Experimental murine acute lung injury induces increase of pulmonary TIE2-expressing macrophages

Ehrentraut, Heidi; Weisheit, Christina; Scheck, Marcel; Frede, Stilla; Hilbert, Tobias

doi:10.1186/s12950-018-0188-5

Cited by 6 publications

(4 citation statements)

References 53 publications

(69 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In animal models of sepsis, loss of Tie2 — both cell surface receptor and Tie2 phosphorylation — is a common feature of several infectious diseases associated with vascular leak ( 41 ). Tie2 is also expressed on a subpopulation of monocytes and recruitment and/or these cells via Angpt-2 may promote pathologic lung injury through secretion of matrix-degrading enzymes and/or inflammatory cytokines ( 44 , 45 ). The role of Tie2 on nonendothelial cells is incompletely defined, and it is difficult to speculate on their role in COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19

Schmaier¹,

Hurtado²,

Manickas-Hill³

et al. 2021

JCI Insight

View full text Add to dashboard Cite

Endothelial dysfunction accompanies the microvascular thrombosis commonly observed in severe COVID-19. Constitutively, the endothelial surface is anticoagulant, a property maintained at least in part via signaling through the Tie2 receptor. During inflammation, the Tie2 antagonist angiopoietin-2 (Angpt-2) is released from endothelial cells and inhibits Tie2, promoting a prothrombotic phenotypic shift. We sought to assess whether severe COVID-19 is associated with procoagulant endothelial dysfunction and alterations in the Tie2-angiopoietin axis. Primary human endothelial cells treated with plasma from patients with severe COVID-19 upregulated expression of thromboinflammatory genes, inhibited expression of antithrombotic genes, and promoted coagulation on the endothelial surface. Pharmacologic activation of Tie2 with the small molecule AKB-9778 reversed the prothrombotic state induced by COVID-19 plasma in primary endothelial cells. Lung autopsies from COVID-19 patients demonstrated a prothrombotic endothelial signature. Assessment of circulating endothelial markers in a cohort of 98 patients with mild, moderate, or severe COVID-19 revealed endothelial dysfunction indicative of a prothrombotic state. Angpt-2 concentrations rose with increasing disease severity and highest levels were associated with worse survival. These data highlight the disruption of Tie2-angiopoietin signaling and procoagulant changes in endothelial cells in severe COVID-19.Our findings provide rationale for current trials of Tie2-activating therapy with AKB-9778 in

show abstract

Section: Discussionmentioning

confidence: 99%

Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19

Schmaier¹,

Hurtado²,

Manickas-Hill³

et al. 2021

JCI Insight

View full text Add to dashboard Cite

show abstract

“…In addition to their proangiogenic potential, TEMs also possess distinct immunomodulatory characteristics; for instance, acute inflammation was shown to promote Tie2 expression in macrophages and upregulate the activity of TEMs. 35 TEMs were also shown to suppress T-cell activation and promote regulatory T-cell expansion in human cancer. 36 In a recent study, Ang2/Tie2+ circulating monocytic myeloid-derived suppressor cell axis was found to participate in tumor immune evasion.…”

Section: Discussionmentioning

confidence: 99%

Tie2‐expressing monocytes as a novel angiogenesis‐related cellular biomarker for non‐small cell lung cancer

Xue

Sheng

Duan

et al. 2020

Intl Journal of Cancer

View full text Add to dashboard Cite

To investigate the clinical value of Tie2‐expressing monocytes (TEMs) in the early diagnosis of lung cancer and assess its correlation with angiogenesis, a total of 184 patients with non‐small cell lung cancer (NSCLC), 101 patients with benign pulmonary disease (BPD), and 77 healthy controls were enrolled in our study. The distribution of TEMs in lung tissue was determined by immunofluorescence staining. Lung microvascular density was assessed by immunohistochemical staining. Receiver‐operating characteristic (ROC) curve analysis was performed to assess the diagnostic value of TEM frequency. Patients with NSCLC were followed up for 26 months. We found that the TEM frequency in peripheral blood monocytes of patients with NSCLC was significantly greater than that in patients with BPD and healthy controls. TEM frequency showed a correlation with NSCLC recurrence. The majority of TEMs in tumor tissues were localized around blood vessels; tumoral TEM frequency showed a positive correlation with microvascular density. High percentage of TEMs in the peripheral blood was associated with poor overall survival. ROC curve analysis revealed the potential diagnostic value of circulating TEM frequency in NSCLC. Thus, we believe that TEM frequency is related to angiogenesis in tumor tissues and may serve as a diagnostic marker for NSCLC.

show abstract

“…At present, it is still unclear whether the predominately M1 MF population we observed contributes to the killing of O. tsutsugamushi and the damage of vascular tissues, as seen for protective versus pathogenic roles in other lung infection models [60]. Since a significant Ang2 release and Tie2 decrease was detected at D6, followed by strong polarization to M1 MFs (Figs 2-4), it will be important to examine whether endothelial activation precedes the MF polarization and contributes to the strong M1 phenotype via the release of endothelial factors, such as Ang2, particularly on Tie2 expressing monocytes/ MFs [61]. Given the reports that anti-Ang2 antibody treatment during pulmonary bacterial infection can decrease MF recruitment and inflammation [29], and that signaling via Tie2 on monocytes/MFs can promote a proinflammatory profile [62], it will be interesting to determine how Ang2/Ang1 signaling on both endothelial cells and MFs promote cellular recruitment and activation during O. tsutsugamushi infection.…”

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

Polarized lung inflammation and Tie2/angiopoietin-mediated endothelial dysfunction during severe Orientia tsutsugamushi infection

et al. 2020

View full text Add to dashboard Cite

Orientia tsutsugamushi infection can cause acute lung injury and high mortality in humans; however, the underlying mechanisms are unclear. Here, we tested a hypothesis that dysregulated pulmonary inflammation and Tie2-mediated endothelial malfunction contribute to lung damage. Using a murine model of lethal O. tsutsugamushi infection, we demonstrated pathological characteristics of vascular activation and tissue damage: 1) a significant increase of ICAM-1 and angiopoietin-2 (Ang2) proteins in inflamed tissues and lung-derived endothelial cells (EC), 2) a progressive loss of endothelial quiescent and junction proteins (Ang1, VE-cadherin/CD144, occuludin), and 3) a profound impairment of Tie2 receptor at the transcriptional and functional levels. In vitro infection of primary human EC cultures and serum Ang2 proteins in scrub typhus patients support our animal studies, implying endothelial dysfunction in severe scrub typhus. Flow cytometric analyses of lung-recovered cells further revealed that pulmonary macrophages (MΦ) were polarized toward an M1-like phenotype (CD80 + CD64 + CD11b + Ly6G-) during the onset of disease and prior to host death, which correlated with the significant loss of CD31 + CD45-ECs and M2-like (CD206 + CD64 + CD11b + Ly6G-) cells. In vitro studies indicated extensive bacterial replication in M2-type, but not M1-type, MΦs, implying the protective and pathogenic roles of M1-skewed responses. This is the first detailed investigation of lung cellular PLOS NEGLECTED TROPICAL DISEASES

show abstract

Experimental murine acute lung injury induces increase of pulmonary TIE2-expressing macrophages

Cited by 6 publications

References 53 publications

Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19

Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19

Tie2‐expressing monocytes as a novel angiogenesis‐related cellular biomarker for non‐small cell lung cancer

Polarized lung inflammation and Tie2/angiopoietin-mediated endothelial dysfunction during severe Orientia tsutsugamushi infection

Contact Info

Product

Resources

About