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3D medical animation still of Cytokines that are important in cell signaling. Image courtesy of Wikimedia Commons

Another cytokine is emerging as a possible link to rosacea, interleukin 17A (IL17A), with a report of using a biologic treatment for rosacea, secukinumab. [1] For several years the cytokine, cathlecidin, has been considered linked to rosacea because it is found in high levels with rosacea patients. [2] The following animated video explains how this works in treatment for psoriasis (secukinumab is now being used to treat rosacea): 

"Cytokines are a broad and loose category of small proteins (~5–20 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents." [3] 

"Their definite distinction from hormones is still part of ongoing research." [3]

Therefore, cytokines are important in health and in disease prevention and when working properly everything is fine. However, just like the hormone insulin, when in proper amount secreted it works like a charm. If you are too low on insulin or too high things get a bit tricky when it comes to health. The same is true with cytokines. Cytokines in the right amount, everything is hunky dory, but when too many are present it can create quite a storm, or if not enough, things can get worse. The theory is that cytokines need to be investigated more in what role they play in rosacea inflammation. 

Cytokines and the Rosacea Immune System Disorder Theory
Cytokines are related to the theory that rosacea is an immune system disorder. [4] Mast cells have important effects on the pathogenesis of rosacea and produce cytokines.  

What is interesting is that "Cytokines also play a role in anti-inflammatory pathways and are a possible therapeutic treatment for pathological pain from inflammation or peripheral nerve injury. There are both pro-inflammatory and anti-inflammatory cytokines that regulate this pathway." [3] The first cytokine discovered was Interferon-alpha, an interferon type I, identified in 1957 as a protein that interfered with viral replication. [5]

Both interleukin 17A and cathlecidin are cytokines that are related to inflammation in disease. 

Could it be possible that the cytokine response in rosacea sufferers is somehow related to virus? [7] For over sixty years the focus has been on bacteria or demodex. Could it be that the investigation should focus more on virus as the culprit why the cytokines are reacting? Virus are so tiny that the bacteria or demodex may carry a pathogen virus that is triggering the cytokine response. Has anyone even looked into this?  Have you seen any paper that has ruled out virus in rosacea?

Cytokine storm is associated with Covid 19 deaths as well as with the 1918 Spanish Flu epidemic. 

Interleukin 17A is an inflammatory cytokine. "Inflammatory cytokines are predominantly produced by and involved in the upregulation of inflammatory reactions.Excessive chronic production of inflammatory cytokines contribute to inflammatory diseases, that have been linked to different diseases...A balance between proinflammatory and anti-inflammatory cytokines is necessary to maintain health. Aging and exercise also play a role in the amount of inflammation from the release of proinflammatory cytokines." [9]

"Cathelicidin antimicrobial peptides (CAMP) LL-37 and FALL-39 are polypeptides...serve a critical role in mammalian innate immune defense against invasive bacterial infection..." [2] "These peptides are potent, broad spectrum antibiotics which demonstrate potential as novel therapeutic agents.  Antimicrobial peptides have been demonstrated to kill Gram negative and Gram positive bacteria, enveloped viruses, fungi and even transformed or cancerous cells." [10] Dr. Gallo, et al, has applied for a patent, PREVENTION OF ROSACEA INFLAMMATION, United States Patent Application 20160030386, related to this. [11]

"Toll-like receptor 2 (TLR2) and TLR4 signaling may induce differential secretion of T helper 1 (Th1) and Th2 cytokines, potentially influencing the development of autoimmune or atopic diseases....TLR proteins mediate cellular activation, including the expression of cytokines induced by a variety of bacterial products..." [14]

Other Cytokines and Rosacea
"Additionally, we identified the upregulation of IL-5 and IL-13 in PPR conditioned culture medium. IL-5 and IL-13 are type 2 cytokines that play important roles in the pathophysiology of allergic diseases. Although the elevation of these cytokines in PPR has not been previously reported, PPR has been associated with airborne allergies (Rainer et al. 2015). A recent publication identified IL4l1 and IL4R as differentially expressed genes in PPR lesional tissue compared to NLS, suggesting the type 2 axis may play a role in PPR pathology (Shih et al. 2019)." [12]

Without a doubt we will be learning more on further research with interleukin 17A (IL17A) and possible other cytokines that are involved in the inflammation of rosacea. 

Magnesium decreases inflammatory cytokine production by modulation of the immune system. [8]

Secukinumab (Cosentyx) [1]

"Treatment of patients with isotretinoin significantly decreased monocyte TLR-2 expression and subsequent inflammatory cytokine response to P. acnes by one week of therapy. This effect was sustained six months following cessation of therapy, indicating that TLR-2 modulation may be involved in the durable therapeutic response to isotretinoin...Disorders characterized by inflammation such as acne, rosacea, psoriasis, psoriatic arthritis, and Behcet’s disease have been linked to dysregulation of innate immune signaling...Isotretinoin’s mechanism of action in inducing long-term remissions of acne is unknown....The mechanism by which retinoids affect TLR expression is unknown." [bold added] [13]

Topical ivermectin has been found effective in the treatment of T‐cell‐mediated skin inflammatory diseases. [6]

Independent Rosacea Research
Could a group of rosacea sufferers in a non profit organization like the RRDi collectively get together and sponsor their own research on rosacea? For example, if 10K members each donated a dollar, could it be possible that this money could be used to sponsor their own independent rosacea research on cytokines?  What do you think? If you want to do something about this read this post

End Notes

[1] Secukinumab (Cosentyx)

[2] Cathelicidin

[3] Cytokine, Wikipedia

[4] Innate Immune Response Disorder

[5] Proc R Soc Lond B Biol Sci. 1957 Sep 12;147(927):258-67.  doi: 10.1098/rspb.1957.0048.
Virus interference. I. The interferon

[6] Ivermectin Anti-Inflammatory Properties

[7] Virus and Rosacea

[8] J Immunol. 2012 Jun 15;188(12):6338-46.  doi: 10.4049/jimmunol.1101765.  Epub 2012 May 18.
Magnesium decreases inflammatory cytokine production: a novel innate immunomodulatory mechanism
Jun Sugimoto, Andrea M Romani, Alice M Valentin-Torres, Angel A Luciano, Christina M Ramirez Kitchen, Nicholas Funderburg, Sam Mesiano, Helene B Bernstein

J Inflamm Res. 2018 Jan 18;11:25-34.  doi: 10.2147/JIR.S136742.  eCollection 2018.
Magnesium deficiency and increased inflammation: current perspectives
Forrest H Nielsen 

[9] Inflammatory cytokine, Wikipedia

[10] Antimicrobial peptides (AMPs), Wikipedia

[11] Gallo Patent for the 'Prevention of Rosacea Inflammation'

[12] J Invest Dermatol. 2020 Sep 14;:
Paired Transcriptomic and Proteomic Analysis Implicates IL-1β in the Pathogenesis of Papulopustular Rosacea Explants.
Harden JL, Shih YH, Xu J, Li R, Rajendran D, Hofland H, Chang ALS

[13] J Invest Dermatol. 2012 Sep; 132(9): 2198–2205.
Systemic isotretinoin therapy normalizes exaggerated TLR-2-mediated innate immune responses in acne patients
Melanie C. Dispenza, Ellen B. Wolpert, Kathryn L. Gilliland, Pingqi Dai, Zhaoyuan Cong, Amanda M. Nelson, Diane M. Thiboutot

[14] J Interferon Cytokine Res. Author manuscript; available in PMC 2007 Nov 2.
TLR2 and TLR4 Stimulation Differentially Induce Cytokine Secretion in Human Neonatal, Adult, and Murine Mononuclear Cells

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