| Extraintestinal pathogenic E.coli targets the central nervous system(CNS),destroys the blood-brain barrier,causes neuronal necrosis and dysfunction,and triggers excessive CNS inflammation.Matrix metalloproteinases(MMPs)can degrade the extracellular matrix,destroy the blood-brain barrier,activate glial cells and macrophages,promote the release of inflammatory factors,and play an important role in the formation of neuroinflammation.In addition,studies have shown that bradykinin(BK)regulates MMPs through bradykinin receptors B1 R and B2R(BDKRB1/2),and thus participates in the regulation of inflammatory response processes in tissues.In this experiment,MMPs and BDKRB1/2 were used as the research objects to explore the expression regulation of MMPs and BDKRB1/2 in E.coli infection and their role and mechanism in mediating inflammation of the central nervous system.The results are as follows:(1)In the U251 cells infected by E.coli strain PCN033,B1 R and B2 R were up-regulated in a time-dependent manner,and were also significantly expressed in the infected brain tissue of mice.The inhibition of B1 R and B2 R significantly reduced the inflammatory response induced by PCN033 in vivo and in vitro.(2)PCN033 infection of U251 cells caused significant up-regulation of MMP7,9,13.MMP inhibitors pretreated mice and U251 cells,and the up-regulation of inflammatory factors and chemokines caused by E.coli infection was also significantly suppressed.(3)PCN033 infection can cause p65 phosphorylation and transportation to the nucleus,and knocking down BDKRB1/2,p65 phosphorylation and transportation to the nucleus is also significantly reduced.After inhibiting the NF-κB signaling pathway,MMP7,9,13 induced by BK were significantly inhibited.At the same time,Pyk2 inhibitors can significantly down-regulate BK-induced MMP7,9,13 expression and activation of NF-κB signaling pathway.The above results indicate that MMPs and BDKRB1/2 play an important role in the central inflammatory response induced by meningitis E.coli infection.E.coli can upregulate MMP7,9,13 expression through the BDKRB1/2-Pyk2-NF-κB signaling way,and then promote the occurrence of central inflammatory response.This study provides important targets and data support for the prevention and alleviation of meningitis E.coli-mediated central inflammatory response and inflammatory damage. |
