Table 1.

Astrocytic signaling in neuroinflammation: the physical barrier

Signaling pathway	Injury	Physical barrier components	Changes in the immune response	Changes in outcomes	Reference(s)
CD36 signaling	Ischemia	Increases GFAP expression		Reduces cell death, reduces infarct size	[22]
Notch signaling	Ischemia	Increases GFAP expression and induces astrocyte proliferation	Inhibits CD45+ cell infiltration		[29]
GFAP and vimentin expression	Ischemia			Stimulate the formation of gap junctions, glutamate transport, PAI-1 expression	[30]
NF-kB signaling	Ischemia	Reduces leukocyte adhesion molecules, reduces GFAP expression	Increases CD11b + leukocyte infiltration, increases iNOS expression	Increases neuronal damage	[31]
	SCI	Reduces GFAP expression and astrocyte morphological changes, reduces the expression of the ECM components neurocan and phosphacan		Increases neuronal damage	[32]
	EAE	Increases leukocyte adhesion molecules	Inhibits CD45+ leukocyte, CD3+ T lymphocyte and B220+ B lymphocyte infiltration	Increases demyelination and axonal pathology, worsens outcomes	[33]
STAT3 signaling	SCI	Induces astrocyte polarization and morphological changes	Inhibits CD45+ leukocyte infiltration	Reduces cell death	[34]
	SCI	Inhibits GFAP expression	Inhibits CD11b + leukocyte infiltration	Improves motor outcomes	[35]
	SCI	Increases GFAP and vimentin expression, induces astrocyte morphological changes	Inhibits CD45+ leukocyte infiltration	Improves motor outcomes	[36]
	SCI	Increases GFAP and vimentin expression, induces astrocyte morphological changes		Promotes regeneration of axons when exogenous growth factors are added	[36, 37]
Socs3 signaling	SCI	Increases GFAP expression	Increases CD11b + leukocyte infiltration	Worsens motor outcomes	[35]
SOX9 signaling	SCI	Increases GFAP expression, increases the expression of ECM components neurocan, brevican, and aggrecan		Prevents axonal outgrowth, worsens motor outcomes	[38]
MMP2 production	SCI	Increases GFAP and CSPG expression		Increases axonal outgrowth, improves motor outcomes	[39]
GFAP+ cell proliferation	SCI		Inhibits CD45+ cell infiltration	Reduces cell death, closes BBB, improves motor outcomes	[40]
TGF-β signaling	TBI	Increases GFAP expression, increases the expression of ECM component neurocan		Prevents axonal outgrowth	[41]
	TBI	Increases the expression of ECM component tenascin C			[42]
	TBI	Increases GFAP expression and astrocyte proliferation, increases the expression of ECM components fibronectin and laminin	Increases neutrophil and macrophage infiltration		[43]
GFAP+ cell proliferation	TBI		Inhibits CD45+ monocyte, macrophage, neutrophil, and lymphocyte infiltration	Reduces cell death, prevents axonal outgrowth, closes BBB	[44, 45]
IL-1β signaling	TBI	Increases GFAP expression		Closes BBB	[46]
CDC42 signaling	TBI	Induces astrocyte proliferation, polarization, and morphological changes			[47]
IFN-γ signaling	TBI	Increases GFAP expression			[48]
JNK/c-jun signaling	EAE	Increases GFAP expression and astrocyte proliferation			[49]
GFAP+ cell proliferation	EAE		Inhibits Iba1+ microglia and macrophage, Ag4/7+ neutrophil, and CD3+ T lymphocyte infiltration	Increases demyelination and axonal pathology, worsens outcomes	[50]
TNFR1 signaling	EAE	Increases leukocyte adhesion molecules	Increases CD4+ T lymphocyte infiltration	Increases demyelination, worsens outcomes	[51]
Gp130/IL-6 signaling	EAE	Inhibits astrocyte apoptosis	Inhibits CD4+ and CD8+ T lymphocytes, increases FoxP3+ regulatory T lymphocyte (Treg) differentiation	Reduces demyelination, improves outcomes	[52]
	Parasitic infection	Increases GFAP+ astrocyte numbers, inhibits astrocyte apoptosis		Reduces pathogen burden, improves recovery	[53]
GFAP expression	Parasitic infection			Reduces pathogen burden	[54]
	Bacterial infection		Inhibits MHC II+ myeloid cell infiltration	Reduces pathogen burden, improves recovery	[54]

For each signaling pathway, the normal pathophysiological role of the pathway is stated. GFAP = glial fibrillary acidic protein; PAI-1 = plasminogen activator inhibitor-1; NF-kB = nuclear factor kappa B; iNOS = inducible nitric oxide synthase; SCI = spinal cord injury; ECM = extracellular matrix; EAE = experimental autoimmune encephalomyelitis; Socs3 = suppressor of cytokine signaling 3; STAT3 = signal transducer and activator of transcription 3; SOX9 = SRY-Box 9; MMP2 = matrix metalloproteinase 2; CSPG = chondroitin sulfate proteoglycan; BBB = blood–brain barrier; TGF = transforming growth factor β; TBI = traumatic brain injury; IL = interleukin; CDC42 = cell division cycle 42; IFN = interferon; JNK = c-Jun N-terminal kinase; TNFR1 = tumor necrosis factor receptor 1; Gp130 = glycoprotein 130; FoxP3 = forkhead box P3; MHC = major histocompatibility complex