Enhanced neutrophil extracellular trap formation in COVID-19 is inhibited by the protein kinase C inhibitor ruboxistaurin

Dowey, Rebecca; Thompson, A. A. Roger; Hull, Rebecca C; Huang, Chenghao; Whatmore, Jacob; Iqbal, Ahmed; Bradley, Kirsty L; Mckenzie, Joanne; Lawrie, Allan; Condliffe, Alison M.; Kiss-Tóth, Endre; Sabroe, Ian; Prince, Lynne R.

doi:10.1183/23120541.00596-2021

Cited by 15 publications

(7 citation statements)

References 44 publications

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“…Neutrophil-soluble mediators, such as elastase and calprotectin, accumulate in plasma of patients with severe disease ( 29 , 30 ). Furthermore, NETs are elevated in the plasma of severe patients and correlate with lung failure and immunothrombosis ( 25 , 31 , 32 , 33 Preprint ), whereas isolated neutrophils from COVID-19 patients display elevated rates of both ROS production ( 34 ) and NETosis ( 35 , 36 ). Several studies have also reported expansion of low-density ( 37 ) and immature (CD10 low ) neutrophils ( 30 , 38 , 39 Preprint , 40 ), whose role in disease remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Hyperactive immature state and differential CXCR2 expression of neutrophils in severe COVID-19

et al. 2022

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Neutrophils are vital in defence against pathogens, but excessive neutrophil activity can lead to tissue damage and promote acute respiratory distress syndrome. COVID-19 is associated with systemic expansion of immature neutrophils, but the functional consequences of this shift to immaturity are not understood. We used flow cytometry to investigate activity and phenotypic diversity of circulating neutrophils in acute and convalescent COVID-19 patients. First, we demonstrate hyperactivation of immature CD10−subpopulations in severe disease, with elevated markers of secondary granule release. Partially activated immature neutrophils were detectable 12 wk post-hospitalisation, indicating long term myeloid dysregulation in convalescent COVID-19 patients. Second, we demonstrate that neutrophils from moderately ill patients down-regulate the chemokine receptor CXCR2, whereas neutrophils from severely ill individuals fail to do so, suggesting an altered ability for organ trafficking and a potential mechanism for induction of disease tolerance. CD10−and CXCR2hineutrophil subpopulations were enriched in severe disease and may represent prognostic biomarkers for the identification of individuals at high risk of progressing to severe COVID-19.

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Section: Introductionmentioning

confidence: 99%

Hyperactive immature state and differential CXCR2 expression of neutrophils in severe COVID-19

et al. 2022

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“…The nuclear localization of TFEB induced by PKC-α/δ occurs via GSK3β in mTORC1-independent manner ( 30 ). Additionally, an orally active PKC inhibitor ruboxistaurin proves to be active against SARS-CoV-2 as it inhibits NETosis, and has passed phase 3 for other indications ( 71 ). Previous studies have also shown that ruboxistaurin was active against GSK3α and GSK3β with IC 50 values of 695.9 nM and 97.3 nM, respectively ( 60 ).…”

Section: Resultsmentioning

confidence: 99%

Modeling structure–activity relationships with machine learning to identify GSK3-targeted small molecules as potential COVID-19 therapeutics

Pirzada

Ahmad²,

Qayyum³

et al. 2023

Front. Endocrinol.

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Coronaviruses induce severe upper respiratory tract infections, which can spread to the lungs. The nucleocapsid protein (N protein) plays an important role in genome replication, transcription, and virion assembly in SARS-CoV-2, the virus causing COVID-19, and in other coronaviruses. Glycogen synthase kinase 3 (GSK3) activation phosphorylates the viral N protein. To combat COVID-19 and future coronavirus outbreaks, interference with the dependence of N protein on GSK3 may be a viable strategy. Toward this end, this study aimed to construct robust machine learning models to identify GSK3 inhibitors from Food and Drug Administration–approved and investigational drug libraries using the quantitative structure–activity relationship approach. A non-redundant dataset consisting of 495 and 3070 compounds for GSK3α and GSK3β, respectively, was acquired from the ChEMBL database. Twelve sets of molecular descriptors were used to define these inhibitors, and machine learning algorithms were selected using the LazyPredict package. Histogram-based gradient boosting and light gradient boosting machine algorithms were used to develop predictive models that were evaluated based on the root mean square error and R-squared value. Finally, the top two drugs (selinexor and ruboxistaurin) were selected for molecular dynamics simulation based on the highest predicted activity (negative log of the half-maximal inhibitory concentration, pIC50 value) to further investigate the structural stability of the protein-ligand complexes. This artificial intelligence-based virtual high-throughput screening approach is an effective strategy for accelerating drug discovery and finding novel pharmacological targets while reducing the cost and time.

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“…S1-7). Neutrophils also play a critical role in hyperinflammation [146][147][148][149][150][151][152][153][154][155] . Activated neutrophils release NETs and ROS to eradicate bacteria 156 .…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stromal cells and alpha-1 antitrypsin have a strong synergy in modulating inflammation and its resolution

Han

Wang

et al. 2022

Preprint

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Many reasons, such as infection, injury, tissue transplantation, and cancer treatment, can cause dysregulated hyperinflammation. Immune cells become excessive and hyperactive, producing sustained, systemic and large quantities of cytokines. The systemic inflammation can rapidly progress to disseminated intravascular coagulation, endothelium damage, capillary leakage, multiorgan (e.g., liver, kidney, heart, and brain) dysfunction, ARDS, and fatality. Although the initial driver may differ, the late-stage clinical features of hyperinflammation and cytokine storm converge. Unfortunately, the outcome of current treatments is still unsatisfactory. Our body has regulatory mechanisms to prevent the over-activation of immune cells, but these mechanisms fail or are insufficient in patients with hyperinflammation. Logically, augmenting these regulators represents a promising approach. Among the various natural negative regulators, mesenchymal stromal cells (MSCs) and alpha-1 antitrypsin (A1AT) are attractive due to their unique characteristics. MSCs and A1AT have shown capabilities to modulate immune cells. However, the efficacy and potency of MSCs or A1AT alone are limited and cannot fully normalize hyperinflammation and cytokine storm. Considering MSCs are cells while A1AT is a protein, we hypothesize that they may suppress inflammation using different mechanisms and have additive or synergistic effects when combined. This report showed that the combination of MSCs and A1AT was much more effective than individual components in modulating inflammation of various immune cells in vitro and in animal models. Our results provide solid evidence to support clinical studies of the combinational use of MSCs and A1AT for normalizing inflammation under various disease conditions.

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Enhanced neutrophil extracellular trap formation in COVID-19 is inhibited by the protein kinase C inhibitor ruboxistaurin

Cited by 15 publications

References 44 publications

Hyperactive immature state and differential CXCR2 expression of neutrophils in severe COVID-19

Hyperactive immature state and differential CXCR2 expression of neutrophils in severe COVID-19

Modeling structure–activity relationships with machine learning to identify GSK3-targeted small molecules as potential COVID-19 therapeutics

Mesenchymal stromal cells and alpha-1 antitrypsin have a strong synergy in modulating inflammation and its resolution

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