Jump to content

Cytokines and Rosacea

Recommended Posts

  • Root Admin

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

While more rosacea research has been focused since 2007 on Cathelicidin, 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 (using secukinumab) which 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. "At the heart of the inflammatory response are the mechanisms that stimulate the production of inflammatory mediators and cytokines." [16]

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

One research paper "provided a comprehensive and objective analysis of the main studies on the influence of cytokines in ocular inflammatory diseases." [22]

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

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]

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?

"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]

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]

"Our study showed increased serum IL-17 levels in rosacea patients and a significant correlation between IL-17 concentrations and secondary features of the disease suggesting IL-17 may contribute to pathogenesis of rosacea and may be a new target for rosacea treatment." [19]

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. 

"...adipokines may contribute to various aspects of the homeostasis of the skin, e.g., melanogenesis, hair growth, or wound healing, just as to the pathogenesis of dermatological diseases such as psoriasis, atopic dermatitis, acne, rosacea, and melanoma." [15] [bold added] Adipokines are cytokines. 

Bradykinin, another cytokine, has long been associated with rosacea. [17]

"Besides, aspirin administration decreased the microvessels density and the VEGF expression in rosacea-like skin. We further demonstrated that aspirin inhibited the activation of NF-κB signaling and the release of its downstream pro-inflammatory cytokines."

Pro-inflammatory cytokine CCL20 "stimulates inflammation by recruiting Th17 T-lymphocytes and dendritic cells and is elevated in papulopustular rosacea." [20]

"Taken together, our findings revealed that mTORC1-mediated angiogenesis responding to LL37 might be essential for the development of rosacea and targeting angiogenesis might be a novel potential therapy." [21]

"In this study, we aimed at examining the serum levels of a series of chemokines (including CCL2, CCL3, CCL20, CXCL1, CXCL8, CXCL9, CXCL10, and CXCL12) implicated in rosacea and their correlation with disease severity." [23] [24]

"In conclusion, our results showed that the destruction of the skin barrier aggravates the inflammation levels and immune infiltration of rosacea partly by activating STAT3-mediated cytokine signal pathways in keratinocytes." [25]

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

Reply to this Topic
There is a reply to this topic button somewhere on the device you are reading 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

[15] Int J Mol Sci. 2020 Nov 28;21(23):
Adipokines in the Skin and in Dermatological Diseases.
Kovács D, Fazekas F, Oláh A, Törőcsik D

[16] Int J Mol Sci. 2021 Jan; 22(2): 721.
The Role of Endogenous Antimicrobial Peptides in Modulating Innate Immunity of the Ocular Surface in Dry Eye Diseases
Youssof Eshac, Rachel L. Redfern, and Vinay Kumar Aakalu

[17] Bradykinin Rosacea Theory

[18] Aspirin alleviates skin inflammation and angiogenesis in rosacea

[19] Serum IL-17 levels in Patients with Rosacea

[20] Glucocorticoids Promote CCL20 Expression in Keratinocytes

[21] PubMed RSS Feed - -mTORC1-Mediated Angiogenesis is Required for the Development of Rosacea

[22] J Clin Med. 2022 Feb; 11(3): 661.
Influence of Cytokines on Inflammatory Eye Diseases: A Citation Network Study
Beatriz G. Gálvez, Clara Martinez-Perez, Cesar Villa-Collar, Cristina Alvarez-Peregrina, Miguel Ángel Sánchez-Tena

[23] "Chemokines (from Ancient Greek χῠμείᾱ (khumeíā) 'alchemy', and κῑ́νησῐς (kī́nēsis) 'movement'), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells." Wikipedia

[24] Increased serum levels of CCL3, CXCL8, CXCL9, and CXCL10 in rosacea patients and their correlation with disease severity

[25] PubMed RSS Feed - -Multi-Transcriptomic Analysis and Experimental Validation Implicate a Central Role of STAT3 in Skin Barrier Dysfunction Induced Aggravation of Rosacea

Link to comment
Share on other sites

  • Guide pinned this topic
  • 4 months later...
  • Root Admin


It is of interest to note that an anti-depressant, fluvoxamine, brand name Luvox,  which is a selective serotonin reuptake inhibitor (SSRI) most often used to treat obsessive compulsive disorder (OCD) and depression is being considered to treat Covid 19. A CNN article states the following about this drug treating cytokines: 

" 'Fluvoxamine may reduce the production of inflammatory molecules called cytokines, that can be triggered by SARS-CoV-2 infection,' Reiersen said in a statement. The drug may also reduce blood platelets, which may affect the clotting effects of coronavirus infection."

Cheap, generic anti-depressant may reduce severe Covid-19 disease, study finds. Maggie Fox, CNN

Link to comment
Share on other sites

Create an account or sign in to comment

You need to be a member in order to leave a comment

Create an account

Sign up for a new account in our community. It's easy!

Register a new account

Sign in

Already have an account? Sign in here.

Sign In Now
  • Create New...

Important Information

Terms of Use