Low molecular weight fragmentation products of hyaluronic acid (sHA) produced during inflammation have been shown to activate dendritic cells (DCs) via the Toll-like receptor (TLR)-4 pathway. This study demonstrates that sHA induces maturation of DCs by activating TLR-4, which results in the phosphorylation of p38/p42/44 MAP kinases and nuclear translocation of NF-κB. Bone marrow-derived DCs from TLR-4-deficient mice were nonresponsive to sHA-induced maturation, while DCs from TLR-2-deficient mice were still susceptible to sHA. In vivo experiments showed that intravenous injection of sHA induced DC emigration from the skin and their maturation in the spleen, which was dependent on TLR-4 expression. These findings suggest that sHA, a degradation product of the extracellular matrix, can serve as an endogenous ligand for the TLR-4 complex on DCs, activating them through a specific signaling pathway.Low molecular weight fragmentation products of hyaluronic acid (sHA) produced during inflammation have been shown to activate dendritic cells (DCs) via the Toll-like receptor (TLR)-4 pathway. This study demonstrates that sHA induces maturation of DCs by activating TLR-4, which results in the phosphorylation of p38/p42/44 MAP kinases and nuclear translocation of NF-κB. Bone marrow-derived DCs from TLR-4-deficient mice were nonresponsive to sHA-induced maturation, while DCs from TLR-2-deficient mice were still susceptible to sHA. In vivo experiments showed that intravenous injection of sHA induced DC emigration from the skin and their maturation in the spleen, which was dependent on TLR-4 expression. These findings suggest that sHA, a degradation product of the extracellular matrix, can serve as an endogenous ligand for the TLR-4 complex on DCs, activating them through a specific signaling pathway.