TICAM2-related pathway mediates neutrophil exhaustion

Lin, RuiCi; Zhang, Yao; Pradhan, Kisha; Li, Liwu

doi:10.1038/s41598-020-71379-y

Cited by 26 publications

(21 citation statements)

References 78 publications

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“…Whereas, neutrophils isolated from septic individuals formed the same numbers of NETs independently of their origin. This might reflect on the exhausted neutrophil phenotype typical for sepsis and characterized by elevated expression of immunosuppression-associated markers (i.e., PD-L1) as well as adhesion molecules resulting in pathogenic and immune-suppressed phenotype [ 76 ]. Nevertheless, our ex vivo studies clearly show a lack of intrinsic problems with casting NETs by neutrophils of obese mice.…”

Section: Discussionmentioning

confidence: 99%

Scrutinizing Mechanisms of the ‘Obesity Paradox in Sepsis’: Obesity Is Accompanied by Diminished Formation of Neutrophil Extracellular Traps (NETs) Due to Restricted Neutrophil–Platelet Interactions

Cichoń

Ortmann

Santocki

et al. 2021

Cells

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Systemic inflammation is a detrimental condition associated with high mortality. However, obese individuals seem to have higher chances of surviving sepsis. To elucidate what immunological differences exist between obese and lean individuals we studied the course of endotoxemia in mice fed high-fat diet (HFD) and ob/ob animals. Intravital microscopy revealed that neutrophil extracellular trap (NET) formation in liver vasculature is negligible in obese mice in sharp contrast to their lean counterparts (ND). Unlike in lean individuals, neutrophil influx is not driven by leptin or interleukin 33 (IL-33), nor occurs via a chemokine receptor CXCR2. In obese mice less platelets interact with neutrophils forming less aggregates. Platelets transfer from ND to HFD mice partially restores NET formation, and even further so upon P-selectin blockage on them. The study reveals that in obesity the overexaggerated inflammation and NET formation are limited during sepsis due to dysfunctional platelets suggesting their targeting as a therapeutic tool in systemic inflammation.

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Section: Discussionmentioning

confidence: 99%

Scrutinizing Mechanisms of the ‘Obesity Paradox in Sepsis’: Obesity Is Accompanied by Diminished Formation of Neutrophil Extracellular Traps (NETs) Due to Restricted Neutrophil–Platelet Interactions

Cichoń

Ortmann

Santocki

et al. 2021

Cells

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“…For example, different subsets of low-grade inflammatory monocytes might be differentially involved in the initiation of low-grade inflammation and the accumulation of foamy macrophages. On the other hand, prolonged challenges with higher dose LPS may lead to dysfunctional innate leukocytes with an exhausted phenotype characterized by pathogenic inflammation and immuno-suppression associated with elevated sepsis ( 65 ). Future single cell sequencing analysis will be helpful in defining additional sub-populations of monocytes adopting distinct phenotypic states representing both chronic atherosclerosis and acute sepsis, dependent upon the duration and intensity of external danger signals.…”

Section: Discussionmentioning

confidence: 99%

Single Cell RNA-Seq and Machine Learning Reveal Novel Subpopulations in Low-Grade Inflammatory Monocytes With Unique Regulatory Circuits

Lee

Geng

et al. 2021

Front. Immunol.

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Subclinical doses of LPS (SD-LPS) are known to cause low-grade inflammatory activation of monocytes, which could lead to inflammatory diseases including atherosclerosis and metabolic syndrome. Sodium 4-phenylbutyrate is a potential therapeutic compound which can reduce the inflammation caused by SD-LPS. To understand the gene regulatory networks of these processes, we have generated scRNA-seq data from mouse monocytes treated with these compounds and identified 11 novel cell clusters. We have developed a machine learning method to integrate scRNA-seq, ATAC-seq, and binding motifs to characterize gene regulatory networks underlying these cell clusters. Using guided regularized random forest and feature selection, our method achieved high performance and outperformed a traditional enrichment-based method in selecting candidate regulatory genes. Our method is particularly efficient in selecting a few candidate genes to explain observed expression pattern. In particular, among 531 candidate TFs, our method achieves an auROC of 0.961 with only 10 motifs. Finally, we found two novel subpopulations of monocyte cells in response to SD-LPS and we confirmed our analysis using independent flow cytometry experiments. Our results suggest that our new machine learning method can select candidate regulatory genes as potential targets for developing new therapeutics against low grade inflammation.

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“…However, the cells might have displayed so called an exhausted phenotype disabling further NET release. This phenotype (known previously as immune paralysis of neutrophils) is characteristic for the cells during sepsis [64]. Such exhausted neutrophils show diminished response to following activating stimuli either because they have already secreted their stored granules and NETs [65] or because they become refractory to the immunologic stimulation [64].…”

Section: Discussionmentioning

confidence: 99%

Metabolic Pathways Involved in Formation of Spontaneous and Lipopolysaccharide-Induced Neutrophil Extracellular Traps (NETs) Differ in Obesity and Systemic Inflammation

Cichoń

Ortmann

Kołaczkowska

2021

IJMS

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Obesity manifests itself with low-grade chronic inflammation that shapes immune responses during infection. Albeit obese individuals are at risk of higher mortality due to comorbidities, they are better protected from systemic inflammation. Recently, we showed that in the vasculature of obese mice kept on high-fat diet (HFD), neutrophils produce less neutrophil extracellular traps (NETs) than in lean controls (normal diet, ND). NETs are used by neutrophils to counteract severe infection, but they also cause collateral damage. Hardly anything is known about metabolic requirements for their formation, especially in the context of obesity and/or sepsis. Thus, we aimed to study the immunometabolism of NET formation by application of ex vivo neutrophil analyses (Seahorse analyzer, selective inhibitors, confocal imaging) and intravital microscopy. The obtained data show that glycolysis and/or pentose phosphate pathway are involved in NETs release by ND neutrophils in both physiological and inflammatory conditions. In contrast, such cells of septic HFD mice utilize these routes only to spontaneously cast NETs, while after secondary ex vivo activation they exhibit so called “exhausted phenotype”, which manifests itself in diminished NET release despite high glycolytic potential and flexibility to oxidize fatty acids. Moreover, impact of ATP synthase inhibition on NET formation is revealed. Overall, the study shows that the neutrophil potential to cast NETs depends on both the metabolic and inflammatory state of the individual.

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TICAM2-related pathway mediates neutrophil exhaustion

Abstract: y www.nature.com/scientificreports/ only the expression of surface markers of neutrophil exhaustion but also for the related swarming phenotype associated with neutrophil exhaustion.

Cited by 26 publications

References 78 publications

Scrutinizing Mechanisms of the ‘Obesity Paradox in Sepsis’: Obesity Is Accompanied by Diminished Formation of Neutrophil Extracellular Traps (NETs) Due to Restricted Neutrophil–Platelet Interactions

Scrutinizing Mechanisms of the ‘Obesity Paradox in Sepsis’: Obesity Is Accompanied by Diminished Formation of Neutrophil Extracellular Traps (NETs) Due to Restricted Neutrophil–Platelet Interactions

Single Cell RNA-Seq and Machine Learning Reveal Novel Subpopulations in Low-Grade Inflammatory Monocytes With Unique Regulatory Circuits

Metabolic Pathways Involved in Formation of Spontaneous and Lipopolysaccharide-Induced Neutrophil Extracellular Traps (NETs) Differ in Obesity and Systemic Inflammation

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