An underlying mechanism of bovine mastitis: PGE(2) regulates Staphylococcus aureus-induced inflammatory response through TLR2, TLR4, and NLRP3 in macrophages.

Staphylococcus aureus (S. aureus) evades host immunity by modulating macrophage functions, including immune regulation and phagocytosis, ultimately contributing to bovine mastitis. This study aimed to elucidate the molecular mechanisms of S. aureus-induced bovine mastitis from both host and pathogen perspectives, focusing on prostaglandin E(2) (PGE(2)) as a key regulator. During bovine mastitis, macrophages were recruited into the mammary gland with elevated inflammatory mediators. S. aureus lipoproteins amplified inflammation by activating MAPK and NF-κB pathways via TLR2, TLR4, and NLRP3, leading to elevated secretion of mediators, including PGE(2), in bBMMs. Inhibition of TLR2, TLR4, or NLRP3 decreased COX-2 and mPGES-1 expression, suppressing PGE(2) synthesis, while inhibition of COX-2 or mPGES-1 can regulate the expression of TLR2 and NLRP3, as well as the activation of MAPKs and NF-κB signaling pathways. Excess PGE(2) can regulate inflammation and phagocytosis mediated by TLR2, TLR4, and NLRP3. S. aureus lipoproteins promote PGE(2) synthesis via TLR2, TLR4, and NLRP3 signaling, while PGE(2), in turn, modulates receptor activity, inflammation, and phagocytosis. These findings reveal crucial functional cross-talk between PGE(2) and innate immune receptors in S. aureus-induced mastitis, suggesting that targeting this interaction may provide novel therapeutic strategies.