Interferon (IFN)-ß1a and IFN-ß1b Block IFN-?-Induced Disintegration of Endothelial Junction Integrity and Barrier

Minagar, Alireza; Long, A.; Ma, T.; Jackson, T. H.; Kelley, R. E.; Ostanin, D. V.; Sasaki, M.; Warren, A. C.; Jawahar, A.; Cappell, B.; Alexander, J. Steven

doi:10.1080/714007544

Cited by 34 publications

(18 citation statements)

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“…The Th1 cytokines TNF-α and IL-1β have previously been shown to disrupt barrier endothelium in vitro and in vivo , increasing permeability (30–32) and dysregulating junction complexes (1, 33, 34). During viral infections, TNF-α, in particular, has been linked to enhanced vascular permeability, poor tissue perfusion, and endothelial cell death (28, 35).…”

Section: Discussionmentioning

confidence: 99%

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Viral Pathogen-Associated Molecular Patterns Regulate Blood-Brain Barrier Integrity via Competing Innate Cytokine Signals

Daniels

Holman

Cruz-Orengo

et al. 2014

mBio

198

275

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Pattern recognition receptor (PRR) detection of pathogen-associated molecular patterns (PAMPs), such as viral RNA, drives innate immune responses against West Nile virus (WNV), an emerging neurotropic pathogen. Here we demonstrate that WNV PAMPs orchestrate endothelial responses to WNV via competing innate immune cytokine signals at the blood-brain barrier (BBB), a multicellular interface with highly specialized brain endothelial cells that normally prevents pathogen entry. While Th1 cytokines increase the permeability of endothelial barriers, type I interferon (IFN) promoted and stabilized BBB function. Induction of innate cytokines by pattern recognition pathways directly regulated BBB permeability and tight junction formation via balanced activation of the small GTPases Rac1 and RhoA, which in turn regulated the transendothelial trafficking of WNV. In vivo, mice with attenuated type I IFN signaling or IFN induction (Ifnar−/− Irf7−/−) exhibited enhanced BBB permeability and tight junction dysregulation after WNV infection. Together, these data provide new insight into host-pathogen interactions at the BBB during neurotropic viral infection.

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Section: Discussionmentioning

confidence: 99%

“…In contrast to Th1 cytokines, type I IFN treatment has been established to promote BBB function (34, 36). However, for the first time, we demonstrate that in vivo induction of type I IFN following WNV infection is a key regulator of BBB permeability and TJ integrity.…”

Section: Discussionmentioning

confidence: 99%

Viral Pathogen-Associated Molecular Patterns Regulate Blood-Brain Barrier Integrity via Competing Innate Cytokine Signals

Daniels

Holman

Cruz-Orengo

et al. 2014

mBio

198

275

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“…IECs that line the intestine play important roles in maintaining a barrier to the potentially pathogenic contents of the GI lumen and in regulating the immune response to microbes that have breached this barrier. Type I IFNs serve essential functions in GI immunity and homeostasis (30,31) and promote barrier integrity in endothelial cells (53,62) and following bacterial infection in the lung (54). Therefore, we investigated the regulation of IFN-␤ and its role in host defense from EPEC, an important human pathogen that disrupts barrier function as a key component of pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…The subsequent stimulation of IEC TLRs by PAMPs, demonstrated by both EPEC infection of human IECs and C. rodentium infection of mice, induces proinflammatory cytokines to maintain GI tract permeability and promote pathogenesis (17,18). Type I IFNs promote barrier integrity in endothelial cells (53,62) and following pneumococcal infection of lung epithelium (54) and may thus serve a protective role to maintain IEC barrier function in the host response to EPEC. Therefore, we investigated the functional consequences of T3SS-mediated inhibition of IFN-␤ induction for IEC barrier function.…”

Section: Ifn-␤ Protects From Epec-induced Barrier Disruption and Regumentioning

confidence: 99%

Enteropathogenic Escherichia coli Inhibits Type I Interferon- and RNase L-Mediated Host Defense To Disrupt Intestinal Epithelial Cell Barrier Function

et al. 2014

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EnteropathogenicEscherichia coli(EPEC) primarily infects children in developing countries and causes diarrhea that can be deadly. EPEC pathogenesis occurs through type III secretion system (T3SS)-mediated injection of effectors into intestinal epithelial cells (IECs); these effectors alter actin dynamics, modulate the immune response, and disrupt tight junction (TJ) integrity. The resulting compromised barrier function and increased gastrointestinal (GI) permeability may be responsible for the clinical symptoms of infection. Type I interferon (IFN) mediates anti-inflammatory activities and serves essential functions in intestinal immunity and homeostasis; however, its role in the immune response to enteric pathogens, such as EPEC, and its impact on IEC barrier function have not been examined. Here, we report that IFN-β is induced following EPEC infection and regulates IEC TJ proteins to maintain barrier function. The EPEC T3SS effector NleD counteracts this protective activity by inhibiting IFN-β induction and enhancing tumor necrosis factor alpha to promote barrier disruption. The endoribonuclease RNase L is a key mediator of IFN induction and action that promotes TJ protein expression and IEC barrier integrity. EPEC infection inhibits RNase L in a T3SS-dependent manner, providing a mechanism by which EPEC evades IFN-induced antibacterial activities. This work identifies novel roles for IFN-β and RNase L in IEC barrier functions that are targeted by EPEC effectors to escape host defense mechanisms and promote virulence. The IFN-RNase L axis thus represents a potential therapeutic target for enteric infections and GI diseases involving compromised barrier function.

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“…The fact that this mechanism is crucial to the pathogenesis of MS is demonstrated by the benefits observed with natalizumab, which blocks the entry of leukocytes into the CNS (del Pilar Martin et al, 2008). Proinflammatory cytokines such as TNF-alpha, IFN-gamma, and IL1-beta released by inflammatory cells mediate the breaching of the BBB by the upregulation of the expression of adhesion molecules (VCAM-1, E-selectin, and PECAM-1) (Dore-Duffy et al, 1995), the loss of junctional integrity (Minagar et al, 2003), and the release of endothelial-derived EVs (EEVs) (Minagar et al, 2001). EEVs from the endothelial cells of BBB and other EVs shed from surrounding cells [leukocytes (LEV), platelets (PEV), microglia (MEV), and astrocytes] are vectors of numerous agents carried inside these vesicles or bound to their plasma membrane.…”

Section: Immune Roles Of Evs In Msmentioning

confidence: 99%

Extracellular Vesicles in Multiple Sclerosis: What are They Telling Us?

Sáenz-Cuesta

Osorio-Querejeta

Otaegui

2014

Front. Cell. Neurosci.

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Extracellular vesicles (EVs) are membrane-bound particles secreted by almost all cell types. They are classified depending on their biogenesis and size into exosomes and microvesicles or according to their cell origin. EVs play a role in cell-to-cell communication, including contact-free cell synapsis, carrying active membrane proteins, lipids, and genetic material both inside the particle and on their surface. They have been related to several physiological and pathological conditions. In particular, increasing concentrations of EVs have been found in many autoimmune diseases including multiple sclerosis (MS). MS is a central nervous system (CNS) demyelinating disease characterized by relapsing of symptoms followed by periods of remission. Close interaction between endothelial cells, leukocytes, monocytes, and cells from CNS is crucial for the development of MS. This review summarizes the pathological role of EVs in MS and the relationship of EVs with clinical characteristics, therapy, and biomarkers of the disease.

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Interferon (IFN)-ß1a and IFN-ß1b Block IFN-?-Induced Disintegration of Endothelial Junction Integrity and Barrier

Cited by 34 publications

References 0 publications

Viral Pathogen-Associated Molecular Patterns Regulate Blood-Brain Barrier Integrity via Competing Innate Cytokine Signals

Viral Pathogen-Associated Molecular Patterns Regulate Blood-Brain Barrier Integrity via Competing Innate Cytokine Signals

Enteropathogenic Escherichia coli Inhibits Type I Interferon- and RNase L-Mediated Host Defense To Disrupt Intestinal Epithelial Cell Barrier Function

Extracellular Vesicles in Multiple Sclerosis: What are They Telling Us?

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