Lipopolysaccharide activates platelet via the TLR4/MYD88 pathway to protect against bacterial lung injury

• Platelet treatment protected against lung injury of S. pneumonia-infected mice. • Platelet treatment inhibited immune response, inflammation and oxidative stress in S. pneumonia-infected mice. • LPS induced platelet activation via the TLR4/MYD88 signaling pathway. • LPS-induced platelet activation inhibited inflammation and oxidative stress in A549 cells. Bacterial infections, particularly those caused by Streptococcus pneumoniae ( S. pneumoniae ), are a leading cause of lung injury and respiratory failure. Although platelets have recently emerged as key modulators of immune responses and inflammation. This study investigated the protective effects and underlying mechanisms of platelets in lung injury using a S. pneumoniae -infected mouse model and a lipopolysaccharide (LPS)-induced A549 cell model. Specifically, LPS was utilized as a tool to activate platelets. In vivo results demonstrated that platelet administration significantly attenuated lung histopathological damage, inhibited immune cell activation, and suppressed the secretion of pro-inflammatory cytokines including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and IL-1β. Furthermore, platelet treatment effectively restored antioxidant balance by reducing malondialdehyde levels and enhancing superoxide dismutase and catalase activities. Mechanistically, LPS triggered platelet activation via the Toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MYD88) signaling pathway. In vitr o experiments further confirmed that activated platelets downregulated the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and suppressed inflammation and oxidative stress in LPS-induced A549 cells; however, these protective effects were abolished by TLR4 or MYD88 inhibitors. In conclusion, platelets activated by LPS through the TLR4/MYD88 pathway confer protection against bacterial infection-induced lung injury by inhibiting inflammation, oxidative stress, and adhesion molecule expression, highlighting the potential of platelets as therapeutic targets for managing bacterial lung injury.