Immune Cell Infiltration into the Brain After Ischemic Stroke in Humans Compared to Mice and Rats: a Systematic Review and Meta-Analysis
- PMID: 33496918
- PMCID: PMC8557159
- DOI: 10.1007/s12975-021-00887-4
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.
© 2021. The Author(s).
Conflict of interest statement
HW: honoraria for Scientific Advisory Boards Biogen, Evgen, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG, and Sanofi-Aventis. Speaker honoraria and travel support from Alexion, Biogen, Cognomed, F. Hoffmann-La Roche Ltd., Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma AG, Genzyme, TEVA, and WebMD Global. Paid consultant for Abbvie, Actelion, Biogen, IGES, Johnson & Johnson, Novartis, Roche, Sanofi-Aventis, and the Swiss Multiple Sclerosis Society. Research is funded by RE Children’s Foundation, Biogen, GlaxoSmithKline GmbH, Roche Pharma AG, Sanofi-Genzyme.
LK: Compensation for Scientific Advisory Boards for Alexion, Genzyme, Janssen, Merck Serono, Novartis and Roche. Speaker honoraria and travel support from Bayer, Biogen, Genzyme, Grifols, Merck Serono, Novartis, Roche, Santhera and Teva. Research support from Biogen, Novartis and Merck Serono.
CJS and WRS are inventors on the patent application “Hematopoietic factors for treatment of neurological condition” including stroke. Recently a part of the application (ALS) was granted. CJS and WRS transferred their rights to Sygnis and received a minor financial compensation upfront. In case of efficacy CJS and WRS participate in form of royalties. WRS: Compensation as PI of the AXIS I study.
SM: Speaker honoraria and travel support from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS und Teva. Research is funded by Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, HERZ Burgdorf, Merck Serono, Novartis, ONO Pharma, Roche, and Teva.
JM: Grants from EVER Pharma Jena GmbH, and Ferrer International, travel grants from Boehringer Ingelheim, and speaking fees from Bayer Vital and Chugai Pharma.
CB, RR, JKS, ASP, HM, and TR declare no conflict of interest.
Figures
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