CX3CL1/CX3CR1-Mediated Microglia Activation Plays a Detrimental Role in Ischemic Mice Brain via p38MAPK/PKC Pathway

Abstract

The exact roles of activated microglia and fractalkine (CX3CL1)/fractalkine receptor (CX3CR1) signaling are not fully understood in brain ischemic injury and the findings reported are controversial. Here, we investigated the effects of CX3CR1 siRNA on the expression of CX3CR1, p38 mitogen-activated protein kinase (p38MAPK), Protein Kinase C (PKC) and inflammatory cytokines, microglia activation, white matter lesions, and cognitive function in mice treated with bilateral common carotid artery stenosis (BCAS) in vivo as well as effects of exogenous CX3CL1, CX3CR1 siRNA, and SB2035080 on expression of inflammatory cytokines in BV2 microglia treated with oxygen-glucose deprivation (OGD) in vitro. We showed that CX3CR1 siRNA significantly inhibited the increased expression of CX3CR1, p38MAPK, PKC as well as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, and also attenuated microglia activation, white matter lesions, and cognitive deficits induced by BCAS in mice brain. We also showed that exogenous CX3CL1 could induce a further enhancement in TNF-α and IL-1β expression, which could be suppressed by CX3CR1 siRNA or by the p38MAPK inhibitor in OGD-treated BV2 microglial cells in vitro. Our findings indicated that CX3CL1/CX3CR1-mediated microglial activation plays a detrimental role in ischemic brain via p38MAPK/PKC signaling and also suggested that CX3CL1/CX3CR1 axis might be a putative therapeutic target to disrupt the cascade of deleterious events that lead to brain ischemic injury.

White matter damage after traumatic brain injury: A role for damage associated molecular patterns

“…Consistent with these reports, administration of the selective microglial inhibitor, minocycline, attenuated microglial activation, decreased IL-1β production, protected developing oligodendrocytes, and attenuated white matter injury in neonatal rat brains [194, 195]. Similarly, inhibition of CX3CR1, a receptor involved in microglial chemotaxis, decreased microglial activation, reduced IL-1β production, attenuated white matter injury, and improved neurocognitive function in a pre-clinical model of vascular cognitive impairment [196]. While the aforementioned findings suggest a detrimental role for microglia after TBI, minocycline failed to attenuate traumatic axonal injury, tissue atrophy, neurodegeneration, or spatial learning deficits in a pediatric head trauma model [197].…”

Microglia may compensate for dopaminergic neuron loss in experimental Parkinsonism through selective elimination of glutamatergic synapses from the subthalamic nucleus

“…Dex overcame the effect of Glu on phagocytosis (Figure D–F). Glu enhanced the expression of mRNA encoding the microglial markers Iba1, CD11b, and CX3CR1 (Liu et al, ) (Figure Ga–Gc). Glu also increased mRNA encoding F4/80 (Lin et al, ), CD68 (Sugimoto et al, ), matrix metalloproteinase 2 (MMP2) (Lively and Schlichter, ), cathepsin S (Hayashi et al, ; Lively and Schlichter, ), and interferon regulatory factor 1 (IRF1) (Higaki et al, ) (Figure Gd–Gh), which have been suggested to participate in phagocytosis, migration, modulation of synapses, or activation of microglia, respectively.…”

Differentially Severe Cognitive Effects of Compromised Cerebral Blood Flow in Aged Mice: Association with Myelin Degradation and Microglia Activation

“…CXCR1 and ERK/p38 MAPK inhibition decreased activation of microglia and blockade of this route also attenuated lesions to the white matter, and the cognitive impairments induced by BCAS (Lee et al, 2013; Liu et al, 2015). …”