antibiotics tend to alleviate the symptoms of rosacea in patients because some of them work to inhibit these enzymes [sTCE]. Our findings may modify the therapeutic approach to treating rosacea, since bacteria aren’t the right target.”
UCSD Researchers Discover Cause of Rosacea
By Debra Kain, University of California, San Diego, August 7, 2007

[7] Cathelicidins: multifunctional defense molecules of the skin.
Peric M, Koglin S, Ruzicka T, Schauber J.
Klinik und Poliklinik für Dermatologie und Allergologie, Ludwig-Maximilians-Universität München.
Dtsch Med Wochenschr. 2009 Jan;134(1-2):35-8. Epub 2008 Dec 17.

[8] Impact of vitamin D3 on cutaneous immunity and antimicrobial peptide expression.
Antal AS, Dombrowski Y, Koglin S, Ruzicka T, Schauber J.
Dermatoendocrinol. 2011 Jan;3(1):18-22.

[9]Ann Dermatol. 2018 Apr;30(2):136-142. doi: 10.5021/ad.2018.30.2.136. Epub 2018 Feb 21.
A Study on Vitamin D and Cathelicidin Status in Patients with Rosacea: Serum Level and Tissue Expression.
Park BW1, Ha JM1, Cho EB1, Jin JK2, Park EJ1, Park HR3, Kang HJ4, Ko SH5, Kim KH1, Kim KJ1.

Cutan Ocul Toxicol. 2014 Mar;33(1):60-2. doi: 10.3109/15569527.2013.797907. Epub 2013 May 28.
Vitamin D status in patients with rosacea.
Ekiz O1, Balta I, Sen BB, Dikilitaş MC, Ozuğuz P, Rifaioğlu EN.

[10] PLoS Pathog. 2018 Dec; 14(12): e1007353.
Published online 2018 Dec 6. doi: 10.1371/journal.ppat.1007353
PMCID: PMC6283644; PMID: 30522130
Innate antimicrobial immunity in the skin: A protective barrier against bacteria, viruses, and fungi
Margaret Coates, Sarah Blanchard, and Amanda S. MacLeod

[11] Journal Cutaneous and Ocular Toxicology, Volume 33, 2014 - Issue 1
Vitamin D status in patients with rosacea
Özlem Ekiz, İlknur Balta, Bilge Bülbül Şen, Meltem Cik Dikilitaş, Pınar Özuğuz & Emine Nur Rifaioğlu

[12] Front Immunol. 2019 Apr 24;10:857.  doi: 10.3389/fimmu.2019.00857.  eCollection 2019.
Antimicrobial Peptide LL-37 Facilitates Intracellular Uptake of RNA Aptamer Apt 21-2 Without Inducing an Inflammatory or Interferon Response
Tom Macleod, Joseph Ward, Adewonuola A Alase, Charlie Bridgewood, Miriam Wittmann, Nicola J Stonehouse 

[13] Molecules. 2020 Nov 26;25(23):
Coptis chinensis Franch Directly Inhibits Proteolytic Activation of Kallikrein 5 and Cathelicidin Associated with Rosacea in Epidermal Keratinocytes.
Roh KB, Ryu DH, Cho E, Weon JB, Park D, Kweon DH, Jung E

[Guide]

"Overall, the results of this study suggest that ivermectin treatment prevents the augmentation of the cathelicidin immune pathway, which has a positive impact on the downstream inflammatory pathway (e.g., decreased IL-8, IL-6 and CCL2 secretion). These results suggest that ivermectin can prevent the inflammatory effects of rosacea triggered by abnormal LL-37 processing, through the inhibition of KLK5and CAMP gene expression in the epidermis."

Dermatol Ther (Heidelb). 2017 Jun; 7(2): 213–225.
Published online 2017 Feb 27. doi:  10.1007/s13555-017-0176-3
PMCID: PMC5453918
Topical Treatment of Rosacea with Ivermectin Inhibits Gene Expression of Cathelicidin Innate Immune Mediators, LL-37 and KLK5, in Reconstructed and Ex Vivo Skin Models
Séverine Thibaut de Ménonville,corresponding author Carine Rosignoli, Estelle Soares, Manon Roquet, Béatrice Bertino, Jean-Paul Chappuis, Claire Defoin-Platel/Chaussade, and David Piwnica

[Guide]

"However, following injury or inflammatory skin diseases such as psoriasis and rosacea, expression of the cathelicidin antimicrobial peptide LL37 breaks tolerance to self-nucleic acids and triggers inflammation."

Cathelicidin promotes inflammation by enabling binding of self-RNA to cell surface scavenger receptors.
Sci Rep. 2018 Mar 05;8(1):4032
Takahashi T, Kulkarni NN, Lee EY, Zhang LJ, Wong GCL, Gallo RL