Type III Secretion System of Pseudomonas aeruginosa Affects Matrix Metalloproteinase 12 (MMP-12) and MMP-13 Expression via Nuclear Factor kappa B Signaling in Human Carcinoma Epithelial Cells and a Pneumonia Mouse Model

Abstract

The type III secretion system (T3SS) in Pseudomonas aeruginosa has been linked to severe disease and poor clinical outcomes in animal and human studies. We aimed to investigate whether the ExoS and ExoT effector proteins of P. aeruginosa affect the expression of matrix metalloproteinase 12 (MMP-12) and MMP-13 via nuclear factor kappa B (NF-kappa B) signaling pathways. To understand the T3SS, we used Delta ExoS, Delta ExoT, and ExsA::Omega mutants, as well as P. aeruginosa strain K (PAK)-stimulated NCI-H292 cells. We investigated the effects of Delta ExoS, Delta ExoT, and ExsA::Omega on the development of pneumonia in mouse models. We examined the effects of Delta ExoS, Delta ExoT, and ExsA::Omega on MMP-12 and MMP-13 production in NCI-H292 cells. Delta ExoS and Delta ExoT markedly decreased the neutrophil count in bronchoalveolar lavage fluid, with a reduction in proinflammatory mediators, MMP-12, and MMP-13. Delta ExoS and Delta ExoT reduced NF-kappa B phosphorylation, together with MMP-12 and MMP-13 expression in PAK-infected mouse models and NCI-H292 cells. To conclude, P. aeruginosa infection induced the expression of MMPs, and P. aeruginosa T3SS appeared to be a key player in MMP-12 and MMP-13 expression, which is further controlled by NF-kappa B signaling. These findings might be useful in devising a novel therapeutic approach to chronic pulmonary infections that involves decreasing the ExoS and ExoT levels.