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Microglia Receptors in Animal Models of Traumatic Brain Injury

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Abstract

Microglia have been implicated as a key mediator of chronic inflammation following traumatic brain injury (TBI). The animal models of TBI vary significantly based on the type of brain injury (focal versus diffuse). This has made it extremely difficult to assess the role of microglia and the window of microglia activation. Hence, the focus of this review is to summarize the time course of microglia activation in various animal models of TBI. The review explores the repertoire of secondary injury mechanisms such as aberrant neurotransmitter release, oxidative stress, blood-brain barrier disruption, and production of pro-inflammatory cytokines that follow microglia activation. Since receptors act as sensors for activation, we highlight certain microglia receptors that have been implicated in TBI pathology, including fractalkine receptor (CX3CR1), purinergic receptor (P2Y12R), Toll-like receptor (TLR4), scavenger receptors, tumor necrosis factor receptor (TNF-1R), interleukin receptor (IL-1R), complement receptors, and peroxisome proliferator-activated receptor (PPAR). In addition to describing their downstream signaling pathways in TBI, we describe the functional consequences of their activation and the implication in behavioral outcomes. Taken together, this review will provide a holistic view of the role of microglia and its receptors in TBI based on animal studies.

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Abbreviations

Akt:

protein kinase B

AP-1:

activator protein-1

APP:

amyloid precursor protein

Arg-1:

arginase-1

ATP:

adenosine triphosphate

BBB:

blood-brain barrier

CCI:

controlled cortical impact/injury

cFPI:

central FPI

cIAP-1:

cellular inhibitor of apoptosis protein-1

CNS:

central nervous system

CR:

complement receptor

CX3CR1:

chemokine receptor 1

CXCL1:

fractalkine

DAMPS:

danger associated molecular patterns

EC:

endothelial cells

FPI:

fluid percussion injury

GOAD:

Gila open access database

HAPI:

highly aggressively proliferating immortalized

HMGB1:

high mobility group box protein 1

HSP:

heat shock protein

IL-1R1:

interleukin 1 receptor

IL-1β:

interleukin 1β

IRAK4:

IL-1R associated kinase 4

IRF-3:

interferon regulatory factor–3

KO:

knockout

LFPI:

lateral FPI

LPA:

lysophosphatidic acid

LPS:

lipopolysaccharide

MAPK:

mitogen-activated protein kinase

MIP-1α:

macrophage inflammatory protein-1α

mRNA:

messenger RNA

NADPH:

nicotinamide adenine dinucleotide phosphate

NFκB:

nuclear factor-kappa B

NOX:

NADPH oxidase

PACAP30:

adenylate cyclase-activating polypeptide

PAMPS:

pathogens associated molecular patterns

PCR:

polymerase chain reaction

PPAR:

peroxisome proliferator-activated receptors

RAGE:

receptor for advanced glycation end products

RIP:

receptor-interacting protein

RNA:

ribonucleic acid

RNA-seq:

RNA sequencing

RNS:

reactive nitrogen species

ROS:

reactive oxygen species

STAT:

signal transducer and activator of transcription

TBI:

traumatic brain injury

TLR4:

Toll-like receptor 4

TNF α:

tumor necrosis factor α

TNF-R1:

TNFα receptor 1

TRADD:

TNF receptor-associated death domain

TRAF-2:

TNF receptor-associated factor-2

TSPO:

translocator protein

WD:

weight drop

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Funding

This work was supported by funding from the US Army Medical Research and Material Command (W81XWH-15-1-0303), New Jersey Commission for Brain Injury Research (CBIR17PIL020), and Rutgers Brain Health Institute (BHI-RUN-NJIT-2016).

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  1. Daniel Younger and Madhuvika Murugan contributed equally to this work.

Authors and Affiliations

  1. Department of Bioengineering, New Jersey Institute of Technology, 111 Lock Street, Room105 CHEN bldg, Newark, NJ, 07102, USA

    Daniel Younger, Madhuvika Murugan, Kakulavarapu V. Rama Rao & Namas Chandra

  2. Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA

    Long-Jun Wu

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  1. Daniel Younger
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  2. Madhuvika Murugan
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  3. Kakulavarapu V. Rama Rao
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  5. Namas Chandra
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Correspondence to Namas Chandra.

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Supplementary Table 1

Microglial receptors and their functional relevance. (DOCX 106 kb)

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Younger, D., Murugan, M., Rama Rao, K.V. et al. Microglia Receptors in Animal Models of Traumatic Brain Injury. Mol Neurobiol 56, 5202–5228 (2019). https://doi.org/10.1007/s12035-018-1428-7

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