An underlying mechanism of bovine mastitis: PGE₂ regulates <i>Staphylococcus aureus</i>-induced inflammatory response through TLR2, TLR4, and NLRP3 in macrophages

<i>Staphylococcus aureus</i> (<i>S. aureus</i>) evades the immune system by altering macrophage functions, including immune regulation and phagocytosis, leading to the development of bovine mastitis. Therefore, this study analyzed bovine mastitis's internal pathogenic mechanism from both the host and pathogen perspectives, using prostaglandin E₂ (PGE₂) as a bridge. The results showed that during bovine mastitis, the macrophages are recruited into the mammary gland, accompanied by a significant upregulation of inflammatory mediators in the mammary tissue. Furthermore, S. aureus lipoproteins could increase the inflammatory response by mediating MAPKs and NF-κB signaling pathway activation through TLR2, TLR4, and NLRP3, leading to the secretion of inflammatory mediators, including PGE₂, in bovine bone marrow-derived macrophages (bBMMs). The bBMMs were treated with TLR2, TLR4, and NLRP3 inhibitors, which can decrease the expression of COX-2 and mPGES-1, further regulating PGE₂synthesis and secretion in <i>S. aureus </i>infection. In addition to TLR2, TLR4, and NLRP3 affecting PGE₂ synthesis and secretion, inhibitors of COX-2 and mPGES-1 can regulate the expression of TLR2 and NLRP3 and the activation of MAPKs and NF-κB signaling pathways in <i>S. aureus</i>-infected bBMMs. Moreover, excess PGE₂ treatment can regulate TLR2-, TLR4-, and NLRP3-mediated inflammatory responses and the phagocytosis of macrophages in <i>S. aureus</i>-infected bBMMs. Altogether, during <i>S. aureus</i> infection, TLR2, TLR4, NLRP3, and <i>S. aureus</i> lipoproteins play essential roles in PGE₂synthesis and secretion. Meanwhile, there is cross-talk between TLR2, TLR4, NLRP3, and PGE₂ during <i>S. aureus</i> infection. Moreover, PGE₂ can regulate macrophage phagocytosis, notably involving <i>S. aureus</i> lipoproteins in this process.