Therapeutic blockade of CD54 attenuates pulmonary barrier damage in T cell-induced acute lung injury

Svedova, Julia; Ménoret, Antoine; Mittal, Payal; Ryan, Joseph M.; Buturla, James A.; Vella, Anthony T.

doi:10.1152/ajplung.00050.2017

Cited by 12 publications

(13 citation statements)

References 87 publications

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“…Similar upregulation is observed in Ang II-induced macrophage infiltration and cardiovascular pathology, which is ameliorated by ICAM-1 blockade (Lin Q. Y. et al, 2019). Blockade of ICAM-1 is also reported to markedly reduce pulmonary barrier damage in ARDS (Svedova et al, 2017).…”

Section: Adhesion and Tissue Retention Of Inflammatory Leukocytesmentioning

confidence: 56%

Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention

2020

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With the objective of linking early findings relating to the novel SARS-CoV-2 coronavirus with potentially informative findings from prior research literature and to promote investigation toward therapeutic response, a coherent cellular and molecular pathway is proposed for COVID-19. The pathway is consistent with a broad range of observed clinical features and biological markers and captures key mediators of pathophysiology. In this proposed pathway, membrane fusion and cytoplasmic entry of SARS-CoV-2 virus via ACE2 and TMPRSS2-expressing respiratory epithelial cells, including pulmonary type-II pneumocytes, provoke an initial immune response featuring inflammatory cytokine production coupled with a weak interferon response, particularly in IFN-l-dependent epithelial defense. Differentiation of non-classic pathogenic T-cells and pro-inflammatory intermediate monocytes contributes to a skewed inflammatory profile, mediated by membrane-bound immune receptor subtypes (e.g., FcgRIIA) and downstream signaling pathways (e.g., NF-kB p65 and p38 MAPK), followed by chemotactic infiltration of monocyte-derived macrophages and neutrophils into lung tissue. Endothelial barrier degradation and capillary leakage contribute to alveolar cell damage. Inflammatory cytokine release, delayed neutrophil apoptosis, and NETosis contribute to pulmonary thrombosis and cytokine storm. These mechanisms are concordant with observed clinical markers in COVID-19, including high expression of inflammatory cytokines on the TNF-a/ IL-6 axis, elevated neutrophil-to-lymphocyte ratio (NLR), diffuse alveolar damage via cell apoptosis in respiratory epithelia and vascular endothelia, elevated lactate dehydrogenase (LDH) and CRP, high production of neutrophil extracellular traps (NETs), depressed platelet count, and thrombosis. Although certain elements are likely to be revised as new findings emerge, the proposed pathway suggests multiple points of investigation for potential therapeutic interventions. Initial candidate interventions include prophylaxis to augment epithelial defense (e.g., AT1 receptor blockade, type III and type I interferons, melatonin, calcitriol, camostat, and lopinavir) and to reduce viral load (e.g., remdesivir, ivermectin, emetine, Abelson kinase inhibitors, dopamine D2 antagonists, and selective estrogen receptor modulators). Additional interventions focus on tempering inflammatory signaling and injury (e.g., dexamethasone, doxycycline, Ang1-7, estradiol, alpha blockers,

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Section: Adhesion and Tissue Retention Of Inflammatory Leukocytesmentioning

confidence: 56%

Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention

2020

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“…Both systemic and intranasal exposure to SEB cause acute lung injury, characterized by increased expression of adhesion molecule ICAM-1 and vascular cell adhesion molecule (VCAM), increased neutrophils and mononuclear cell infiltrates, endothelial cell injury, and increased vascular permeability [28,33,115]. A blockade of ICAM-1 by anti-ICAM-1 antibodies attenuated pulmonary barrier damage in a murine model of SEA-mediated acute lung injury [121].…”

Section: Contributions By Other Cytokines and Chemokinesmentioning

confidence: 99%

“…Cell activation induces ER stress, oxidative stress, mitochondrial ROS, and damage, which also promotes cell death. An upregulation of damage response genes contributes to the irreversible multiorgan damage seen in animal models of superantigen-induced toxic shock and human toxic shock syndrome [33,98,115,121,143,144,145]. In this regard, superantigen-induced mTORC1 activation increases oxidative stress, contributing to inflammation, DAMPs, and cell death.…”

Section: Lessons Learned From Therapeutics That Prevent Seb-inducmentioning

confidence: 99%

Staphylococcal Superantigens: Pyrogenic Toxins Induce Toxic Shock

Krakauer

2019

Toxins

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Staphylococcal enterotoxin B (SEB) and related superantigenic toxins produced by Staphylococcus aureus are potent activators of the immune system. These protein toxins bind to major histocompatibility complex (MHC) class II molecules and specific Vβ regions of T-cell receptors (TCRs), resulting in the activation of both monocytes/macrophages and T lymphocytes. The bridging of TCRs with MHC class II molecules by superantigens triggers an early “cytokine storm” and massive polyclonal T-cell proliferation. Proinflammatory cytokines, tumor necrosis factor α, interleukin 1 (IL-1), IL-2, interferon γ (IFNγ), and macrophage chemoattractant protein 1 elicit fever, inflammation, multiple organ injury, hypotension, and lethal shock. Upon MHC/TCR ligation, superantigens induce signaling pathways, including mitogen-activated protein kinase cascades and cytokine receptor signaling, which results in NFκB activation and the phosphoinositide 3-kinase/mammalian target of rapamycin pathways. In addition, gene profiling studies have revealed the essential roles of innate antimicrobial defense genes in the pathogenesis of SEB. The genes expressed in a murine model of SEB-induced shock include intracellular DNA/RNA sensors, apoptosis/DNA damage-related molecules, endoplasmic reticulum/mitochondrial stress responses, immunoproteasome components, and IFN-stimulated genes. This review focuses on the signaling pathways induced by superantigens that lead to the activation of inflammation and damage response genes. The induction of these damage response genes provides evidence that SEB induces danger signals in host cells, resulting in multiorgan injury and toxic shock. Therapeutics targeting both host inflammatory and cell death pathways can potentially mitigate the toxic effects of staphylococcal superantigens.

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“…Thus, it will be important to determine the identity of the binding site of enterotoxin A on AMs as well as the processing of the enterotoxin by these phagocytes. Previous studies showed that following intranasal S. aureus enterotoxin exposure, mice experience a systemic oligoclonal T cell activation and cytokine release to blood (26,33,51). To examine the role of AMs in the enterotoxin A-induced inflammatory response, WT and CD169-DTR mice were treated with DT and 2 d later, they were exposed to vehicle or enterotoxin A.…”

Section: Discussionmentioning

confidence: 99%

“…Harvest and processing of bronchoalveolar lavage (BAL) fluid, lung, and spleen, and staining for flow cytometry were performed as described previously (26,33). The single-cell suspensions were labeled with Live/Dead fixable blue dead cell stain (Thermo Fisher Scientific, Waltham, MA) and stained with the following Abs: CD45.2 clone 104 (shown as CD45), anti-Siglec F clone E50-2440, anti-CD11c clone N418, anti-CD169 clone SER-4, anti-CD3 clone 17A2, anti-Vb3 clone KJ25, anti-Vb14 clone 14-2, anti-CD25 clone PC61, and anti-CD69 clone H1.2F3 (purchased from BD Biosciences, San Jose, CA or eBioscience, San Diego, CA).…”

Section: Flow Cytometrymentioning

confidence: 99%

CD169+ Macrophages Restrain Systemic Inflammation Induced by Staphylococcus aureus Enterotoxin A Lung Response

et al. 2017

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Material ABSTRACTAlveolar macrophages (AMs) are considered the first line of defense in the airways. Exposure to harmful substances and certain infections can lead to dysfunction or depletion of AMs. Importantly, these conditions have been associated with increased risk of sepsis and acute lung injury. Staphylococcus aureus enterotoxins are superantigens that induce oligoclonal activation of T cells and a robust cytokine release, leading to systemic inflammatory response and tissue injury. In this study we investigated the relationship between S. aureus enterotoxins and AMs. Following inhalation, S. aureus enterotoxin was preferentially bound to AMs and MHC class II was not required. Furthermore, the enterotoxin was internalized and its presence in the cells decreased by 24 h after exposure. Ablation of AMs in CD169-diphtheria toxin receptor mice was associated with increased activation of enterotoxin-specific T cells and enhanced cytokine release into circulation. Thus, conditions causing depletion of AMs may increase the risk of S. aureus enterotoxin-induced diseases. ImmunoHorizons, 2017, 1: 213-222.

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Therapeutic blockade of CD54 attenuates pulmonary barrier damage in T cell-induced acute lung injury

Cited by 12 publications

References 87 publications

Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention

Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention

Staphylococcal Superantigens: Pyrogenic Toxins Induce Toxic Shock

CD169+ Macrophages Restrain Systemic Inflammation Induced by Staphylococcus aureus Enterotoxin A Lung Response

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