Expression of MCP‐1 and fractalkine on endothelial cells and astrocytes may contribute to the invasion and migration of brain macrophages in ischemic rat brain lesions

Abstract

Some macrophages expressing NG2 chondroitin sulfate proteoglycan (NG2) and the macrophage marker Iba1 accumulate in the ischemic core of a rat brain subjected to transient middle cerebral artery occlusion (MCAO) for 90 min. These cells are termed BINCs (for brain Iba1(+) /NG2(+) cells) and may play a neuroprotective role. Because BINCs are bone marrow-derived cells, they are able to invade ischemic tissue after the onset of an ischemic insult. In this study, chemokine-based mechanisms underlying the invasion of BINCs or their progenitor cells were investigated. We found that isolated BINCs expressed mRNA encoding CCR2 and CX3CR1 at high levels. Cultured astrocytes expressed mRNA encoding their ligands, MCP-1 and fractalkine. Recombinant MCP-1 and/or fractalkine, as well as astrocytes, induced the migration of BINCs in vitro. mRNA for MCP-1, fractalkine, CCR2, and CX3CR1 was expressed in the ischemic core during the acute phase of the ischemic event. Immunohistochemical studies revealed that vascular endothelial cells and astrocytic endfeet expressed MCP-1 and fractalkine, respectively, in the ischemic core during the acute phase. CCR2(+) /Iba1(+) monocytes attached to the inside of the vascular wall at 1 day postreperfusion (dpr), and there were CCR2(+) /CX3CR1(+) macrophage-like cells in the parenchyma in the ischemic lesion core at 2 dpr, which may be the progenitors for BINCs. These results suggest that CCR2(+) monocytes are first attracted to the ischemic lesion by MCP-1(+) endothelial cells and migrate toward fractalkine(+) astrocytic endfeet through the disrupted blood-brain barrier. Thus, chemokines may play a critical role in the accumulation of neuroprotective BINCs. © 2013 Wiley Periodicals, Inc.

Aging alters the immunological response to ischemic stroke

“…While CCL2 concentrations were significantly similarly augmented in the acute ischemic brain, the cellular source of this chemokine was not assessed. Previous studies support a strong role for endothelial cells and astrocytes as important mediators of monocyte recruitment [37, 84]. Our findings also highlight the importance of modeling stroke injury in aged mice as the finding of this biased recruitment of neutrophils in older mice represents an important translational advance for therapeutic discovery that would not have been seen if only young mice were evaluated.…”

A20 deficiency causes spontaneous neuroinflammation in mice

“…Having demonstrated that A20 KO mice suffer important gliosis, we checked the status of brain EC in these mice. As anticipated, astrogliosis and microglial activation corresponded with overt EC activation in A20 KO brain vasculature, as demonstrated by increased expression of the adhesion molecules VCAM-1, ICAM-1 and endothelial specific E-selectin, as well as the chemokine MCP-1, although the latter may be a product of glial cells, in addition to EC [75]. Increased endothelial activation in brains of A20 KO mice is in keeping with the well-documented anti-inflammatory and homeostatic function of A20 in EC [15,76], and agrees with our recent data demonstrating that mere partial loss of A20 aggravates the inflammatory phenotype of the endothelium in a vascular allograft model of transplant arteriosclerosis (Lee et al ., manuscript in preparation).…”

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

“…For instance, CXCL1 stimulates chemoattraction of neutrophils into the damaged areas [7]. CCL2 and CX3CL (fractalkine) alter the permeability of the blood brain barrier (BBB), promote migration of both macrophages [8] and bone marrow-derived stem cells into ischemic cerebral areas, and contribute to the regeneration of the injured area [9]. CCL3 and CCL4, which are increased 6 hours after ischemia, recruit lymphocytes, macrophages, and microglia [10, 11].…”