Matrine alleviates Staphylococcus aureus-induced acute lung injury in mice by inhibiting MLKL and NLRP3-mediated inflammatory activity.

Acute lung injury (ALI) is a serious clinical condition with high incidence and mortality. The inflammatory response induced by gram-positive bacteria, especially Staphylococcus aureus (S. aureus), is a key factor contributing to ALI progression and other infectious diseases. Matrine, known for its diverse biological and pharmacological properties, has not been fully explored for its potential to prevent or treat S. aureus-induced ALI. Our study demonstrated that matrine exerts a protective effect against lung injury in mice infected with S. aureus. Specifically, matrine reduced pulmonary edema and decreased neutrophil infiltration in the infected lungs. Furthermore, matrine significantly reduced the expression of high-mobility group box protein 1 (HMGB1) and hyaluronic acid-binding protein 2 (HABP2) in the lungs of infected mice. Additionally, matrine modulated the production of inflammatory mediators, including tumor necrosis factor-α (TNF-α); interleukin-1β (IL-1β); regulated upon activation normal T cell expressed and secreted (RANTES) and Interleukin 10 (IL-10), in both infected lungs and macrophages, suggesting a protective role against tissue damage. Moreover, matrine influenced the secretion of proinflammatory cytokines and regulated the activation of the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways, along with the activation of Nod-like receptor pyrin domain-containing protein 3 (NLRP3) and Mixed-lineage kinase domain-like protein (MLKL) in macrophages. Notably, when MLKL, but not NLRP3, is deleted, the ability of matrine to regulate damage-associated proteins and prevent tissue injury is diminished. These findings suggest that matrine may be a promising therapeutic agent for the prevention and treatment of ALI.