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Inflammation in Traumatic Brain Injury: Roles for Toxic A1 Astrocytes and Microglial–Astrocytic Crosstalk

  • David P. Q. Clark
  • Victoria M. Perreau
  • Sandy R. Shultz
  • Rhys D. Brady
  • Enie Lei
  • Shilpi Dixit
  • Juliet M. Taylor
  • Philip M. BeartEmail author
  • Wah Chin Boon
Original Paper
  • 182 Downloads

Abstract

Traumatic brain injury triggers neuroinflammation that may contribute to progressive neurodegeneration. We investigated patterns of recruitment of astrocytes and microglia to inflammation after brain trauma by firstly characterising expression profiles over time of marker genes following TBI, and secondly by monitoring glial morphologies reflecting inflammatory responses in a rat model of traumatic brain injury (i.e. the lateral fluid percussion injury). Gene expression profiles revealed early elevation of expression of astrocytic marker glial fibrillary acidic protein relative to microglial marker allograft inflammatory factor 1 (also known as ionized calcium-binding adapter molecule 1). Adult rat brains collected at day 7 after injury were processed for immunohistochemistry with allograft inflammatory factor 1, glial fibrillary acidic protein and complement C3 (marker of bad/disruptive astrocytic A1 phenotype). Astrocytes positive for glial fibrillary acidic protein and complement C3 were significant increased in the injured cortex and displayed more complex patterns of arbourisation with significantly increased bifurcations. Our observations suggested that traumatic brain injury changed the phenotype of microglia from a ramified appearance with long, thin, highly branched processes to a swollen amoeboid shape in the injured cortex. These findings suggest differential glial activation with astrocytes likely undergoing strategic changes in morphology and function. Whilst a detailed analysis is needed of temporal patterns of glial activation, ours is the first evidence of a role for the bad/disruptive astrocytic A1 phenotype in an open head model of traumatic brain injury.

Keywords

Traumatic brain injury Inflammation Astrocyte Toxic phenotype Glial crosstalk 

Abbreviations

A1

Neurotoxic phenotype of reactive astrocytes

A2

Neuroprotective phenotype of reactive astrocytes

Aif1

Allograft inflammatory factor 1

AuD

Auditory cortex

BBB

Blood–brain barrier

BDNF

Brain-derived neurotrophic factor

C3

Complement component 3

C3+

Complement component 3 immunoreactive positive

CCI

Controlled cortical impact injury

CNS

Central nervous system

CSPG

Chondroitin sulphate proteoglycan

C1q

Complement component 1q

CD68

Cluster of differentiation 68

CSF-1

Colony stimulating factor 1

DAMPs

Damage-associated molecular patterns

DAM

Disease-associated microglia

DAPI

4′-6-diamidino-2-phenylindole

FPI

Lateral fluid percussion injury

GFAP

Glial fibrillary acidic protein

GFAP+

Glial fibrillary acidic protein immunoreactive positive

HCl

Hydrochloric acid

Iba1

Ionized calcium-binding adapter molecule 1

IL

Interleukin

M1

Neurotoxic phenotype of reactive microglia

M2

Neuroprotective phenotype of reactive microglia

NDS

Normal donkey serum

PBS

Phosphate buffered saline

S2

Region somatosensory cortex

Sham

Sham-injury

TBI

Traumatic brain injury

TGF-β

Transforming growth factor beta 1

TNF

Tumor necrosis factor

Notes

Acknowledgements

PMB is pleased to contribute a paper to this Special Issue honouring Tony Turner who has been a colleague furthering the neurochemical cause via the Journal of Neurochemistry and internationally (ISN) and in Europe (ESN) for some 20 years. This work is partly funded by the J and M Nolan Family Trust. This work was supported by the Victorian Government through the Operational Infrastructure Scheme.

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • David P. Q. Clark
    • 1
  • Victoria M. Perreau
    • 1
  • Sandy R. Shultz
    • 2
    • 3
  • Rhys D. Brady
    • 2
    • 3
  • Enie Lei
    • 1
  • Shilpi Dixit
    • 1
  • Juliet M. Taylor
    • 4
  • Philip M. Beart
    • 1
    • 4
    Email author
  • Wah Chin Boon
    • 1
  1. 1.The Florey Institute of Neuroscience and Mental HealthParkvilleAustralia
  2. 2.Department of Neuroscience, Central Clinical SchoolMonash UniversityMelbourneAustralia
  3. 3.Department of Medicine, The Royal Melbourne HospitalThe University of MelbourneParkvilleAustralia
  4. 4.Department of Pharmacology & TherapeuticsUniversity of MelbourneParkvilleAustralia

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