Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, La Jolla, CA, United States.
Department of Microbiology and Immunology, Emory School of Medicine, Atlanta GA, United States.
EBioMedicine. 2020 Oct;60:102984. doi: 10.1016/j.ebiom.2020.102984. Epub 2020 Sep 23.
Pulmonary damage by Pseudomonas aeruginosa during cystic fibrosis lung infection and ventilator-associated pneumonia is mediated both by pathogen virulence factors and host inflammation. Impaired immune function due to tissue damage and inflammation, coupled with pathogen multidrug resistance, complicates the management of these deep-seated infections. Pathological inflammation during infection is driven by interleukin-1β (IL-1β), but the molecular processes involved are not fully understood.
We examined IL-1β activation in a pulmonary model infection of Pseudomonas aeruginosa and in vitro using genetics, specific inhibitors, recombinant proteins, and targeted reporters of protease activity and IL-1β bioactivity.
Caspase-family inflammasome proteases canonically regulate maturation of this proinflammatory cytokine, but we report that plasticity in IL-1β proteolytic activation allows for its direct maturation by the pseudomonal protease LasB. LasB promotes IL-1β activation, neutrophilic inflammation, and destruction of lung architecture characteristic of severe P. aeruginosa pulmonary infection.
Preservation of lung function and effective immune clearance may be enhanced by selectively controlling inflammation. Discovery of this IL-1β regulatory mechanism provides a distinct target for anti-inflammatory therapeutics, such as matrix metalloprotease inhibitors that inhibit LasB and limit inflammation and pathology during P. aeruginosa pulmonary infections.
Full details are provided in the Acknowledgements section.
铜绿假单胞菌在囊性纤维化肺部感染和呼吸机相关性肺炎期间引起的肺部损伤，既由病原体毒力因子介导，也由宿主炎症介导。由于组织损伤和炎症导致免疫功能受损，再加上病原体的多药耐药性，使得这些深部感染的治疗变得复杂。感染期间的病理性炎症由白细胞介素-1β（IL-1β）驱动，但涉及的分子过程尚未完全了解。
我们使用遗传学、特定抑制剂、重组蛋白以及蛋白酶活性和 IL-1β生物活性的靶向报告基因，在铜绿假单胞菌肺部感染模型中以及体外研究了 IL-1β的激活情况。
半胱天冬酶家族炎性体蛋白酶通常调节这种促炎细胞因子的成熟，但我们报告称，IL-1β蛋白水解激活的可塑性允许其被假单胞菌蛋白酶 LasB 直接成熟。LasB 促进 IL-1β激活、中性粒细胞炎症和肺组织结构破坏，这是严重铜绿假单胞菌肺部感染的特征。
通过有选择地控制炎症，可能会增强肺功能和有效的免疫清除。发现这种 IL-1β调节机制为抗炎治疗提供了一个明确的靶点，例如基质金属蛋白酶抑制剂，它可以抑制 LasB 并限制铜绿假单胞菌肺部感染期间的炎症和病理学。
全文详细信息见致谢部分。
