High and Low Molecular Weight Hyaluronic Acid Differentially Influence Macrophage Activation

Abstract

Macrophages exhibit phenotypic diversity permitting wide-ranging roles in maintaining physiologic homeostasis. Hyaluronic acid, a major glycosaminoglycan of the extracellular matrix, has been shown to have differential signaling based on its molecular weight. With this in mind, the main objective of this study was to elucidate the role of hyaluronic acid molecular weight on macrophage activation and reprogramming. Changes in macrophage activation were assessed by activation state selective marker measurement, specifically quantitative real time polymerase chain reaction, and cytokine enzyme-linked immunoassays, after macrophage treatment with differing molecular weights of hyaluronic acid under four conditions: the resting state, concurrent with classical activation, and following inflammation involving either classically or alternatively activated macrophages. Regardless of initial polarization state, low molecular weight hyaluronic acid induced a classically activated-like state, confirmed by up-regulation of pro-inflammatory genes, including nos2, tnf, il12b, and cd80, and enhanced secretion of nitric oxide and TNF-α. High molecular weight hyaluronic acid promoted an alternatively activated-like state, confirmed by up regulation of pro-resolving gene transcription, including arg1, il10, and mrc1, and enhanced arginase activity. Overall, our observations suggest that macrophages undergo phenotypic changes dependent on molecular weight of hyaluronan that correspond to either (1) pro-inflammatory response for low molecular weight HA or (2) pro-resolving response for high molecular weight HA. These observations bring significant further understanding of the influence of extracellular matrix polymers, hyaluronic acid in particular, on regulating the inflammatory response of macrophages. This knowledge can be used to guide the design of HA-containing biomaterials to better utilize the natural response to HAs.

Bioconjugated Manganese Dioxide Nanoparticles Enhance Chemotherapy Response by Priming Tumor-Associated Macrophages toward M1-like Phenotype and Attenuating Tumor Hypoxia

“…It is reported that hyaluronic acid (HA) has immunotoxicological effect on macrophages, which can activate macrophages and increase the production of endogenous reactive oxygen species (ROS). 20,21 Herein, we question whether HA has the ability to shape the inflammatory behavior of TAMs and contribute to macrophage polarization. Furthermore, to improve the biocompatibility of MnO 2 NPs, we conjugated HA to polyelectrolyte-coated MnO 2 NPs and obtained HA-MnO 2 NPs (Figure S1A).…”

Schwann-cell cylinders grown inside hyaluronic-acid tubular scaffolds with gradient porosity

“…Actually, different reactive oxygen species involved in the degradation process lead to different chemically modified HA oligomers, which are the ones involved in inflammation [75,76]. Low molecular weight fragments of HA tend to be pro-inflammatory, whereas high-molecular weight fragments have anti-inflammatory effects [77]. Crosslinking with DVS increases the molecular weight of HA chain scission fragments, and, actually, several DVScrosslinked HA products are approved for human use (references in the introduction).…”

Efficacy of a Corticosteroid-Free, 5% Hyaluronic-Based Facial Cream in the Treatment of Seborrheic Dermatitis. A Proof-of-Concept Study

“…400.000-600.000 Da). It is well known that biological effect of HA could be influenced by its molecular size [30]. In the trial of Schlesinger IGA score improved by 65.5% (4 weeks of treatment).…”