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

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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.

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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

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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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  1. David P. Q. Clark and Victoria M. Perreau have contributed equally to this manuscript.

Authors and Affiliations

  1. The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3051, Australia

    David P. Q. Clark, Victoria M. Perreau, Enie Lei, Shilpi Dixit, Philip M. Beart & Wah Chin Boon

  2. Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia

    Sandy R. Shultz & Rhys D. Brady

  3. Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3052, Australia

    Sandy R. Shultz & Rhys D. Brady

  4. Department of Pharmacology & Therapeutics, University of Melbourne, Parkville, VIC, 3010, Australia

    Juliet M. Taylor & Philip M. Beart

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Clark, D.P.Q., Perreau, V.M., Shultz, S.R. et al. Inflammation in Traumatic Brain Injury: Roles for Toxic A1 Astrocytes and Microglial–Astrocytic Crosstalk. Neurochem Res 44, 1410–1424 (2019). https://doi.org/10.1007/s11064-019-02721-8

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