Interplay between blood-brain barrier disruption and neuroinflammation following severe traumatic brain injury
Author: Lindblad, Caroline
Date: 2022-02-04
Location: Rolf Luft Centrum, L1:00, Karolinska University Hospital, Solna
Time: 09.00
Department: Inst för klinisk neurovetenskap / Dept of Clinical Neuroscience
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Thesis (17.90Mb)
Abstract
A severe traumatic brain injury (TBI) holds deleterious consequences for the afflicted, its next-of-kin and society. Still today, prognosis is semi-desolate. One explanation for this might be pathophysiological processes ensuing the primary trauma that are but indirectly targeted for treatment. Among such processes, blood-brain barrier (BBB) disruption and neuroinflammation constitute two astrocyte-dependent mechanisms that interplay in the aftermath of a severe TBI. The overall aim of this thesis was to characterize both BBB disruption and neuroinflammation translationally.
In paper I, n = 17 patients with severe TBI were included in a prospective observational longitudinal study. Here, the protein biomarkers S100B and neuron-specific enolase (NSE) were sampled with high temporal resolution from both cerebrospinal fluid (CSF) and blood. We found that BBB disruption occurred among numerous patients and remained throughout the first week following injury. Interestingly, BBB disruption also affected clearance from brain to blood of S100B, but not NSE. This indicates that biomarkers are cleared differently from the injured CNS. We elaborated on this by utilizing a larger cohort size (n = 190 patients), which enabled outcome prediction modelling, in paper II. In this prospective, observational, cross-sectional study, we found that BBB disruption comprised a novel, independent outcome predictor that strongly related to levels of neuroinflammatory proteins in CSF and inflammatory processes within the injured brain. Among pathways assessed, particularly the complement system entailed proteins of future interest. We next assessed the relationship between in situ neuroinflammatory protein expression, BBB disruption, and brain edema in paper III. By utilizing a rodent model of severe TBI, we found that the cytotoxic edema region was associated with an innate neuroinflammatory response, and astrocytic aquaporin-4 retraction from the BBB interface. In fact, the astrocyte itself is an important neuroinflammatory cell, which we showed in paper IV, where we constructed a disease-modelling system of stem cell-derived astrocytes that we exposed to neuroinflammatory substances. Following neuroinflammatory stimulus, astrocytes exhibited an important increase in canonical stress-response pathways. Importantly, following stimulation with clinically relevant neuroinflammatory substances seen in human TBI from paper II, they also acquired a neurotoxic potential, of plausible importance for local cell survival following a severe TBI.
Taken together, BBB disruption and neuroinflammation ensue a severe TBI. Neuroinflammation, particularly mediated by the complement system, stands out as a future therapeutic target in order to mitigate exacerbated BBB disruption. Locally in the lesion vicinity, additional neuroinflammatory mechanisms are in part mediated by astrocytes, where these cells seem to have an important role in local cell survival. Onwards, our findings suggest that future efforts should be directed at evaluating if neuroinflammatory modulation of complement inhibition yields improved outcome, while elaborating on the promising experimental data of astrocyte-mediated effects in the lesion vicinity.
In paper I, n = 17 patients with severe TBI were included in a prospective observational longitudinal study. Here, the protein biomarkers S100B and neuron-specific enolase (NSE) were sampled with high temporal resolution from both cerebrospinal fluid (CSF) and blood. We found that BBB disruption occurred among numerous patients and remained throughout the first week following injury. Interestingly, BBB disruption also affected clearance from brain to blood of S100B, but not NSE. This indicates that biomarkers are cleared differently from the injured CNS. We elaborated on this by utilizing a larger cohort size (n = 190 patients), which enabled outcome prediction modelling, in paper II. In this prospective, observational, cross-sectional study, we found that BBB disruption comprised a novel, independent outcome predictor that strongly related to levels of neuroinflammatory proteins in CSF and inflammatory processes within the injured brain. Among pathways assessed, particularly the complement system entailed proteins of future interest. We next assessed the relationship between in situ neuroinflammatory protein expression, BBB disruption, and brain edema in paper III. By utilizing a rodent model of severe TBI, we found that the cytotoxic edema region was associated with an innate neuroinflammatory response, and astrocytic aquaporin-4 retraction from the BBB interface. In fact, the astrocyte itself is an important neuroinflammatory cell, which we showed in paper IV, where we constructed a disease-modelling system of stem cell-derived astrocytes that we exposed to neuroinflammatory substances. Following neuroinflammatory stimulus, astrocytes exhibited an important increase in canonical stress-response pathways. Importantly, following stimulation with clinically relevant neuroinflammatory substances seen in human TBI from paper II, they also acquired a neurotoxic potential, of plausible importance for local cell survival following a severe TBI.
Taken together, BBB disruption and neuroinflammation ensue a severe TBI. Neuroinflammation, particularly mediated by the complement system, stands out as a future therapeutic target in order to mitigate exacerbated BBB disruption. Locally in the lesion vicinity, additional neuroinflammatory mechanisms are in part mediated by astrocytes, where these cells seem to have an important role in local cell survival. Onwards, our findings suggest that future efforts should be directed at evaluating if neuroinflammatory modulation of complement inhibition yields improved outcome, while elaborating on the promising experimental data of astrocyte-mediated effects in the lesion vicinity.
List of papers:
I. Lindblad C, Nelson DW, Zeiler FA, Ercole A, Ghatan PH, von Horn H, Risling M, Svensson M, Agoston DV, Bellander B-M, Thelin EP. Influence of Blood–Brain Barrier Integrity on Brain Protein Biomarker Clearance in Severe Traumatic Brain Injury: A Longitudinal Prospective Study. J Neurotrauma. 2020;11:1–11.
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II. Lindblad C, Pin E, Just D, Al Nimer F, Nilsson P, Bellander B-M, Svensson M, Piehl F, Thelin EP. Fluid Proteomics of CSF and Serum Reveal Important Neuroinflammatory Proteins in Blood-Brain Barrier Disruption and Outcome Prediction Following Severe Traumatic Brain Injury: A Prospective, Observational Study. Crit Care. 2021;1–28.
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III. Lindblad C, Mitsios N, Falk-Delgado A, Mattsson P, Morganti-Kossmann MC, Frostell A, Mulder J, Risling M, Damberg P, Bellander BM, Thelin EP, Svensson M. Cytotoxic Brain Edema is Associated with Neuroinflammation and Retraction of Perivascular Aquaporin-4 following Experimental Severe Traumatic Brain Injury – a Multi-Modal Imaging Study. [Manuscript]
IV. Lindblad C, Neumann S, Kolbeinsdóttir S, Zachariadis V, Thelin EP, Enge M, Thams S, Brundin L, Svensson M. Embryonic stem cell-derived brainstem and spinal astrocyte-like cells develop a neurotoxic phenotype in vitro following clinically relevant pro-inflammatory stimulation. [Manuscript]
I. Lindblad C, Nelson DW, Zeiler FA, Ercole A, Ghatan PH, von Horn H, Risling M, Svensson M, Agoston DV, Bellander B-M, Thelin EP. Influence of Blood–Brain Barrier Integrity on Brain Protein Biomarker Clearance in Severe Traumatic Brain Injury: A Longitudinal Prospective Study. J Neurotrauma. 2020;11:1–11.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Lindblad C, Pin E, Just D, Al Nimer F, Nilsson P, Bellander B-M, Svensson M, Piehl F, Thelin EP. Fluid Proteomics of CSF and Serum Reveal Important Neuroinflammatory Proteins in Blood-Brain Barrier Disruption and Outcome Prediction Following Severe Traumatic Brain Injury: A Prospective, Observational Study. Crit Care. 2021;1–28.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Lindblad C, Mitsios N, Falk-Delgado A, Mattsson P, Morganti-Kossmann MC, Frostell A, Mulder J, Risling M, Damberg P, Bellander BM, Thelin EP, Svensson M. Cytotoxic Brain Edema is Associated with Neuroinflammation and Retraction of Perivascular Aquaporin-4 following Experimental Severe Traumatic Brain Injury – a Multi-Modal Imaging Study. [Manuscript]
IV. Lindblad C, Neumann S, Kolbeinsdóttir S, Zachariadis V, Thelin EP, Enge M, Thams S, Brundin L, Svensson M. Embryonic stem cell-derived brainstem and spinal astrocyte-like cells develop a neurotoxic phenotype in vitro following clinically relevant pro-inflammatory stimulation. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Svensson, Mikael
Co-supervisor: Thelin, Eric; Thams, Sebastian; Mattsson, Per
Issue date: 2022-01-13
Rights:
Publication year: 2022
ISBN: 978-91-8016-434-4
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