- •Autophagy inhibition blocks the cytokine storm and vascular leakage that occur during sepsis.
- •Autophagy inhibition promotes the uptake and clearance of E. coli by leukocytes.
- •Hydroxychloroquine (HCQ) treatment protects E. coli-infected mice from lethality.
- •However, pretreatment of mice with HCQ before infection causes opposite outcome.
Sepsis is an overwhelming systemic inflammatory response for which no satisfactory therapeutic drug is available. Previous studies have shown that autophagy is involved in the cytokine storm and vascular leakage that occur during sepsis. Therefore, we aimed to evaluate the therapeutic potential of autophagy inhibitors against bacterial infection-induced sepsis.
Cytokine production and phagocytosis of bacteria by human leukocytes and the permeability of endothelial cells were determined after the co-incubation of cells with lipopolysaccharide (LPS) or Escherichia coli in the presence or absence of autophagy inhibitors in vitro. Furthermore, the therapeutic effects of the autophagy inhibitors in E. coli-infected mice were analysed.
In the presence of the autophagy inhibitors, the LPS-triggered cytokine secretion of human leucocytes and LPS (or LPS-conditioned medium from leucocytes)-induced endothelial hyperpermeability were significantly reduced. Moreover, the inhibition of autophagy enhanced the clearance of E. coli by leucocytes in vitro. Finally, we demonstrated that post-treatment but not pretreatment with an autophagy inhibitor (hydroxychloroquine) completely protected mice against E. coli infection-induced lethality by simultaneously reducing cytokine production and vascular leakage and enhancing bacterial clearance.
These results suggest that autophagy plays an important role in the pathogenesis of sepsis and could serve as a potential therapeutic target for sepsis.
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- Severe sepsis and septic shock.N Engl J Med. 2013; 369: 840-851
- Epidemiology of sepsis: an update.Crit Care Med. 2001; 29: S109-S116
- Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations.Am J Respir Crit Care Med. 2016; 193: 259-272
- Management of sepsis.N Engl J Med. 2006; 355: 1699-1713
- The pathophysiology and treatment of sepsis.N Engl J Med. 2003; 348: 138-150
- Cytokine storm and sepsis disease pathogenesis.Semin Immunopathol. 2017; 39: 517-528
- The "cytokine profile": a code for sepsis.Trends Mol Med. 2005; 11: 56-63
- Sepsis and endothelial permeability.N Engl J Med. 2010; 363: 689-691
- The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome.Blood. 2003; 101: 3765-3777
- Endothelial barrier dysfunction in septic shock.J Intern Med. 2015; 277: 277-293
- Cytokines in sepsis: potent immunoregulators and potential therapeutic targets–an updated view.Mediat Inflamm. 2013; 2013165974
- Role of cytokines as a double-edged sword in sepsis.In Vivo. 2013; 27: 669-684
- Effects of autophagy on lipopolysaccharide-induced vascular hyper-permeability.Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2016; 28: 673-677
- Macrophage migration inhibitory factor induces vascular leakage via autophagy.Biol Open. 2015; 4: 244-252
- Autophagy and cytokines.Cytokine. 2011; 56: 140-144
- Macrophage migration inhibitory factor-induced autophagy contributes to thrombin-triggered endothelial hyperpermeability in sepsis.Shock. 2018; 50: 103-111
- Autophagy and IL-1 family cytokines.Front Immunol. 2013; 4: 83
- Regulation of mammalian autophagy in physiology and pathophysiology.Physiol Rev. 2010; 90: 1383-1435
- Mammalian autophagy: core molecular machinery and signaling regulation.Curr Opin Cell Biol. 2010; 22: 124-131
- Following autophagy step by step.BMC Biol. 2011; 9: 39
- Autophagy in infection, inflammation and immunity.Nat Rev Immunol. 2013; 13: 722-737
- Autophagy in sepsis: Degradation into exhaustion?.Autophagy. 2016; 12: 1073-1082
- ATG16L1 deficiency in macrophages drives clearance of uropathogenic E. coli in an IL-1beta-dependent manner.Mucosal Immunol. 2015; 8: 1388-1399
- Autophagy inhibition promotes phagocytosis of macrophage and protects mice from methicillin-resistant staphylococcus aureus pneumonia.J Cell Biochem. 2018; 119: 4808-4814
- Kinetics and protective role of autophagy in a mouse cecal ligation and puncture-induced sepsis.Crit Care. 2013; 17: R160
- Chloroquine inhibits HMGB1 inflammatory signaling and protects mice from lethal sepsis.Biochem Pharmacol. 2013; 86: 410-418
- Intermedin protects against sepsis by concurrently re-establishing the endothelial barrier and alleviating inflammatory responses.Nat Commun. 2018; 9: 2644
- Regulated secretion of macrophage migration inhibitory factor is mediated by a non-classical pathway involving an ABC transporter.FEBS Letters. 2003; 551: 78-86
- NF-κB signaling in inflammation.Signal Transduct Target Ther. 2017; 2: 17023
- Autophagy intersections with conventional and unconventional secretion in tissue development, remodeling and inflammation.Trends Cell Biol. 2012; 22: 397-406
- NF-kappaB signaling in inflammation.Signal Transduct Target Ther. 2017; 2: e17023
- Involvement of nuclear factor-kappaB in macrophage migration inhibitory factor gene transcription up-regulation induced by interleukin- 1 beta in ectopic endometrial cells.Fertil Steril. 2009; 91: 2148-2156
- Dengue virus nonstructural protein 1 induces vascular leakage through macrophage migration inhibitory factor and autophagy.PLoS Negl Trop Dis. 2016; 10e0004828
- Autophagy maintains the integrity of endothelial barrier in LPS-induced lung injury.J Cell Physiol. 2018; 233: 688-698
- Innate and adaptive immunity through autophagy.Immunity. 2007; 27: 11-21
- Roles of autophagy in elimination of intracellular bacterial pathogens.Front Immunol. 2013; 4: 97
- Bacterial Pathogens versus autophagy: implications for therapeutic interventions.Trends Mol Med. 2016; 22: 1060-1076
- Autophagy and bacterial clearance: a not so clear picture.Cell Microbiol. 2013; 15: 395-402
- Autophagy regulates phagocytosis by modulating the expression of scavenger receptors.Immunity. 2013; 39: 537-547
- The interrelationship between phagocytosis, autophagy and formation of neutrophil extracellular traps following infection of human neutrophils by Streptococcus pneumoniae.Innate Immun. 2017; 23: 413-423
- Mitophagy and quality control mechanisms in mitochondrial maintenance.Curr Biol CB. 2018; 28: R170-r185
- Reactive oxygen species and mitochondria: A nexus of cellular homeostasis.Redox Biol. 2015; 6: 472-485
- Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases.J Antimicrob Chemother. 2015; 70: 1608-1621
Published online: January 14, 2019
Accepted: December 17, 2018
Received in revised form: October 24, 2018
Received: August 1, 2018
© 2019 The British Infection Association. Published by Elsevier Ltd. All rights reserved.