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Immunomodulation Properties of Hyaluronic Acid: History
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Subjects: Materials Science, Biomaterials
Contributor: Ciara Buckley

The principal function of the immune system is defence, either against foreign matter, including pathogens, or against disease, including cancer. The complexity of the immune system occurs when the immune response either fails to respond to a pathogen or is over-exasperated. Interventions such as vaccines can improve the immune response. Steroids or anti-inflammatory medications can reduce hyper-inflammation. Inflammation is a key, protective immunological function. If not appropriately controlled, it can cause harm to the host and lead to pathologies. Inflammation is linked to several chronic diseases. With increasing numbers of autoimmune conditions and infectious agents, molecules that interact positively with the immune system are always in demand.

Hyaluronic acid (HA) is a natural polysaccharide that is abundant in the human body and can be obtained through animal extraction or bacterial fermentation. This unique biopolymer has been shown to have contrasting immune effects depending on the molecular weight of the molecule. Both low molecular weight and high molecular weight HA have found uses as moderators of inflammation and immune response which lends this molecule to a host of applications from wound repair to vaccine adjuvants. This review seeks to evaluate the immunomodulatory uses and potentials of hyaluronic acid. 

  • Immunomodulation Properties
  • Hyaluronic Acid
  • polysaccharide
  • Biomaterial
  • Bioengineering
  • Vaccine
  • Inflammation
  • Adjuvant

1. Introduction

Bioactives are molecules that can interact with the immune system in particular cells of first-line defence, including monocytes or macrophages. Bioactives with immune-modulatory activity are of particular interest as they can reduce inflammation without affecting pathogen clearance. Physiochemical properties of bioactives are correlated to activity. These properties include; the final form of the polymer (3D printed, hydrogel, or solid), crosslinking density, and whether the material is synthetic or natural. It has been reported that a high crosslinking density of biomaterials can promote inflammatory macrophage responses [1][2]. In contrast, the opposite appears to be true in the case of HA [3].
Immunity can be roughly categorised as innate or nonspecific or acquired or specific. Innate immunity, a rapid response is the earliest line of defence against nonspecific invaders. Included under the innate system are monocytes, macrophages, dendritic cells, and neutrophils. Acquired immunity is a slower response that develops after the initial exposure and is reliant on B- and T-cells. After the initial exposure, the secondary response is rapid and specific. Immune cells, both innate and adaptive, are integrated as they communicate with each other through soluble mediators [4].

2. The Role of Hyaluronic Acid in Inflammation

HA is a significant component of the extracellular matrix (ECM), which becomes fragmented during infection and tissue injury and is repaired when inflammation subsides. During inflammation, HA turnover is disrupted and HA fragments collect extracellularly. These fragments are linked to the proliferation of the inflammatory response, whereas the full-length, high molecular mass HA is linked to the resolution of inflammation. While all immune cells express the HA receptor CD44, under homeostatic circumstances only a few bind HA. This, however, is altered when immune cells are activated [5].
In response to changes in cell sensitivity and signaling pathway regulation, the expression levels of inflammatory genes are modulated by complex mechanisms. Most likely attributed to hyaluronidase activity, the chain length of high-molecular-weight HA reduces during inflammation [5]. HA absorption and fragmentation by macrophages may reduce inflammation [5].
Toll-like receptors are a family of pattern recognition receptors, which distinguish specific structures in pathogens. Plasma membranes express extracellular TLRs (TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10). Through their extracellular/luminar leucine-rich repeats (LRRs) and cytosolic toll-like/interleukin-1 receptors, these molecules detect infection-derived ligands (TIR). TLRs are expressed on macrophages, neutrophils, dendritic cells (DCs), natural killer (NK) cells, mast cells, T and B lymphocytes, stromal cells, and tumour cells [6].
Both low and high molecular weight HA stimulates TLR-4. Conversely, LMW HA induces the activation of the NF-κB pathway which is associated with inflammation. HMW HA prevents lipopolysaccharide (LPS) a bacterial endotoxin, and activation of macrophages which is anti-inflammatory activity [7]. This contrasting activity demonstrates that the molecular weight of HA has a huge influence on the mode of action and ultimately response.

3. The Importance of Molecular Weight in HA Immunomodulation

Considering the importance of physicochemical properties in relation to bioactivity, it is surprising that there are currently very few investigations of the immunological responses induced by HA of varying molecular weights. Studies have demonstrated that antiangiogenic, immunosuppressive, and anti-inflammatory properties are seen in HA with a molecular weight larger than 1000 kDa. In contrast, pro-inflammatory, pro-angiogenic, and immunostimulatory characteristics are seen in medium- and low-molecular-weight HA [8].
An interesting study by Lee et al. (2021) tested HA at molecular weights of 10 to 1500 kDa and concentrations of 10 and 100 µg/mL on LPS-stimulated macrophages which are essentially inflamed [7]. They tested these parameters for the pro and anti-inflammatory effects of HA. Nitric Oxide (NO) generation from LPS-stimulated macrophages was used to measure HA-induced inflammation. They also evaluated the impact of different molecular weights of HA on M1 (Inflammatory) and M2 (anti-inflammatory) polarisation of macrophages. They also measured pro- and anti-inflammatory gene expression. Results demonstrated that various molecular weights of HA have distinct effects. LPS-unstimulated and LPS-stimulated macrophages exhibited differential regulation of inflammatory mediators, including cytokines and chemokines, based on the HA molecular weight. In the NO experiment with LPS-stimulated macrophages, HA demonstrated molecular weight-dependent effects on macrophages. Low molecular weight HA (50 kDa) increases iNOS levels significantly in LPS-stimulated chondrocytes. HA with a molecular weight of 1000 kDa had no noticeable effect on iNOS in LPS-stimulated chondrocytes. HA with a high molecular weight (5000 kDa) effectively decreases the iNOS increase generated by LPS.
In addition, they evaluated the impact of various HA molecular weights on the expression levels of certain immune gene expression levels in LPS-unstimulated and LPS-stimulated macrophages. In response to LPS, macrophages will secrete inflammatory mediators, such as IL-6 and TNF-α. Macrophages treated concurrently with LPS and HA have the opposite effect, with TNF-α expression levels decreasing. Il-10 is a cytokine associated with anti-inflammatory pathways. In unstimulated macrophages, HMW HA significantly up-regulated IL-10 compared to other conditions tested again demonstrating that HMW HA influences an anti-inflammatory phenotype [6].

4. Immunomodulatory Applications of HA

There is always a need to enhance the immune-boosting capabilities of vaccinations. Efforts are being focused on enhancing the immunogenicity of viral vaccines through the use of bio-adhesive delivery systems containing natural ingredients in order to counteract the negative side effects of conventional adjuvants. These bio adhesives adhere to the surfaces of mucosal cells via receptor-mediated processes. HA is one of these natural bio-adhesives that has the ability to stimulate an effective immune response.
In a study β-propiolactone (βPL), binary ethyleneimine (BEI), and hydrogen peroxide (H2O2) were assessed for their inactivation potentials. Monitoring the humoral and cellular immune response induced by rabies vaccinations adjuvanted with Staphylococcus aureus-derived HA and BCG pure protein derivative (PPD). Results showed that both adjuvants may boost the release of anti-rabies total immunoglobulin G and pro-inflammatory mediators in a progressive manner. HA adjuvanted rabies vaccination produced a greater immunological response compared to PPD adjuvanted rabies vaccine [9]. This further demonstrates that HA has a significant influence on the immune response.
Mortality and morbidity linked with chronic obstructive pulmonary disease (COPD) are on the rise globally. HA with high molecular weight is a physiological component of the lung extracellular matrix and possesses considerable anti-inflammatory and hydration capabilities. Therefore, HA was administered in a pilot study of 41 patients. Significantly shorter durations of non-invasive positive-pressure breathing (NIPPV) were seen in patients treated with HA. Additionally, HA-treated individuals had reduced ventilator-measured peak airway pressures and lower systemic inflammatory biomarkers. HA considerably increased mucociliary transport in air-liquid interface cultures of primary bronchial cells from COPD patients and healthy primary cells exposed to cigarette smoke extract, based on simultaneous in-vitro assays [10].
Collectively, the research studying the impact of HA on immune system disorders, namely inflammation, reveals that the molecular weight of the chemical is crucial. HA with a greater molecular weight appears to have anti-inflammatory effects that might be beneficial for a variety of inflammatory illnesses and needs to be explored further.

This entry is adapted from the peer-reviewed paper 10.3390/polym14173442

References

  1. Knopf-Marques, H.; Pravda, M.; Wolfova, L.; Velebny, V.; Schaaf, P.; Vrana, N.E.; Lavalle, P. Hyaluronic acid and its derivatives in coating and delivery systems: Applications in tissue engineering, regenerative medicine and immunomodulation. Adv. Healthc. Mater. 2016, 5, 2841–2855.
  2. Ye, Q.; Harmsen, M.C.; van Luyn, M.J.A.; Bank, R.A. The relationship between collagen scaffold cross-linking agents and neutrophils in the foreign body reaction. Biomaterials 2010, 31, 9192–9201.
  3. Wang, K.; Liu, J.; Sun, X.; Yang, H.; Gao, X. Using cross-linked hyaluronic acid gel to prevent postoperative lumbar epidural space adhesion: In vitro and in vivo studies. Eur. Spine J. 2020, 29, 129–140.
  4. Thomas, S.; Rezoagli, E.; Abidin, I.Z.; Major, I.; Murray, P.; Murphy, E.J. β-Glucans from yeast—Immunomodulators from novel waste resources. Appl. Sci. 2022, 12, 5208.
  5. Petrey, A.C.; de la Motte, C.A. Hyaluronan, a crucial regulator of inflammation. Front. Immunol. 2014, 5, 101.
  6. Lee, B.M.; Park, S.J.; Noh, I.; Kim, C.H. The effects of the molecular weights of hyaluronic acid on the immune responses. Biomater. Res. 2021, 25, 27.
  7. Huang, L.; Xu, H.; Peng, G. TLR-mediated metabolic reprogramming in the tumor microenvironment: Potential novel strategies for cancer immunotherapy. Cell. Mol. Immunol. 2018, 15, 428–437.
  8. Yoon, J.Y.; Kim, D.W.; Ahn, J.H.; Choi, E.J.; Kim, Y.H.; Jeun, M.; Kim, E.J. Propofol suppresses LPS-induced inflammation in amnion cells via inhibition of NF-κB activation. Tissue Eng. Regen. Med. 2019, 16, 301–309.
  9. Shebl, R.; Amer, M.E.; Abuamara, T.M.; Matar, E.R.; Ahmed, H.F.; Gomah, T.A.; El Moselhy, L.E.; Abu-Elghait, M.; Mohamed, A.F. Staphylococcus aureus derived hyaluronic acid and bacillus Calmette-Guérin purified proteins as immune enhancers to rabies vaccine and related immuno-histopathological alterations. Clin. Exp. Vaccine Res. 2021, 10, 229.
  10. Galdi, F.; Pedone, C.; McGee, C.A.; George, M.; Rice, A.B.; Hussain, S.S.; Vijaykumar, K.; Boitet, E.R.; Tearney, G.J.; McGrath, J.A.; et al. Inhaled high molecular weight hyaluronan ameliorates respiratory failure in acute COPD exacerbation: A pilot study. Respir. Res. 2021, 22, 30.
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