Modeling leukocyte trafficking at the human blood-nerve barrier in vitro and in vivo geared towards targeted molecular therapies for peripheral neuroinflammation

Greathouse, Kelsey M.; Palladino, Steven P.; Dong, Chaoling; Helton, E. Scott; Ubogu, Eroboghene E.

doi:10.1186/s12974-015-0469-3

Cited by 18 publications

(15 citation statements)

References 87 publications

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“…This observation supports published observations that failed to demonstrate a reduction in BNB transendothelial resistance following treatment of confluent cultures with physiological cytokine concentrations for 24 hours in vitro [37]. AIDP leukocyte trafficking at the BNB is an active coordinated process, supported by published in vitro video microscopy under flow conditions [37,7,28] (also shown in this study), and the widely accepted multi-step paradigm [13,28,36,17,25]. …”

Section: Discussionsupporting

confidence: 87%

“…Despite known limitations of in vitro leukocyte trafficking assays and animal models of AIDP [7,34,37,14], we propose a crucial pathogenic role for CD11b in AIDP leukocyte BNB trafficking, recognizing that we had access to a limited number of patient nerve biopsies. CD11b antagonism is a plausible therapeutic approach worth considering for early stage clinical trials based on our proof-of-concept data.…”

Section: Discussionmentioning

confidence: 99%

“…Intravital microscopy is not currently possible in rodent peripheral nerves. A parallel plate flow chamber was attached to cytokine-treated confluent primary endoneurial endothelial cells cultured on rat-tail collagen-coated CellBIND ® petri dishes, coupled to time-lapse video microscopy as previously described [37,7,26]. Videos were cropped, magnified and analyzed to determine the route of leukocyte transmigration at the BNB using the NIS-Elements AR software program (Nikon).…”

Section: Methodsmentioning

confidence: 99%

“…The molecular determinants and signaling mechanisms of pathogenic leukocyte trafficking at the BNB, as well as BNB structural changes that occur during transmigration are incompletely elucidated. The recent isolation and characterization of human endoneurial endothelial cells and development of in vitro BNB models provides an avenue to study these mechanisms [38,27,26,1,9,7]. …”

Section: Introductionmentioning

confidence: 99%

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The pathogenic relevance of αM-integrin in Guillain–Barré syndrome

et al. 2016

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The molecular determinants and mechanisms involved in leukocyte trafficking across the blood-nerve barrier (BNB) in the Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP) variant of Guillain-Barré syndrome are incompletely understood. Prior work using a flow-dependent in vitro human BNB model demonstrated a crucial role for αM-integrin (CD11b)-intercellular adhesion molecule-1 interactions in AIDP patient leukocyte trafficking. The aim of this study is to directly investigate the biological relevance of CD11b in AIDP pathogenesis. Immunohistochemistry was performed on three AIDP patient sural nerve biopsies to evaluate endoneurial leukocyte CD11b expression. A severe murine experimental autoimmune neuritis (sm-EAN) model was utilized to determine the functional role of CD11b in leukocyte trafficking in vivo and determine its effect on neurobehavioral measures of disease severity, electrophysiological assessments of axonal integrity and myelination and histopathological measures of peripheral nerve inflammatory demyelination. Time-lapse video microscopy and electron microscopy were employed to observe structural alterations at the BNB during AIDP patient leukocyte trafficking in vitro and in situ respectively. Large clusters of endoneurial CD11b+ leukocytes associated with demyelinating axons were observed in AIDP patient sural nerves. Leukocyte CD11b expression was upregulated during sm-EAN. 5mg/kg of a function-neutralizing monoclonal rat-anti mouse CD11b antibody administered after sm-EAN disease onset significantly ameliorated disease severity, as well as electrophysiological and histopathological parameters of inflammatory demyelination compared to vehicle- and isotype antibody-treated mice. Consistent with in vitro observations of leukocyte trafficking at the BNB, electron micrographs of AIDP patient sural nerves demonstrated intact electron-dense endoneurial microvascular intercellular junctions during paracellular mononuclear leukocyte transmigration. Our data supports a crucial pathogenic role of CD11b in AIDP leukocyte trafficking, providing a potential therapeutic target for demyelinating variants of Guillain-Barré syndrome.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The pathogenic relevance of αM-integrin in Guillain–Barré syndrome

et al. 2016

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“…Tight regulation of ion, metabolite, protein, and water concentrations within peripheral nerves is critical to maintaining the internal microenvironment needed for axonal signal transmission (Greathouse et al, 2016; Mizisin and Weerasuriya, 2011; Olsson, 1990). The blood supply to human nerves is derived from extrinsic arteries that form the vasa nervosum.…”

Section: Introductionmentioning

confidence: 99%

A novel method for measuring hydraulic conductivity at the human blood-nerve barrier in vitro

Helton

Palladino

Ubogu

2017

Microvascular Research

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Microvascular barrier permeability to water is an essential biophysical property required for the homeostatic maintenance of unique tissue microenvironments. This is of particular importance in peripheral nerves where strict control of ionic concentrations is needed for axonal signal transduction. Previous studies have associated inflammation, trauma, toxin exposure and metabolic disease with increases in water influx and hydrostatic pressure in peripheral nerves with resultant endoneurial edema that may impair axonal function. The regulation of water permeability across endoneurial microvessels that form the blood-nerve barrier (BNB) is poorly understood. Variations exist in apparatus and methods used to measure hydraulic conductivity. The objective of the study was to develop a simplified hydraulic conductivity system using commercially available components to evaluate the BNB. We determined the mean hydraulic conductivity of cultured confluent primary and immortalized human endoneurial endothelial cell layers as 2.00 × 10−7 and 2.17 × 10−7 cm/s/cm H2O respectively, consistent with restrictive microvascular endothelial cells in vitro. We also determined the mean hydraulic conductivity of immortalized human brain microvascular endothelial cell layers, a commonly used blood-brain barrier (BBB) cell line, as 0.20 × 10−7 cm/s/cm H2O, implying a mean 10-fold higher resistance to transendothelial water flux in the brain compared to peripheral nerves. To our knowledge, this is the first reported measurement of human BNB and BBB hydraulic conductivities. This model represents an important tool to further characterize the human BNB and deduce the molecular determinants and signaling mechanisms responsible for BNB hydraulic conductivity in normal and disease states in vitro.

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COVID‐19 as a trigger of Guillain‐Barré syndrome: A review of the molecular mechanism

Malekpour

Khanmohammadi

Meybodi

et al. 2023

Immunity Inflam & Disease

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Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) caused a pandemic with serious complications. After coronavirus disease 2019 (COVID‐19), several post‐acute COVID‐19 syndromes (PACSs) and long‐COVID sequels were reported. PACSs involve many organs, including the nervous, gustatory, and immune systems. One of the PACSs after SARS‐CoV‐2 infection and vaccination is Guillain‐Barré syndrome (GBS). The incidence rate of GBS after SARS‐CoV‐2 infection or vaccination is low. However, the high prevalence of COVID‐19 and severe complications of GBS, for example, autonomic dysfunction and respiratory failure, highlight the importance of post‐COVID‐19 GBS. It is while patients with simultaneous COVID‐19 and GBS seem to have higher admission rates to the intensive care unit, and demyelination is more aggressive in post‐COVID‐19 GBS patients. SARS‐CoV‐2 can trigger GBS via several pathways like direct neurotropism and neurovirulence, microvascular dysfunction and oxidative stress, immune system disruption, molecular mimicry, and autoantibody production. Although there are few molecular studies on the molecular and cellular mechanisms of GBS occurrence after SARS‐CoV‐2 infection and vaccination, we aimed to discuss the possible pathomechanism of post‐COVID‐19 GBS by gathering the most recent molecular evidence.

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Modeling leukocyte trafficking at the human blood-nerve barrier in vitro and in vivo geared towards targeted molecular therapies for peripheral neuroinflammation

Cited by 18 publications

References 87 publications

The pathogenic relevance of αM-integrin in Guillain–Barré syndrome

The pathogenic relevance of αM-integrin in Guillain–Barré syndrome

A novel method for measuring hydraulic conductivity at the human blood-nerve barrier in vitro

COVID‐19 as a trigger of Guillain‐Barré syndrome: A review of the molecular mechanism

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