Park Ji-Won, Kim Yong-Jae, Shin In-Sik, Kwon Ok-Kyoung, Hong Ju Mi, Shin Na-Rae, Oh Sei-Ryang, Ha Un-Hwan, Kim Jae-Hong, Ahn Kyung-Seop
Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju-si College of Life Sciences and Biotechnology, Korea University, Seoul.
Department of Biotechnology and Bioinformatics, Korea University, Sejong.
J Infect Dis. 2016 Sep 15;214(6):962-9. doi: 10.1093/infdis/jiw278. Epub 2016 Jul 4.
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 κB (NF-κB) signaling pathways. To understand the T3SS, we used ΔExoS, ΔExoT, and ExsA::Ω mutants, as well as P. aeruginosa strain K (PAK)-stimulated NCI-H292 cells. We investigated the effects of ΔExoS, ΔExoT, and ExsA::Ω on the development of pneumonia in mouse models. We examined the effects of ΔExoS, ΔExoT, and ExsA::Ω on MMP-12 and MMP-13 production in NCI-H292 cells. ΔExoS and ΔExoT markedly decreased the neutrophil count in bronchoalveolar lavage fluid, with a reduction in proinflammatory mediators, MMP-12, and MMP-13. ΔExoS and ΔExoT reduced NF-κB 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-κB signaling. These findings might be useful in devising a novel therapeutic approach to chronic pulmonary infections that involves decreasing the ExoS and ExoT levels.
在动物和人体研究中，铜绿假单胞菌的III型分泌系统（T3SS）与严重疾病及不良临床预后相关。我们旨在研究铜绿假单胞菌的ExoS和ExoT效应蛋白是否通过核因子κB（NF-κB）信号通路影响基质金属蛋白酶12（MMP-12）和MMP-13的表达。为了解T3SS，我们使用了ΔExoS、ΔExoT和ExsA::Ω突变体，以及经铜绿假单胞菌菌株K（PAK）刺激的NCI-H292细胞。我们研究了ΔExoS、ΔExoT和ExsA::Ω对小鼠模型肺炎发展的影响。我们检测了ΔExoS、ΔExoT和ExsA::Ω对NCI-H292细胞中MMP-12和MMP-13产生的影响。ΔExoS和ΔExoT显著降低了支气管肺泡灌洗液中的中性粒细胞计数，并减少了促炎介质、MMP-12和MMP-13。在PAK感染的小鼠模型和NCI-H292细胞中，ΔExoS和ΔExoT降低了NF-κB磷酸化以及MMP-12和MMP-13的表达。总之，铜绿假单胞菌感染诱导了基质金属蛋白酶的表达，铜绿假单胞菌T3SS似乎是MMP-12和MMP-13表达的关键因素，其表达进一步受NF-κB信号通路调控。这些发现可能有助于设计一种新的慢性肺部感染治疗方法，即降低ExoS和ExoT水平。
