Angiopoietin-2 blockade ameliorates autoimmune neuroinflammation by inhibiting leukocyte recruitment into the CNS

Li, Zhilin; Korhonen, Emilia A.; Merlini, Arianna; Strauß, Johannes; Wihuri, Eleonoora; Nurmi, Harri; Antila, Salli; Paech, Jennifer; Deutsch, Urban; Engelhardt, Britta; Chintharlapalli, Sudhakar; Koh, Gou Young; Flügel, Alexander; Alitalo, Kari

doi:10.1172/jci130308

Cited by 35 publications

(21 citation statements)

References 67 publications

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“…Endothelial cells up-regulate Angiopoietin 2 ( Angpt2 ) in the absence of pericytes ( 1 , 2 ), and neutralizing antibodies to Angpt2 reduce vascular leakage and microaneurysm formation in the retina caused by pericyte deficiency ( 26 ). Blocking of Angpt2 also ameliorates EAE by suppressing vascular inflammation and leakage of plasma proteins ( 27 ). Thus, it is plausible that a deregulated Ang2–Tie2 signaling axis in endothelial cells in the absence of pericytes contributes to the aggravated neuroinflammation in Pdgfb ret/ret mice.…”

Section: Discussionmentioning

confidence: 99%

Pericytes regulate vascular immune homeostasis in the CNS

Torok

Schreiner

Schaffenrath

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

105

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Pericytes regulate the development of organ-specific characteristics of the brain vasculature such as the blood–brain barrier (BBB) and astrocytic end-feet. Whether pericytes are involved in the control of leukocyte trafficking in the adult central nervous system (CNS), a process tightly regulated by CNS vasculature, remains elusive. Using adult pericyte-deficient mice (Pdgfbret/ret), we show that pericytes limit leukocyte infiltration into the CNS during homeostasis and autoimmune neuroinflammation. The permissiveness of the vasculature toward leukocyte trafficking in Pdgfbret/ret mice inversely correlates with vessel pericyte coverage. Upon induction of experimental autoimmune encephalomyelitis (EAE), pericyte-deficient mice die of severe atypical EAE, which can be reversed with fingolimod, indicating that the mortality is due to the massive influx of immune cells into the brain. Additionally, administration of anti-VCAM-1 and anti–ICAM-1 antibodies reduces leukocyte infiltration and diminishes the severity of atypical EAE symptoms of Pdgfbret/ret mice, indicating that the proinflammatory endothelium due to absence of pericytes facilitates exaggerated neuroinflammation. Furthermore, we show that the presence of myelin peptide-specific peripheral T cells in Pdgfbret/ret;2D2tg mice leads to the development of spontaneous neurological symptoms paralleled by the massive influx of leukocytes into the brain. These findings indicate that intrinsic changes within brain vasculature can promote the development of a neuroinflammatory disorder.

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Section: Discussionmentioning

confidence: 99%

Pericytes regulate vascular immune homeostasis in the CNS

Torok

Schreiner

Schaffenrath

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

105

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“…Several immune cells produce sPLA 2 [86][87][88], ANGPTs [15,17,18,24,70,89], VEGF-A [43,52,74,90], and VEGF-C/VEGF-D [52,74,91]. In this study, we did not address the issue of the contribution of different cells to the increased plasma levels of these powerful inflammatory mediators observed in patients with IHF or NIHF.…”

Section: Discussionmentioning

confidence: 91%

“…ANGPT2 also binds to Tie2 [27] and antagonizes ANGPT1-mediated Tie2 phosphorylation, thereby inducing vascular instability and leakage [25,26,69]. In addition, ANGPT2 is an important permeability [63,70] and proinflammatory mediator [16].…”

Section: Discussionmentioning

confidence: 99%

“…Second, the unique role of the ANGPTs/Tie2 signaling pathway in vascular stability suggests that it could serve as a target for therapeutic intervention in diseases whose pathophysiology comprises the alteration of vascular integrity [27], such as HF. Recently, it has been demonstrated that ANGPT2 inhibition, through an anti-ANGPT2 blocking antibody, substantially alleviated autoimmune inflammation [70]. Importantly, specific ANGPT2 deletion or the use of an anti-ANGPT2 antibody markedly reduced cardiac hypoxia, proinflammatory macrophage polarization, adverse vascular remodeling, and the consequent progression of HF after myocardial infarction in mice [15].…”

Section: Discussionmentioning

confidence: 99%

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Angiopoietins, Vascular Endothelial Growth Factors and Secretory Phospholipase A2 in Ischemic and Non-Ischemic Heart Failure

Varricchi

Loffredo

Bencivenga

et al. 2020

JCM

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Heart failure (HF) is a growing public health burden, with high prevalence and mortality rates. In contrast to ischemic heart failure (IHF), the diagnosis of non-ischemic heart failure (NIHF) is established in the absence of coronary artery disease. Angiopoietins (ANGPTs), vascular endothelial growth factors (VEGFs) and secretory phospholipases A2 (sPLA2s) are proinflammatory mediators and key regulators of endothelial cells. In the present manuscript, we analyze the plasma concentrations of angiogenic (ANGPT1, ANGPT2, VEGF-A) and lymphangiogenic (VEGF-C, VEGF-D) factors and the plasma activity of sPLA2 in patients with IHF and NIHF compared to healthy controls. The concentrations of ANGPT1, ANGPT2 and their ratio significantly differed between HF patients and healthy controls. Similarly, plasma levels of VEGF-D and sPLA2 activity were higher in HF as compared to controls. Concentrations of ANGPT2 and the ANGPT2/ANGPT1 ratio (an index of vascular permeability) were increased in NIHF patients. VEGF-A and VEGF-C concentrations did not differ among the three examined groups. Interestingly, VEGF-D was selectively increased in IFH patients compared to controls. Plasma activity of sPLA2 was increased in IHF and NIHF patients compared to controls. Our results indicate that several regulators of vascular permeability and smoldering inflammation are specifically altered in IHF and NIHF patients. Studies involving larger cohorts of these patients will be necessary to demonstrate the clinical implications of our findings.

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“…The stained cells were then washed, centrifuged, and resuspended into 1 mL of FACS buffer, and acquired on a two-laser, six-color Gallios cytometer (Beckman Coulter, Pasadena, CA). The threshold for FACS analysis was set based on the surface expression of each individual marker in the samples as compared to isotype control using IgG-stained cells in the same channel, and Flow cytometric data were analyzed with the Kaluza 1.3 software (Beckman Coulter, Brea, CA), as reported [35,36]. Cell populations were calculated as the percentages among the total cells.…”

Section: Fluorescence-activated Cell Sorting (Facs)mentioning

confidence: 99%

Regulation of Neurogenesis in Mouse Brain by HMGB1

Zhao

Rouhiainen

et al. 2020

Cells

Self Cite

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The High Mobility Group Box 1 (HMGB1) is the most abundant nuclear nonhistone protein that is involved in transcription regulation. In addition, HMGB1 has previously been found as an extracellularly acting protein enhancing neurite outgrowth in cultured neurons. Although HMGB1 is widely expressed in the developing central nervous system of vertebrates and invertebrates, its function in the developing mouse brain is poorly understood. Here, we have analyzed developmental defects of the HMGB1 null mouse forebrain, and further examined our findings in ex vivo brain cell cultures. We find that HMGB1 is required for the proliferation and differentiation of neuronal stem cells/progenitor cells. Enhanced apoptosis is also found in the neuronal cells lacking HMGB1. Moreover, HMGB1 depletion disrupts Wnt/β-catenin signaling and the expression of transcription factors in the developing cortex, including Foxg1, Tbr2, Emx2, and Lhx6. Finally, HMGB1 null mice display aberrant expression of CXCL12/CXCR4 and reduced RAGE signaling. In conclusion, HMGB1 plays a critical role in mammalian neurogenesis and brain development.

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Angiopoietin-2 blockade ameliorates autoimmune neuroinflammation by inhibiting leukocyte recruitment into the CNS

Cited by 35 publications

References 67 publications

Pericytes regulate vascular immune homeostasis in the CNS

Pericytes regulate vascular immune homeostasis in the CNS

Angiopoietins, Vascular Endothelial Growth Factors and Secretory Phospholipase A2 in Ischemic and Non-Ischemic Heart Failure

Regulation of Neurogenesis in Mouse Brain by HMGB1

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