Table 2.

Interactions of EVs with microglia in neural injury and disease

Disease	EV type	Recipient cell type	Functional effect or interaction
Glioblastoma Multiforme (GBM)	GBM EVs [51] [54] EL-4 EVs [44].	Primary mouse microglia KW3 Primary human GBM cells (11/5-) and (20/3) [51]	Increase in proliferation, expression of Arg-1mRRNA43], MT1-MMP [54] and CCL5, CCL2, CXCL1, CXCL10, TIMP-1 [51] Decrease in IL-27, IL-23, Il-17, and IL-16(51), STAT3, IL-1B, and Il-6 [44]. GBM EVs were seen interacting with CxCr1-GFP+ microglia in vivo [51] Increase of miRNA-21 and miRNA451 [51]
Spinal cord injury (SCI)	TNF-α and INF-γ stimulated mesenchymal stem cell EVs (MSCEV+) or non-stimulated MSC EVs (MSCEVswt)	In vivo microglia	Decrease M1-like microglia (CD32+ and Cd86+) Decrease in M2-like microglia (Cd100R, Cd163, and RT1B) [56]
Perinatal brain injury through LPS injection at P3	MSC EVs	In vivo IBA1+ microglia	Decreased in number of IBA+ microglia and decreased ameboid transition [57]
Cortical injury in aged animals	-MSC EVs [58]	In vivo IBA1+ microglia	Increase in ramified MCHII expressing IBA1+ [58] Correlations between ramified morphology and functional recovery [58]
Alzheimer’s disease	N2a EVs exposed to Aβ [39]. Pre conditioned [65] MSC EV or MSC EVs [59].	BV2 microglia [39, 59]. Primary IBA1+ microglia [59].	Significant decrease in IBA1+ cells, TNF-a and IL-1B secretion and STAT3 and NF-kB expression [59]. Increases CD11c cells, IL-4, IL-10 secretion and mir-21[59]. Increased uptake, clearance, and degradation of Aβ by microglia in the presence of EVs [39;59].
Bacterial (LPS) challenge	Curcumin loaded EL-4 EVs (Exo-cur)	-In vivo Cd45.2+ and ILB+ microglia	Decrease in activated inflammatory microglia Increased microglial apoptosis [44].
Myelin oligodendrocyte glycoprotein (MOG)- induced experimental autoimmune encephalomyelitis (EAE)	Curcumin loaded EL-4 EVs (Exo-cur)	In vivo Cd45.2+ and ILB+ microglia	Decrease in activated inflammatory microglia, and decreased disease severity compared to curcumin alone and PBS [44].
Parkinson’s disease	Plasma derived EVs	In vivo IBA1+ microglia, and in vitro BV2 microglial	Colocalization with IBA1+ positive cells bilaterally, even though unilateral EV injection [63] Preferential internalization over neurons and astrocytes [63] Increase in IBA1+ cells and NO [63]
Traumatic brain injury (TBI)	Plasma derived EVs BV2 derived VEs	In vivo IBA1+ microglia, and in vitro BV2 microglial	Increases in IL-1B and CCL2 in BV2s with TBI primed plasma EVs Increases in IL-1B, TNF-a, CCL2, IL-6, AND NOS2 and ameboid transition in BV2 microglia with LPS primed BV2 EVs [64]
Opioid use	Human primary astrocyte derived EVs (ADEVs)	Mouse primary microglia	Increases in toll like receptor 7 (TLR7), NFkBp65 trafficking to the nucleus and decreases phagocytosis [40]