Dexamethasone Inhibits S. aureus-Induced Neutrophil Extracellular Pathogen-Killing Mechanism, Possibly through Toll-Like Receptor Regulation

Wan, Ting; Zhao, Yingying; Fan, Fangli; Hu, Renjian; Jin, Xiuming

doi:10.3389/fimmu.2017.00060

Cited by 44 publications

(32 citation statements)

References 35 publications

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“…8c-g (unpublished data). Dexamethasone has indeed been shown to dampen myeloid inflammatory signalling (notably IL-1 and IL-6 release), reduce neutrophil inflammation 43 , promote an 'M2-like" macrophage phenotype, which has anti-inflammatory and phagocytic traits 44 , as well as to maintain clonal balance in T-cells 45 . Given the findings we report here, the therapeutic effects of dexamethasone are not entirely unexpected.…”

Section: Cell-to-cell Communication To Unravel the Immune Context Of mentioning

confidence: 99%

Discriminating Mild from Critical COVID-19 by Innate and Adaptive Immune Single-cell Profiling of Bronchoalveolar Lavages

Wauters

Mol

Garg

et al. 2020

Preprint

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How innate and adaptive lung immune responses to SARS-CoV-2 synchronize during COVID-19 pneumonitis and regulate disease severity is poorly established. To address this, we applied single-cell profiling to bronchoalveolar lavages from 44 patients with mild or critical COVID-19 versus non-COVID-19 pneumonia as control. Viral RNA-tracking delineated the infection phenotype to epithelial cells, but positioned mainly neutrophils at the forefront of viral clearance activity during COVID-19. In mild disease, neutrophils could execute their antiviral function in an immunologically controlled fashion, regulated by fully-differentiated T-helper-17 (TH17)-cells, as well as T-helper-1 (TH1)-cells, CD8+ resident-memory (TRM) and partially-exhausted (TEX) T-cells with good effector functions. This was paralleled by orderly phagocytic disposal of dead/stressed cells by fully-differentiated macrophages, otherwise characterized by anti-inflammatory and antigen-presenting characteristics, hence facilitating lung tissue repair. In critical disease, CD4+ TH1- and CD8+ TEX-cells were characterized by inflammation-associated stress and metabolic exhaustion, while CD4+ TH17- and CD8+ TRM-cells failed to differentiate. Consequently, T-cell effector function was largely impaired thereby possibly facilitating excessive neutrophil-based inflammation. This was accompanied by impaired monocyte-to-macrophage differentiation, with monocytes exhibiting an ATP-purinergic signalling-inflammasome footprint, thereby enabling COVID-19 associated fibrosis and worsening disease severity. Our work represents a major resource for understanding the lung-localised immunity and inflammation landscape during COVID-19.

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Section: Cell-to-cell Communication To Unravel the Immune Context Of mentioning

confidence: 99%

Discriminating Mild from Critical COVID-19 by Innate and Adaptive Immune Single-cell Profiling of Bronchoalveolar Lavages

Wauters

Mol

Garg

et al. 2020

Preprint

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“…Vargas et al reported that NETs generation in the lungs was inhibited by glucocorticosteroids in an asthma model ( 30 ). We also previously showed that DXM decreased NETs formation via a toll-like receptor (TLR)-dependent mechanism ( 17 ). Moreover, we found that glucocorticoids reduced neutrophil infiltration and inhibited NETs generation in fungal keratitis ( 31 ).…”

Section: Discussionmentioning

confidence: 95%

“…SYTOX green stained dead-cell cultures were imaged with an inverted fluorescence microscope (Olympus IX-50). Besides, quantification of the extracellular DNA in supernatants was accomplished by using Quant-iT PicoGreen dsDNA assay kit according to the manufacturer's instructions, as previously described ( 17 ).…”

Section: Methodsmentioning

confidence: 99%

Acetylsalicylic Acid Promotes Corneal Epithelium Migration by Regulating Neutrophil Extracellular Traps in Alkali Burn

et al. 2020

Self Cite

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Neutrophils are the first cells to migrate into the cornea in response to alkali burns, and excessive neutrophil infiltration is associated with inflammatory injury and a poorer prognosis. In an effort to understand the mechanisms underlying the inflammation mediated by neutrophils after alkali burns, we examined the role of alkali-activated neutrophils on human corneal epithelial cells (HCEs) proliferation and migration, as well as the effects of acetylsalicylic acid (ASA) and dexamethasone (DXM) on NETosis. We stimulated human neutrophils with sodium hydroxide (NaOH) and observed dose- and time-dependent neutrophil extracellular traps (NETs) formation. We also observed that ASA, but not DXM, significantly inhibited NaOH-induced NETosis. Furthermore, the activation of nuclear factor (NF)-κB, but not the production of reactive oxygen species, was involved in ASA-regulated NETosis. Moreover, NETs were found to be involved in alkali-activated neutrophils (ANs) induced neutrophil-HCE adhesion. ANs enhanced HCEs proliferation via phagocytosis. Meanwhile, ANs inhibited HCEs migration through the release of NETs, which was partially rescued by 5 mM ASA. In conclusion, ANs may interfere with HCEs proliferation and migration by phagocytosis and NETs formation, respectively. ASA may enhance HCEs migration by decreasing NETs formation through inhibition of NF-κB activation and could be a promising strategy for improving the prognosis of corneal alkali burns.

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“…The TLRs involved in S. aureus -induced NET formation seem to be TLR2 and TLR4, as agonists of these receptors rescued Dex inhibition. Interestingly, although Dex reduced NET formation, it did not significantly affect ROS production [ 74 ].…”

Section: Netosis As a Therapeutic Targetmentioning

confidence: 99%

The Role of Neutrophil NETosis in Organ Injury: Novel Inflammatory Cell Death Mechanisms

Cahilog

Zhao

et al. 2020

Inflammation

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NETosis is a type of regulated cell death dependent on the formation of neutrophil extracellular traps (NET), where net-like structures of decondensed chromatin and proteases are produced by polymorphonuclear (PMN) granulocytes. These structures immobilise pathogens and restrict them with antimicrobial molecules, thus preventing their spread. Whilst NETs possess a fundamental anti-microbial function within the innate immune system under physiological circumstances, increasing evidence also indicates that NETosis occurs in the pathogenic process of other disease type, including but not limited to atherosclerosis, airway inflammation, Alzheimer’s and stroke. Here, we reviewed the role of NETosis in the development of organ injury, including injury to the brain, lung, heart, kidney, musculoskeletal system, gut and reproductive system, whilst therapeutic agents in blocking injuries induced by NETosis in its primitive stages were also discussed. This review provides novel insights into the involvement of NETosis in different organ injuries, and whilst potential therapeutic measures targeting NETosis remain a largely unexplored area, these warrant further investigation.

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Dexamethasone Inhibits S. aureus-Induced Neutrophil Extracellular Pathogen-Killing Mechanism, Possibly through Toll-Like Receptor Regulation

Cited by 44 publications

References 35 publications

Discriminating Mild from Critical COVID-19 by Innate and Adaptive Immune Single-cell Profiling of Bronchoalveolar Lavages

Discriminating Mild from Critical COVID-19 by Innate and Adaptive Immune Single-cell Profiling of Bronchoalveolar Lavages

Acetylsalicylic Acid Promotes Corneal Epithelium Migration by Regulating Neutrophil Extracellular Traps in Alkali Burn

The Role of Neutrophil NETosis in Organ Injury: Novel Inflammatory Cell Death Mechanisms

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