Hyaluronic acid (HA) degradation products, known as sHA, activate dendritic cells (DCs) via Toll-like receptor 4 (TLR-4). This study demonstrates that sHA induces DC maturation through TLR-4 signaling, which involves the phosphorylation of p38/p42/44 MAPKs and the nuclear translocation of NF-κB. sHA treatment leads to increased production of proinflammatory cytokines such as TNF-α, which is blocked by anti-TLR-4 antibodies. Bone marrow-derived DCs from TLR-4-deficient mice do not respond to sHA, while those from TLR-2-deficient mice do. In vivo, sHA induces DC emigration from the skin and their maturation in the spleen, which is dependent on TLR-4 expression. These findings suggest that sHA, a degradation product of the extracellular matrix, acts as an endogenous ligand for TLR-4 on DCs, triggering immune responses during inflammation. The study highlights the role of TLR-4 in sHA-induced DC activation and the signaling pathways involved, including MAPK and NF-κB pathways. The results indicate that sHA can independently activate DCs through TLR-4, contributing to the immune response during inflammation.Hyaluronic acid (HA) degradation products, known as sHA, activate dendritic cells (DCs) via Toll-like receptor 4 (TLR-4). This study demonstrates that sHA induces DC maturation through TLR-4 signaling, which involves the phosphorylation of p38/p42/44 MAPKs and the nuclear translocation of NF-κB. sHA treatment leads to increased production of proinflammatory cytokines such as TNF-α, which is blocked by anti-TLR-4 antibodies. Bone marrow-derived DCs from TLR-4-deficient mice do not respond to sHA, while those from TLR-2-deficient mice do. In vivo, sHA induces DC emigration from the skin and their maturation in the spleen, which is dependent on TLR-4 expression. These findings suggest that sHA, a degradation product of the extracellular matrix, acts as an endogenous ligand for TLR-4 on DCs, triggering immune responses during inflammation. The study highlights the role of TLR-4 in sHA-induced DC activation and the signaling pathways involved, including MAPK and NF-κB pathways. The results indicate that sHA can independently activate DCs through TLR-4, contributing to the immune response during inflammation.