Inappropriate use of antibiotics exacerbates inflammation through OMV-induced pyroptosis in MDR Klebsiella pneumoniae infection

• Published in: Cell reports (Cambridge) Vol. 36; no. 12; p. 109750
• Main Authors: Ye, Chao, Li, Weiran, Yang, Ying, Liu, Qingwen, Li, Sijing, Zheng, Peng, Zheng, Xiao, Zhang, Ye, He, Jinrong, Chen, Yongjun, Hua, Liangqun, Yang, Zhongqian, Li, Duo, Ren, Zhaoling, Qi, Jialong, Huang, Weiwei, Ma, Yanbing
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.09.2021; Elsevier
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; antibiotics; Bacterial Proteins - metabolism; carbapenem; Carbapenems - pharmacology; Chaperonin 60 - metabolism; Cytokines - metabolism; Drug Resistance, Multiple, Bacterial - drug effects; Extracellular Vesicles - metabolism; inflammation; Inflammation - metabolism; Inflammation - pathology; Inflammation - veterinary; Klebsiella Infections - mortality; Klebsiella Infections - pathology; Klebsiella Infections - veterinary; Klebsiella pneumoniae; Klebsiella pneumoniae - metabolism; Klebsiella pneumoniae - pathogenicity; macrophage; Macrophages - cytology; Macrophages - immunology; Macrophages - metabolism; Mice; Mice, Inbred C57BL; OMV; outer membrane vesicle; Phagocytosis; Pyroptosis; RNA Interference; RNA, Small Interfering - metabolism; Scavenger Receptors, Class E - antagonists & inhibitors; Scavenger Receptors, Class E - genetics; Scavenger Receptors, Class E - metabolism; Survival Rate; pyroptosis; outer membrane vesicle; carbapenem; inflammation; OMV; macrophage; antibiotics; Klebsiella pneumoniae
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109750

The inappropriate use of antibiotics is a severe public health problem worldwide, contributing to the emergence of multidrug-resistant (MDR) bacteria. To explore the possible impacts of the inappropriate use of antibiotics on the immune system, we use Klebsiella pneumoniae (K. pneumoniae) infection as an example and show that imipenem increases the mortality of mice infected by MDR K. pneumoniae. Further studies demonstrate that imipenem enhances the secretion of outer membrane vesicles (OMVs) with significantly elevated presentation of GroEL, which promotes the phagocytosis of OMVs by macrophages that depends on the interaction between GroEL and its receptor, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). OMVs cause the pyroptosis of macrophages and the release of proinflammatory cytokines, which contribute to exacerbated inflammatory responses. We propose that the inappropriate use of antibiotics in the cases of infection by MDR bacteria such as K. pneumoniae might cause damaging inflammatory responses, which underlines the pernicious effects of inappropriate use of antibiotics. [Display omitted] •Carbapenems increase mouse inflammation and mortality in MDR K. pneumoniae infection•OMVs released by K. pneumoniae mediate the exacerbated inflammatory responses•Carbapenems enhance the release of OMVs with elevated GroEL content•Increased uptake of OMVs promotes proinflammatory pyroptosis in macrophages Ye et al. show that inappropriate use of antibiotics in the case of multidrug-resistant (MDR) Klebsiella pneumoniae (K. pneumoniae) infection might cause severe inflammatory damage. Carbapenems enhance the secretion of OMVs with upregulated membrane presentation of GroEL, which promotes macrophages to take up OMVs, develop pyroptosis, and release proinflammatory cytokines.