Neuropilin-1 modulates interferon-γ-stimulated signaling in brain microvascular endothelial cells

Wang, Ying; Cao, Ying; Mangalam, Ashutosh K.; Guo, Yuxin; LaFrance‐Corey, Reghann G.; Gamez, Jeffrey D.; Atanga, Pascal Aliihnui; Clarkson, Benjamin D.; Zhang, Yuebo; Wang, Enfeng; Angom, Ramcharan Singh; Dutta, Kirthica; Ji, Baoan; Pirko, Istvan; Lucchinetti, Claudia F.; Howe, Charles L.; Mukhopadhyay, Debabrata

doi:10.1242/jcs.190702

Cited by 37 publications

(42 citation statements)

References 66 publications

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“…Meanwhile, IFN-γ could activate transcription factors STAT3, STAT5, and AP-1. The canonical and non-canonical signaling pathways form its complex signal network ( 106 – 128 ) (Figure 2 ).…”

Section: Ifn-γ In Osteoimmunologymentioning

confidence: 99%

Interferon-Gamma-Mediated Osteoimmunology

et al. 2018

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Osteoimmunology is the interdiscipline that focuses on the relationship between the skeletal and immune systems. They are interconnected by shared signal pathways and cytokines. Interferon-gamma (IFN-γ) plays important roles in immune responses and bone metabolism. IFN-γ enhances macrophage activation and antigen presentation. It regulates antiviral and antibacterial immunity as well as signal transduction. IFN-γ can promote osteoblast differentiation and inhibit bone marrow adipocyte formation. IFN-γ plays dual role in osteoclasts depending on its stage. Furthermore, IFN-γ is an important pathogenetic factor in some immune-mediated bone diseases including rheumatoid arthritis, postmenopausal osteoporosis, and acquired immunodeficiency syndrome. This review will discuss the contradictory findings of IFN-γ in osteoimmunology and its clinical application potential.

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Section: Ifn-γ In Osteoimmunologymentioning

confidence: 99%

Interferon-Gamma-Mediated Osteoimmunology

et al. 2018

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“…26 However, only 2 other reports studied the regulation of CXCL10 production by Rac1. On 1 hand, Wang et al 27 showed that knockdown of Neuropilin-1, a co-receptor of several structurally diverse ligands, suppressed CXCL10 expression in human brain microvascular endothelial cells in a Rac1-STAT1dependent manner. On the other hand, Pedersen et al 28 showed that loss of Rac1 in keratinocytes increased the expression of CXCL10.…”

Section: Discussionmentioning

confidence: 99%

Growth Hormone Aggregates Activation of Human Dendritic Cells Is Controlled by Rac1 and PI3 Kinase Signaling Pathways

Nabhan

Gallais

Pallardy

et al. 2020

Journal of Pharmaceutical Sciences

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The presence of protein aggregates in biological products is suggested to promote immunogenicity, leading to the production of anti-drug antibodies with neutralizing capacities. This suggests a CD4 þ T-cell dependent adaptive immune response, thus a pivotal role for antigen-presenting cells, such as dendritic cells (DCs). We previously showed that human growth hormone aggregates induced DC maturation, with notably an increase in CXCL10 production. DC phenotypic modifications were sufficient to promote allogeneic CD4 þ T-cell proliferation with Th1 polarization. In this work, we identified the main intracellular signaling pathways involved in DC activation by human growth hormone aggregates, showing that aggregates induced p38 mitogen-activated protein kinase, extracellular signaleregulated kinase, and c-Jun N-terminal kinase phosphorylation, as well as nuclear factor kB subunit p65 nuclear translocation. Next, investigating the implication of Rho GTPases and phosphoinositide 3-kinase (PI3K) in activated DC showed that Rac1 and Cdc42 regulated the phosphorylation of MAP kinases, whereas PI3K was only implicated in c-Jun N-terminal kinase phosphorylation. Furthermore, we showed that Rac1 and PI3K pathways, but not Cdc42, regulated the production of CXCL10 via the MAP kinases and nuclear factor kB. Taken together, our results bring new insight on how protein aggregates could induce DC activation, leading to a better understanding of aggregates role in therapeutic proteins immunogenicity.

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“…Tamoxifen-inducible endothelial-specific NRP1 knockout mice were generated and administered tamoxifen (MilliporeSigma, Burlington, MA, USA) as previously described (12). Animal care and experimental procedures were performed under protocols approved by the Institutional Animal Care and Use Committees of Mayo Clinic.…”

Section: Micementioning

confidence: 99%

Neuropilin‐1 maintains dimethylarginine dimethylaminohydrolase 1 expression in endothelial cells, and contributes to protection from angiotensin II–induced hypertension

Wang

Zhang

et al. 2018

The FASEB Journal

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Dimethylarginine dimethylaminohydrolases (DDAHs) are known to degrade asymmetric dimethylarginine, an endogenous inhibitor of NOS, and maintain vascular homeostasis; however, the regulatory pathways of DDAHs remain unclear. In this study, we aimed to define the role of transmembrane glycoprotein neuropilin-1 (NRP1) in the expression of DDAHs and investigate the potential roles of NRP1 in regulation of blood pressure. Short hairpin RNA-mediated knockdown of NRP1 reduced the level and mRNA stability of DDAH1 but not DDAH2 in HUVECs, whereas overexpression of NRP1 increased the mRNA stability of DDAH1. Meanwhile, mesenteric arteries and lung vascular endothelial cells of tamoxifen-inducible endothelial cell-specific NRP1 knockout mice exhibited decreased expression of DDAH1 and slightly increased expression of DDAH2. Mechanistically, the regulation of NRP1 on DDAH1 expression is mediated by a posttranscriptional mechanism involving miR-219-5p in HUVECs. Although the endothelial cell-specific NRP1 knockout mice did not exhibit any significant change in blood pressure at the basal level, they were more sensitive to low-dose angiotensin II infusion-induced increases in blood pressure. Our results show that NRP1 is required for full expression of DDAH1 in endothelial cells and that NRP1 contributes to protection from low-dose angiotensin II-induced increases in blood pressure.-Wang, Y., Wang, E., Zhang, Y., Madamsetty, V. S., Ji, B., Radisky, D. C., Grande, J. P., Misra, S., Mukhopadhyay, D. Neuropilin-1 maintains dimethylarginine dimethylaminohydrolase 1 expression in endothelial cells, and contributes to protection from angiotensin II-induced hypertension.

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Neuropilin-1 modulates interferon-γ-stimulated signaling in brain microvascular endothelial cells

Cited by 37 publications

References 66 publications

Interferon-Gamma-Mediated Osteoimmunology

Interferon-Gamma-Mediated Osteoimmunology

Growth Hormone Aggregates Activation of Human Dendritic Cells Is Controlled by Rac1 and PI3 Kinase Signaling Pathways

Neuropilin‐1 maintains dimethylarginine dimethylaminohydrolase 1 expression in endothelial cells, and contributes to protection from angiotensin II–induced hypertension

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