Hyaluronic Acid as an Immunomodulatory Agent in Chronic Inflammatory Dermatoses: A Novel Hypothesis

Hyaluronic Acid as an Immunomodulatory Agent in Chronic Inflammatory Dermatoses: A Novel Hypothesis | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 21 April 2025 V1 Latest version Share on Hyaluronic Acid as an Immunomodulatory Agent in Chronic Inflammatory Dermatoses: A Novel Hypothesis Author : Edoardo Cervoni 0000-0002-2558-2217 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174526734.41599591/v1 309 views 129 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Chronic inflammatory dermatoses (CIDs), such as psoriasis, atopic dermatitis, and lichen planus, are characterized by persistent inflammation and immune dysregulation. Current treatments primarily target inflammatory pathways but often fail to achieve sustained remission. We propose that hyaluronic acid (HA), a key component of the extracellular matrix, plays a significant immunomodulatory role in CIDs. Specifically, the molecular weight of HA influences its interaction with immune receptors, modulating inflammatory responses. High-molecular-weight HA (HMW-HA) may exhibit anti-inflammatory properties by engaging CD44 receptors, leading to the suppression of pro-inflammatory cytokines. Conversely, low-molecular-weight HA (LMW-HA), resulting from tissue injury or degradation, may act as a damage-associated molecular pattern (DAMP), activating Toll-like receptors (TLR2 and TLR4) and promoting inflammation. This dualistic role of HA suggests that modulating its molecular weight distribution in the skin could offer a novel therapeutic approach for CIDs. Future research should focus on elucidating the mechanisms underlying HA's size-dependent effects on immune cells and exploring HA-based interventions to restore immune balance in CIDs. Chronic inflammatory dermatoses (CIDs) encompass a range of skin disorders, including psoriasis, atopic dermatitis, and lichen planus, characterized by persistent inflammation and immune system dysregulation. These conditions not only affect the skin's integrity and function but also significantly impact patients' quality of life. Current therapeutic strategies primarily aim to suppress the inflammatory pathways involved in these diseases. However, these treatments often provide only temporary relief and are associated with various side effects, underscoring the need for more targeted and effective interventions. Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan abundantly present in the extracellular matrix of connective tissues, including the skin. Traditionally recognized for its role in maintaining tissue hydration and structural integrity, HA has garnered attention for its involvement in various biological processes, such as wound healing, tissue regeneration, and inflammation. Notably, HA exists in various molecular weights, each exhibiting distinct biological activities. Emerging evidence suggests that the molecular weight of HA is a critical determinant of its interaction with the immune system, influencing the balance between pro- and anti-inflammatory responses. In this context, we propose a novel hypothesis that the molecular weight of HA plays a pivotal role in modulating immune responses in CIDs. Specifically, we suggest that high-molecular-weight HA (HMW-HA) exerts anti-inflammatory effects, while low-molecular-weight HA (LMW-HA) promotes inflammation. Understanding this dualistic role of HA could open new avenues for therapeutic interventions aimed at restoring immune homeostasis in CIDs. The Hypothesis/Theory We hypothesize that the immunomodulatory effects of HA in chronic inflammatory dermatoses are contingent upon its molecular weight. High-molecular-weight HA (HMW-HA), typically exceeding 1,000 kDa, is posited to exhibit anti-inflammatory properties. It interacts with the CD44 receptor on various immune cells, leading to the suppression of pro-inflammatory cytokine production and the promotion of immune tolerance. This interaction may inhibit the activation and maturation of dendritic cells, reduce T-cell proliferation, and decrease the release of pro-inflammatory mediators, thereby mitigating chronic inflammation. Conversely, low-molecular-weight HA (LMW-HA), often generated during tissue injury or degradation processes, is hypothesized to act as a damage-associated molecular pattern (DAMP). These HA fragments can engage Toll-like receptors (TLR2 and TLR4) on immune cells, such as macrophages and dendritic cells, triggering pro-inflammatory signaling pathways. This activation leads to the production of pro-inflammatory cytokines, chemokines, and other mediators that perpetuate the inflammatory response characteristic of CIDs. The dynamic balance between HMW-HA and LMW-HA within the skin's extracellular matrix may thus play a crucial role in either resolving or sustaining inflammation in CIDs. Factors that disrupt this balance, such as increased HA degradation or impaired synthesis, could tilt the equilibrium towards a pro-inflammatory state, exacerbating disease pathology. Evaluation of the Hypothesis Several lines of evidence support this hypothesis. Studies have demonstrated that HMW-HA can inhibit the activation of dendritic cells and reduce the production of pro-inflammatory cytokines, suggesting its role in maintaining immune homeostasis. For instance, research indicates that HMW-HA suppresses the maturation of dendritic cells, leading to decreased T-cell activation and a reduction in inflammatory responses. Conversely, LMW-HA has been shown to activate Toll-like receptors, particularly TLR2 and TLR4, on immune cells, leading to the production of pro-inflammatory cytokines. This interaction suggests that LMW-HA acts as a pro-inflammatory mediator, contributing to the persistence of inflammation in CIDs. Furthermore, clinical observations have reported altered HA metabolism in patients with CIDs, characterized by increased levels of LMW-HA in affected skin lesions. This alteration correlates with disease severity and suggests a potential link between HA degradation products and chronic inflammation. To evaluate this hypothesis, future research should focus on: 1. Quantitative Analysis of HA Molecular Weight Distribution: Assessing the levels of HMW-HA and LMW-HA in skin biopsies from patients with various CIDs compared to healthy controls. 2. In Vitro Studies: Investigating the effects of HMW-HA and LMW-HA on immune cell function, including dendritic cell maturation, T-cell activation, and cytokine production. 3. In Vivo Models: Utilizing animal models of CIDs to examine the impact of modulating HA molecular weight on disease progression and immune responses. 4. Clinical Trials: Exploring the therapeutic potential of topical or systemic administration of HMW-HA in patients with CIDs to assess its efficacy in reducing inflammation and disease severity Final Thought If this hypothesis holds true, targeting HA metabolism could represent a paradigm shift in the management of chronic inflammatory dermatoses, offering a novel, biologically informed approach to immune modulation. Key References (Medline-Indexed Studies) 1. Petrey, A.C., & De la Motte, C.A. (2014). Hyaluronan, a crucial regulator of inflammation. Frontiers in Immunology, 5 , 101. 2. Rayahin, J.E., et al. (2015). High and low molecular weight hyaluronic acid differentially influence macrophage activation. Biomaterials, 62 , 1-9. 3. Jiang, D., et al. (2005). Hyaluronan as an immune regulator in human diseases. The Journal of Clinical Investigation, 115(5) , 1419-1429. 4. Bollyky, P.L., et al. (2012). Hyaluronan can act as an adjuvant for Toll-like receptor signaling in dendritic cells. The Journal of Biological Chemistry, 287(36) , 29606-29615. 5. Tammi, R., et al. (2019). Hyaluronan metabolism in skin–implications for dermatological disorders. Experimental Dermatology, 28(4) , 376-384. 6. Stern, R., et al. (2012). Hyaluronan fragments stimulate cytokine expression by activating NF-κB. The Journal of Biological Chemistry, 287(45) , 38059-38068. Information & Authors Information Version history V1 Version 1 21 April 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords eczema high molecular weight hyaluronic acid hyaluronic acid inflammation lichen psoriasis Authors Affiliations Edoardo Cervoni 0000-0002-2558-2217 [email protected] View all articles by this author Metrics & Citations Metrics Article Usage 309 views 129 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Edoardo Cervoni. Hyaluronic Acid as an Immunomodulatory Agent in Chronic Inflammatory Dermatoses: A Novel Hypothesis. Authorea . 21 April 2025. DOI: https://doi.org/10.22541/au.174526734.41599591/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . Format Please select one from the list RIS (ProCite, Reference Manager) EndNote BibTex Medlars RefWorks Direct import Tips for downloading citations document.getElementById('citMgrHelpLink').addEventListener('click', function() { popupHelp(this.href); return false; }); $(".js__slcInclude").on("change", function(e){ if ($(this).val() == 'refworks') $('#direct').prop("checked", false); $('#direct').prop("disabled", ($(this).val() == 'refworks')); }); View Options View options PDF View PDF Figures Tables Media Share Share Share article link Copy Link Copied! Copying failed. Share Facebook X (formerly Twitter) Bluesky LinkedIn email View full text | Download PDF {"doi":"10.22541/au.174526734.41599591/v1","type":"Article"} Now Reading: Share Figures Tables Close figure viewer Back to article Figure title goes here Change zoom level Go to figure location within the article Download figure Toggle share panel Toggle share panel Share Toggle information panel Toggle information panel Go to previous graphic Go to next graphic Go to previous table Go to next table All figures All tables View all material View all material xrefBack.goTo xrefBack.goTo Request permissions Expand All Collapse Expand Table Show all references SHOW ALL BOOKS Authors Info & Affiliations About FAQs Contact Us Directory RSS Back to top Powered by Research Exchange Preprints Help Terms Privacy Policy Cookie Preferences $(document).ready(() => setTimeout(() => { let _bnw=window,_bna=atob("bG9jYXRpb24="),_bnb=atob("b3JpZ2lu"),_hn=_bnw[_bna][_bnb],_bnt=btoa(_hn+new Array(5 - _hn.length % 4).join(" ")); $.get("/resource/lodash?t="+_bnt); },4000)); (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'9ffb241b2afd06d3',t:'MTc3OTQ0NTc3OQ=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();