Table 1.

Rodent models used to characterize the role of signaling pathways and immune cell types in TBI. Table 1A describes molecular signaling pathways and Table 1B describes the cellular components of the immune system in TBI, illustrating approaches based on antibody targeting, as well as genetically modified mice (Reproduced from McKee CA, Lukens JR (2016) Emerging roles for the immune system in traumatic brain injury. Front Immunol 7, 556)

Table 1A. Molecular signaling pathways
Inflammatory mediator	Animal line/model	Purpose	Major findings in animals exposed to TBI	Reference
IL-1	Anti-IL-1β antibody	Blockade of IL-1β signaling	Reductions in macrophages/microglia, neutrophils, and T cell numbers in the brain, improvement in learning tasks, and decreased tissue loss	[289, 290]
	IL-1 R antagonist	Neutralize IL-1	Higher expression of proinflammatory cytokines in macrophages	[291]
ASC	Anti-ASC	Limit inflammasome assembly	Reduced caspase-1 activation and IL-1β production, decreased lesion volume	[292]
	ASC knockout	Abrogate inflammasome assembly	No improvements in lesion volume, histopathology, cell death, or motor function	[293]
NLRP1	NLRP1 knockout	Prevent NLRP1 inflammasome assembly	No improvements in lesion volume, histopathology, cell death, or motor function	[293]
IL-6	IL-6 knockout	Ablation of IL-6 signaling	Fewer reactive astrocytes and macrophages, increased neuronal death	[294]
	IL-6 knockout	Ablation of IL-6 signaling	Poor behavioral performance, higher IL-1β levels in the cortex	[295]
	GFAP-IL-6 overexpression	Increase IL-6 expression in astrocytes	Greater recruitment of glia and immune cells to the lesion, decreased oxidative stress and neuronal death	[296]
	Anti-IL-6 antibody	Neutralize IL-6	Reduced some inflammatory and behavioral effects of post-injury hypoxia	[297]
TNF-α	TNF-α inhibitor post-TBI	Inhibit TNF-α signaling	Early administration improved cognitive performance, and decreased neuronal apoptosis and astrogliosis	[298]
	TNFR1 knockout	Disrupt TNF-α signaling through TNFR1	Improved neurological function and neuronal survival/lesion volume, decreased numbers of CD11b+cells in the brain	[299]
	TNFR2 knockout	Reduce TNFR2 signaling	Worsened neurological function and no protection from tissue loss	[299]
	TNFR2/Fas knockout	Abrogate TNF-α signaling through TNFR2	Impaired motor and cognitive performance	[142]
G-CSF	G-CSF injection post-TBI	Enhance G-CSF signalling	Improved cognitive performance and increased hippocampal neurogenesis, higher glial activation and production of BDNF and GDNF	[300]
GM-CSF	GM-CSF knockout	Disrupt GM-CSF signalling	Worsened cognitive deficits as well as cell and tissue loss, reduced astrogliosis	[301]
Type 1 IFN	IFNAR knockout or IFNAR blocking antibody	Block type 1 IFN signalling	Reduced lesion volume, more anti-inflammatory cytokine signaling, increased glial activation, these effects were hematopoietic cell-dependent	[302]
IL-10	IL-10 knockout, IL-10 injection	Modulate IL-10 signaling	Diminished protective effects of hyperbaric oxygen treatment, including lesion volume, edema, cognitive improvement, and decreased cytokine production in IL-10 knockout mice, while IL-10 injection improved these outcomes	[303]
TGF-β	TAK1 inhibition	Disrupt signaling downstream of TGF-β	Improved neuronal survival and motor function, decreased NF-κB signaling and inflammatory cytokine production	[304]
	TGIF shRNAv knockdown	Ablation of downstream TGF-β signalling	Decreased infarct volume and microglia numbers, improved motor function	[305]
APOE	APOEϵ4 overexpression	APOEϵ4 overexpression	Worsened brain pathology, BBB breakdown, and neurological impairments	[306, 307]
TREM2	TREM2 knockout	Abrogate TREM2 signaling	Altered macrophage distribution, hippocampal neuroprotection, and fewer cognitive deficits	[308]
Table 1B. Cellular mediators
Cell type	Animal line/model	Purpose	Major findings in animals exposed to TBI	Reference
Neutrophils	IgM RP-3	Neutrophil depletion	No significant decrease in BBB permeability	[151]
	Anti-Gr1 antibody	Neutrophil depletion	Decreased edema, apoptosis, and microglia/macrophage activation, no significant changes in BBB integrity	[153]
	CXCR2 knockout	Reduce neutrophil infiltration	Decreased cell death, no significant changes in BBB permeability or behavior	[148]
	Neutrophil elastase knockout	Reduce neutrophil effector functions	Decreased edema and apoptotic neurons, but no decrease in tissue volume loss or behavioral improvement	[154]
Macrophages and microglia	CD11b-TK	Deplete CD11b-expressing cells	Reductions in microglia numbers in the brain, no improvement in axonal injury, treatment toxic at high dosage	[309]
	CD11b-DTR	Deplete CD11b-expressing cells	No change in lesion size, treatment caused inflammatory response without injury	[310]
	CCX872 (CCR2 antagonist)	Reduce CCR2 signaling functions	Reduced macrophages in the brain, altered pro- and anti-inflammatory cytokine expression, less cognitive dysfunction	[162]
	CCR2 knockout	Limit CCR2-mediated recruitment of monocytes	Reduced numbers of infiltrating monocytes, improved learning and memory	[161]
	CCR2RFP/RFP	Disrupt recruitment of monocytes	Reduced monocyte recruitment, cavity volume, and axonal pathology	[160]
	CX3CR1 knockout	Abrogate CX3CR1 signaling functions in macrophages and microglia	Short-term neuroprotection and lower inflammatory response, long-term functional impairments and elevated myeloid cell activation	[311]
T cells	Rag1 knockout	Genetic ablation of B and T cells	No changes in neurological outcome, BBB integrity, pro- or anti-apoptotic mediators, hippocampal architecture, or astroglial activation	[312]
	FTY720	Sequester lymphocytes and reduce their migration to the brain	Decreased circulating lymphocytes, decreased neutrophils and macrophages/microglia in ipsilateral hemisphere	[313]