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

Staphylococcus aureus (S. aureus) 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 PGE2 synthesis and secretion in S. aureus 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 S. aureus-infected bBMMs. Moreover, excess PGE2 treatment can regulate TLR2-, TLR4-, and NLRP3-mediated inflammatory responses and the phagocytosis of macrophages in S. aureus-infected bBMMs. Altogether, during S. aureus infection, TLR2, TLR4, NLRP3, and S. aureus lipoproteins play essential roles in PGE2 synthesis and secretion. Meanwhile, there is cross-talk between TLR2, TLR4, NLRP3, and PGE2 during S. aureus infection. Moreover, PGE2 can regulate macrophage phagocytosis, notably involving S. aureus lipoproteins in this process.