Matrix‐Bound Hyaluronan Molecular Weight as a Regulator of Dendritic Cell Immune Potency

Abstract Hyaluronic acid (HA) is a glycosaminoglycan in the extracellular matrix with immunoregulatory properties depending on its molecular weight (MW). However, the impact of matrix‐bound HA on dendritic cells (DCs) remains unclear due to varying distribution of HA MW under different physiological conditions. To investigate DCs in defined biosystems, 3D collagen matrices modified with HA of specific MW with similar microstructure and HA levels are used. It is found that HA MW influences cytokine binding to matrix, suggesting modulation of cytokine availability by the different HA MWs. These studies on DC immune potency reveal that low MW HA (8–15 kDa) enhances immature DC differentiation and antigen uptake, while medium (MMW‐HA; 500–750 kDa) and high MW HA (HMW‐HA; 1250–1500 kDa) increase cytokine secretion in mature DCs. The effect on DC phenotype and cytokine secretion by different MWs of HA is independent of CD44. However, blocking the CD44 receptor reveals its potential role in regulating acute inflammation through increased secretion of CCL2, CXCL8, and IL‐6. Additionally, MMW‐ and HMW‐HA matrices reduce migratory capacity of DCs, dependent on CD44. Overall, these findings provide insights into MW‐dependent effects of matrix‐bound HA on DCs, opening avenues for the design of DC‐modulating materials to enhance DC‐based therapy.