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J. Venugopal et al.
stroke onset. In order to determine whether stroke size could be reduced by pharmacologic blockade of the IL-1R, even when administered following MCA occlusion, the IL- 1R antagonist, anakinra, was administered 1 hour following stroke induction in Wt,SCDbmt mice. Compared to vehicle control, mice given anakinra after stroke onset experienced reduction in stroke volume when analyzed 3 days follow- ing MCA occlusion (Figure 5). A decrease in peri-infarct MAC3-positive cells was also observed (Figure 6), similar to what was seen in IL1R-/-,SCDbmt brain sections post-stroke.
Discussion
SCD results from a missense mutation leading to an amino acid substitution in the β-globin gene.48 Although SCD is a monogenic disease, there is marked phenotypic heterogeneity in patients with SCD that applies to anemia,
cerebrovascular disease, acute chest syndrome, pain crises, and death.49,50 Differential activation of inflammatory path- ways may be a mechanism which accounts for the observed phenotypic heterogeneity and may be a critical link between hemolysis and subsequent vascular complica- tions.10 Multiple cytokines, including IL-1β and IL-6, have been postulated to play a role in SCD phenotypes, and as these cytokines are also known to regulate stroke volume in non-SCD populations, the hypothesis that the deletion of the endothelial IL-1R pool may be beneficial in SCD was pursued by utilizing an MCA occlusion model. This model of stroke leads to sustained occlusion of the MCA in the absence of treatment51 and the increased stroke size in sick- le cell mice is likely due to vaso-occlusion in the penumbra microvasculature.42 Since potential deleterious effects of IL- 1R signaling in SCD could be mediated via downstream production of IL-6, this pathway was also studied.
Figure 1. Blood parameter analysis at 15 weeks post-bone marrow transplantation. Circulating erythrocytes (A), hemoglobin (B), hematocrit (C), reticulocytes (D), and leukocytes (E) of Wt,WTbmt, Wt,SCDbmt, IL1R-/-,SCDbmt and IL6-/-,SCDbmt mice (mean ± standard deviation). Total WBC: total white blood cells; NE: neutrophils; LY: lymphocytes; MO: monocytes, *P=< 0.05, **P<0.01, ***P<0.005 as determined by ANOVA. In Figure 1E, asterisks indicates significance to Wt,WTbmt and pound signs indicate significance to Wt,SCDbmt.
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