Editorial: Endothelial cells as innate immune cells

Lu, Yifan; Sun, Yu; Xu, Keman; Shao, Ying; Saaoud, Fatma; Snyder, Nathaniel W.; Yang, Ling; Wu, Sheng; Hu, Wenhui; Sun, Jianxin; Wang, Hong; Yang, Xiaofeng

doi:10.3389/fimmu.2022.1035497

Cited by 7 publications

(6 citation statements)

References 51 publications

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“…During sepsis, the activated endothelium becomes more adhesive, leaky, pro-apoptotic, pro-inflammatory, pro-thrombotic and vasoactive (Fig. 3 ) [ 81 , 83 , 105 , 123 ]. Glycocalyx shedding is facilitated by stress-activated membrane-bound enzymes, called sheddases, in response to pro-inflammatory cytokines (e.g.…”

Section: Pathophysiology From a System’s Perspectivementioning

confidence: 99%

“…Possible sources of TNF-α and IL-1β are activated monocytes and macrophages. [ 120 – 122 , 54 , 123 – 125 , 105 ] 2 Overexpression of cardiac mitochondrial NOS Excess NO synthesis (and reactive oxygen species), which may partially open the mitochondrial pore, depolarize the inner membrane, and reduce ATP production for contraction. [ 126 , 114 ] 3 Myofilament Ca 2+ responsiveness Decrease cardio-myofilament Ca 2+ sensitivity, reduces cross-bridge cycling responsiveness to reduce contractile activation and force development.…”

Section: Pathophysiology From a System’s Perspectivementioning

confidence: 99%

“… [ 129 ] 5 Downregulation of master genes encoding for sarcomeric and mitochondrial proteins Reduce cross-bridge cycling and ATP availability generated by oxidative phosphorylation. [ 105 ] TNF-α tumor necrosis factor-alpha, IL-1β interleukin-1beta, NO nitric oxide, L-NAME N G -nitro- L -arginine methyl ester, ATP adenosine triphosphate …”

Section: Pathophysiology From a System’s Perspectivementioning

confidence: 99%

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Revolution in sepsis: a symptoms-based to a systems-based approach?

Dobson,

Letson,

Morris

2024

J Biomed Sci

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Severe infection and sepsis are medical emergencies. High morbidity and mortality are linked to CNS dysfunction, excessive inflammation, immune compromise, coagulopathy and multiple organ dysfunction. Males appear to have a higher risk of mortality than females. Currently, there are few or no effective drug therapies to protect the brain, maintain the blood brain barrier, resolve excessive inflammation and reduce secondary injury in other vital organs. We propose a major reason for lack of progress is a consequence of the treat-as-you-go, single-nodal target approach, rather than a more integrated, systems-based approach. A new revolution is required to better understand how the body responds to an infection, identify new markers to detect its progression and discover new system-acting drugs to treat it. In this review, we present a brief history of sepsis followed by its pathophysiology from a systems’ perspective and future opportunities. We argue that targeting the body’s early immune-driven CNS-response may improve patient outcomes. If the barrage of PAMPs and DAMPs can be reduced early, we propose the multiple CNS-organ circuits (or axes) will be preserved and secondary injury will be reduced. We have been developing a systems-based, small-volume, fluid therapy comprising adenosine, lidocaine and magnesium (ALM) to treat sepsis and endotoxemia. Our early studies indicate that ALM therapy shifts the CNS from sympathetic to parasympathetic dominance, maintains cardiovascular-endothelial glycocalyx coupling, reduces inflammation, corrects coagulopathy, and maintains tissue O2 supply. Future research will investigate the potential translation to humans.

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Section: Pathophysiology From a System’s Perspectivementioning

confidence: 99%

Section: Pathophysiology From a System’s Perspectivementioning

confidence: 99%

Section: Pathophysiology From a System’s Perspectivementioning

confidence: 99%

See 1 more Smart Citation

Revolution in sepsis: a symptoms-based to a systems-based approach?

Dobson,

Letson,

Morris

2024

J Biomed Sci

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“…TNF can also induce the EC expression of IFN regulatory factors and IFN-stimulated genes (ISGs) ( 8 , 9 ). Indeed, the concept that ECs are multifaceted conditional innate immune cells has gained traction in recent years ( 10 , 11 ). However, the global dynamics of the EC response to TNF is not well understood, with existing studies tending to focus on specific gene(s) or phenotypic characteristics [e.g., ( 12–14 )] or global transcriptional changes at a single or a small number of time points ( 15 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

Global Transcriptome Analysis Reveals Distinct Phases of the Endothelial Response to TNF

Struck,

Belova,

Hsieh

et al. 2023

The Journal of Immunology

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The vascular endothelium acts as a dynamic interface between blood and tissue. TNF-α, a major regulator of inflammation, induces endothelial cell (EC) transcriptional changes, the overall response dynamics of which have not been fully elucidated. In the present study, we conducted an extended time-course analysis of the human EC response to TNF, from 30 min to 72 h. We identified regulated genes and used weighted gene network correlation analysis to decipher coexpression profiles, uncovering two distinct temporal phases: an acute response (between 1 and 4 h) and a later phase (between 12 and 24 h). Sex-based subset analysis revealed that the response was comparable between female and male cells. Several previously uncharacterized genes were strongly regulated during the acute phase, whereas the majority in the later phase were IFN-stimulated genes. A lack of IFN transcription indicated that this IFN-stimulated gene expression was independent of de novo IFN production. We also observed two groups of genes whose transcription was inhibited by TNF: those that resolved toward baseline levels and those that did not. Our study provides insights into the global dynamics of the EC transcriptional response to TNF, highlighting distinct gene expression patterns during the acute and later phases. Data for all coding and noncoding genes is provided on the Web site (http://www.endothelial-response.org/). These findings may be useful in understanding the role of ECs in inflammation and in developing TNF signaling–targeted therapies.

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“…However, the role of the diversity of other cellular subpopulations found in healthy and SSC-ILD lungs in shaping SSC-ILD pathophysiology is unclear.Single-cell sequencing, which includes single-cell RNA sequencing (scRNA-seq) and the assay for transposase-accessible chromatin sequencing (scATAC-seq), is a valuable method for investigating the molecular and cellular heterogeneity of cell types. EC, one of the innermost cell types lined along vessels in all organs and tissues through hosts, is also in the bloodstream, where it can modulate inflammation by regulating immune cell transport, activation status, and function [5][6][7]. Furthermore, EC in the lungs and liver not only promotes immune homeostasis but also mediates the balance between tolerance and inflammation [6].…”

mentioning

confidence: 99%

Integrative single-cell analysis of epigenomic and transcriptomic states in patients with systemic sclerosis-associated interstitial lung disease

Li,

Gong

2023

Preprint

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Interstitial lung disease is the primary cause of death in individuals who have systemic sclerosis, one of the autoimmune connective tissue diseases. Understanding the pathophysiology of the disease is crucial to developing treatment options. Here, we performed a single-cell multi-omic analysis on lung tissue samples from patients with systemic sclerosis-associated interstitial lung disease (SSC-ILD), profiling chromatin accessibility and gene expression in the same samples and discovering significant cellular heterogeneity. Systemic-venous endothelial cells (ECs) have been shown to be pro-inflammatory and highly active. In addition, it was shown that the transcription factor FOSL2 targets the genes involved in response to unfolded proteins in systemic-venous ECs. Furthermore, we prioritized functional risk variants for systemic sclerosis using a genome-wide association study. Ligand-receptor analysis revealed that ECs significantly increased interaction with B cells via CXCL10-CXCR3 in patients with SSC-ILD. Overall, our analysis emphasizes epigenetic and transcriptional patterns in systemic-venous ECs, which might be beneficial in understanding the pathogenesis of SSC-ILD.

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Editorial: Endothelial cells as innate immune cells

Cited by 7 publications

References 51 publications

Revolution in sepsis: a symptoms-based to a systems-based approach?

Revolution in sepsis: a symptoms-based to a systems-based approach?

Global Transcriptome Analysis Reveals Distinct Phases of the Endothelial Response to TNF

Integrative single-cell analysis of epigenomic and transcriptomic states in patients with systemic sclerosis-associated interstitial lung disease

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