Experimental Stroke Induces Massive, Rapid Activation of the Peripheral Immune System

Abstract

Clinical experimental stroke induces injurious local brain inflammation. However, effects on the peripheral immune system have not been well characterized. We quantified mRNA and protein levels for cytokines, chemokines, and chemokine receptors (CCR) in brain, spinal cord, peripheral lymphoid organs (spleen, lymph node, blood, and cultured mononuclear cells from these sources), and blood plasma after reversible middle cerebral artery occlusion (MCAO) or sham treatment in male C57BL/6 mice. Middle cerebral artery occlusion induced a complex, but organ specific, pattern of inflammatory factors in the periphery. At both 6 and 22 h after MCAO, activated spleen cells from stroke-injured mice secreted significantly enhanced levels of TNF-a, IFN-c, IL-6, MCP-1, and IL-2. Unstimulated splenocytes expressed increased chemokines and CCR, including MIP-2 and CCR2, CCR7 & CCR8 at 6 h; and MIP-2, IP-10, and CCR1 & CCR2 at 22 h. Also at 22 h, T cells from blood and lymph nodes secreted increased levels of inflammatory cytokines after activation. As expected, there were striking proinflammatory changes in postischemic brain. In contrast, spinal cord displayed suppression of all mediators, suggesting a compensatory response to intracranial events. These data show for the first time that focal cerebral ischemia results in dynamic and widespread activation of inflammatory cytokines, chemokines, and CCR in the peripheral immune system.

T- and B-Cell-Deficient Mice with Experimental Stroke have Reduced Lesion Size and Inflammation

“…We previously reported that focal cerebral ischemia in immunologically intact C57BL/6 mice resulted in a marked reduction in spleen cell numbers when evaluated at 22 h postischemia (1673 million in MCAO versus 3575 million in sham versus 9178 million in naïve mice; Offner et al, 2006). We show here that naïve SCID mice have drastically reduced splenocyte numbers (2.771.4 million cells, Table 1) as would be expected in the absence of T and B cells.…”

“…Middle cerebral artery occlusion induced marked increases in secretion of inflammatory cytokines in spleens from intact WT mice at 6 and 22 h after occlusion (Offner et al, 2006). As is shown in Figure 2 (upper panel, filled bars), these changes at 22 h of MCAO were reflected by increased expression of mRNA for IFN-g, TNF-a, IL-6, MIP-2, IP-10, CCR1, and CCR2.…”

PKC-βExacerbatesin vitroBrain Barrier Damage in Hyperglycemic Settings via Regulation of RhoA/Rho-kinase/MLC2 Pathway

“…Furthermore, using a cell culture model of human BBB established with relatively late passage endothelial cells and astrocytes, in this study only one factor, i.e., glucose, out of many involved in ischemic damage could be manipulated, whereas a number of pro-inflammatory cytokines and circulating components during an ischemic stroke, notably tumor necrosis factor-a, interleukin-6, vascular endothelial growth factor, and thrombin, are known to affect BBB permeability. 37,38 …”

Microglia and Monocyte-Derived Macrophages in Stroke

“…The literature has consistently described stroke-induced early peripheral immune activation, which is defined by increased inflammatory cytokines in both experimental animal models and humans [10][11][12][13]. This early immune activation often progresses to immune suppression in patients with stroke.…”