The PDZ motif peptide of ZO-1 attenuates Pseudomonas aeruginosa LPS-induced airway inflammation

Abstract

Pseudomonas aeruginosa is known to play a role in many human diseases. Therefore, examining the negative control mechanisms of tight junction protein ZO-1 on the exotoxin LPS of P. aeruginosa-induced diseases could be critical in the development of novel therapeutics. We found that ZO-1 expression dramatically decreased in inflammatory human lung tissues. Interestingly, PDZ1 deletion of the PDZ domain in the ZO-1 protein dramatically decreased LPS-induced F-actin formation and increased the expression of genes for pro-inflammatory cytokines, but not PDZ2 and PDZ3 of the ZO-1 protein. We also found that the consensus PDZ peptide (based on PDZ1) of ZO-1 down-regulates the expression of pro-inflammatory cytokine genes and F-actin formation; in contrast, the GG24,25AA mutant PDZ peptide cannot control these genes. LPS activates IL-8 secretion extracellularly in a time-dependent manner, while the secretion is inhibited by PDZ peptide. Whereas increased IL-8 secretion by LPS activates the CXCR2 receptor, overexpressed RGS12 negatively regulates LPS-induced CXCR2/IL-8 signaling. The PDZ peptide also decreases LPS-induced inflammatory cell populations, pro-inflammatory cytokine gene expression, and TEER in bronchoalveolar lavage fluid and cultured alveolar macrophages. Collectively, we suggest that the PDZ peptide may be a potential therapeutic for bacteria-induced respiratory diseases.

Identification of different proteins binding to Na, K-ATPase α1 in LPS-induced ARDS cell model by proteomic analysis

“…Ni JJ et al found that plasma ZO-1 proteins appear to be a valuable prognostic biomarker for the severity of sepsis and a predictor of 30-day mortality for patients with sepsis [ 19 ]. And Lee TJ et al found that ZO-1 on the exotoxin LPS of P. aeruginosa -induced diseases could be critical in the development of novel therapeutics [ 20 ]. It is interesting that, Na, K-ATPase β1 promotes the expression of key proteins such as ZO-1, ZO-2, occludin and claudin-18 in tight junction complex and reduces the production of lung water [ 21 ].…”

Rapid Synergistic Biofilm Production of Pseudomonas and Candida on the Pulmonary Cell Surface and in Mice, a Possible Cause of Chronic Mixed Organismal Lung Lesions

“…Because the epithelial barrier integrity [ 32 , 52 ] is important for the first defense against pathogens [ 53 , 54 ] and because the loss of ZO-1 tight junction molecules in human lungs with P. aeruginosa infection has also been previously demonstrated [ 55 , 56 ], studies of biofilms on epithelial cell surfaces might better resemble the clinical situation. Here, there were increased biofilms in Pseudomonas–Candida compared to Pseudomonas alone on both the cell line and lung tissue, with an increased cell abundance of both bacteria and fungi, which was more prominent than the abundance on the glass slides, implying that the biotic surface has an impact on microbial growth and biofilm production.…”

Distinct Transcriptional Profile of PDZ Genes after Activation of Human Macrophages and Dendritic Cells

“…ZO-1 (TJP-1) and ZO-2 (TJP-2) are PDZ proteins commonly related to ABCP and the maintenance of tight junctions (TJ). In response to proinflammatory cytokines or bacterial products, such as LPS, the expression of ZO-1 is reduced and redistributed away from the TJ, resulting in increased epithelial permeability [22][23][24]. However, in the immune system, LPS can trigger the reorganization of TJ proteins with the upregulation of ZO-1 in mouse DCs.…”