RANTES has a potential to play a neuroprotective role in an autocrine/paracrine manner after ischemic stroke

Abstract

Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) is a well-known pro-inflammatory chemokine and its role in ischemic stroke remains controversial. We examined the significance of RANTES in ischemic stroke and aimed to elucidate the direct effect of RANTES on neurons. Plasma concentrations of major C-C chemokines, including RANTES, and neurotrophic factors were examined in 171 ischemic stroke patients and age- and gender- matched healthy subjects. Plasma concentrations of RANTES at day 0 after onset were significantly elevated in stroke patients, compared with controls, and were highly correlated with those of BDNF, EGF, and VEGF. In a mouse middle cerebral artery occlusion model (MCAO), plasma RANTES was significantly elevated and the expression of RANTES was markedly upregulated in neurons particularly in peri-infarct areas. The expression of CCR3 and CCR5, receptors for RANTES, was also induced in neurons, while another receptor, CCR1, was observed in vascular cells, in peri-infarct areas after MCAO. We examined the effects of RANTES on differentiated PC12 cells, a model of neuronal cells. Treatment with RANTES induced the activation of Akt and Erk1/2, and attenuated the cleavage of caspase-3 in the cells. RANTES increased the expression of BDNF, EGF, and VEGF in the cells. Moreover, RANTES maintained the number of cells under serum free conditions. The RANTES-mediated upregulation of neurotrophic factors and cell survival were significantly attenuated by the inhibition of Akt or Erk1/2. Taken together, RANTES is an interesting chemokine that is produced from neurons after ischemic stroke and has the potential to protect neurons directly or indirectly through the production of neurotrophic factors in peri-infarct areas.

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

“…The immediate increase in TNFα, IL1α, IL1β, and IL18 could induce the increases in chemotactic factors for immune cells (MCP1, G-CSF, GM-CSF, MIP3α, and RANTES) detected post pFUS+MB (33,62,66,67). Although these chemotactic factors are associated with injury or inflammation, the increased expression of MIP, RANTES, and GM-CSF also may contribute to the closure of the BBB, thereby protecting the brain from further neuronal injury (9,48,66,68). The increased expression of antiinflammatory cytokines (IL4, IL10, and IL13) following pFUS+MB could limit the extent of injury, promote neuronal survival, and induce microglial apoptosis (69)(70)(71)(72).…”

Prophylactic Chronic Zinc Administration Increases Neuroinflammation in a Hypoxia-Ischemia Model

“…Increased levels of CCL5, CCL2, CCL3, and CXCL12 found in the early phase of endothelin-1 induced stroke model were not the cause of neurodegeneration [63]. CCL5 is produced from neurons after ischemic stroke to induce the production of neurotrophic factors in peri-infarct areas [64]. CXCL12 is reported to play a critical role in neuroprotection after stroke, by recruitment of endothelial progenitor cells and neuronal progenitor cells in the subventricular zone (SVZ) [54, 65, 66] as well as by promoting proliferation, differentiation, and migration of those progenitor cells [55, 67].…”

Nox4 Is a Major Source of Superoxide Production in Human Brain Pericytes

“…Focal brain ischemia was produced using permanent occlusion of the right middle cerebral artery (MCAO) as described previously [23,24]. The operated mouse was sacrificed with deep anesthesia 4 days after MCAO and was perfused transcardially with ice-cold heparinized saline and 4% (w/v) paraformaldehyde.…”