Immune Cell Infiltration into the Brain After Ischemic Stroke in Humans Compared to Mice and Rats: a Systematic Review and Meta-Analysis

Abstract

Although several studies have suggested that anti-inflammatory strategies reduce secondary infarct growth in animal stroke models, clinical studies have not yet demonstrated a clear benefit of immune modulation in patients. Potential reasons include systematic differences of post-ischemic neuroinflammation between humans and rodents. We here performed a systematic review and meta-analysis to summarize and compare the spatial and temporal distribution of immune cell infiltration in human and rodent stroke. Data on spatiotemporal distribution of immune cells (T cells, macrophages, and neutrophils) and infarct volume were extracted. Data from all rodent studies were pooled by means of a random-effect meta-analysis. Overall, 20 human and 188 rodent stroke studies were included in our analyses. In both patients and rodents, the infiltration of macrophages and neutrophils preceded the lymphocytic influx. Macrophages and neutrophils were the predominant immune cells within 72 h after infarction. Although highly heterogeneously across studies, the temporal profile of the poststroke immune response was comparable between patients and rodents. In rodent stroke, the extent of the immune cell infiltration depended on the duration and location of vessel occlusion and on the species. The density of infiltrating immune cells correlated with the infarct volume. In summary, we provide the first systematic analysis and comparison of human and rodent post-ischemic neuroinflammation. Our data suggest that the inflammatory response in rodent stroke models is comparable to that in patients with stroke. However, the overall heterogeneity of the post-ischemic immune response might contribute to the translational failure in stroke research.

Keywords: Immune cell infiltration; Inflammation; Ischemic stroke; Meta-analysis.

Fig. 1

Temporal and quantitative characterization of immune cell infiltration in rodent stroke at days 1–7 after induction of ischemia. Flow cytometric analysis of the ipsilateral brain hemisphere (a) and histological analysis (b infarct core, c penumbra) showing the absolute numbers (bare circles) of infiltrating immune cells (macrophages, neutrophils, and T cells) in the ischemic hemisphere in rats (blue) and mice (green). Meta-analyzed data are shown as mean with higher and lower 95% confidence interval. In case of negative confidence intervals, lower confidence limits are not shown. For clarity, data are shown as data of 10 (logarithmic scale)

Fig. 2

Immune cell infiltration in relation to animal stroke model at days 1–7 after induction of ischemia. Flow cytometric analysis of the ipsilateral brain hemisphere (a) and histological analysis (b infarct core, c penumbra) showing the absolute numbers of infiltrating immune cells (macrophages, neutrophils, and T cells) in the ischemic hemisphere for each type of ischemia: distal permanent (bare triangle), proximal transient (bare circle), distal transient (bare square), and proximal permanent (bare rhombus). Meta-analyzed data are shown as mean with higher and lower 95% confidence interval (red). In case of negative confidence intervals, lower confidence limits are not shown

Fig. 3

Meta-regression analysis of the association between immune cell density of macrophages/microglia, neutrophils, or T cells and infarct volume 1–42 days after induction of ischemia. Due to the significant difference in infarct size, values for mice (a) and rats (b) are calculated separately. Values represent numbers of immune cells/mm³ in the infarct core and infarct volume in mm³

Fig. 4

Schematics of temporal profile of immune cell infiltration in rodent (a, b, c) and human (b) stroke. Curves are created from data obtained from this study. In rodent stroke, numbers of immune cells are graphically calculated from the original data of histological (cells/mm³; a, b) and of FACS analysis (cells per ischemic hemisphere; c)