Temporal and spatial dynamics of cerebral immune cell accumulation in stroke.
OBJECTIVE
Ischemic stroke leads to significant morbidity and mortality in the Western world. Early reperfusion strategies remain the treatment of choice but can initiate and augment an inflammatory response causing secondary brain damage. The understanding of postischemic inflammation is very limited. The objectives of this study were to define the temporal and spatial infiltration of immune cell populations and their activation patterns in a murine cerebral ischemia-reperfusion injury model.


METHODS
Transient middle cerebral artery occlusion was induced for 1 hour followed by 12-hour to 7-day reperfusion in C57/BL6 mice. Immunohistochemistry and flow cytometry were used to quantify the infiltrating immune cell subsets.


RESULTS
Accumulation of microglia and infiltration of the ischemic hemisphere by macrophages, lymphocytes, and dendritic cells (DCs) preceded the neutrophilic influx. DCs were found to increase 20-fold and constituted a substantial proportion of infiltrating cells. DCs exhibited a significant upregulation of major histocompatibility complex II and major histocompatibility complex II high-expressing DCs were found 100 times more abundant than in sham conditions. Upregulation of the costimulatory molecule CD80 was observed in DCs and microglial cells but did not further increase in major histocompatibility complex II high-expressing DCs. No lymphocyte activation was observed. Additionally, regulatory immune cells (natural killer T-cells, CD4(-)/CD8(-)T lymphocytes) cumulated in the ischemic hemisphere.


CONCLUSIONS
This study provides a detailed analysis of the temporal dynamics of immune cell accumulation in a rodent stroke model. The peculiar activation pattern and massive increase of antigen-presenting cells in temporal conjunction with regulatory cells might provide additional insight into poststroke immune regulation.
Gelderblom
Mathias
M
Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. m.gelderblom@uke.uni-hamburg.de.
Leypoldt
Frank
F
Steinbach
Karin
K
Behrens
Doerthe
D
Choe
Chi-Un
CU
Siler
Dominic A
DA
Arumugam
Thiruma V
TV
Orthey
Ellen
E
Gerloff
Christian
C
Tolosa
Eva
E
Magnus
Tim
T
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D007111:Immunity, Cellular / Q000276:immunology*; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology; D007700:Kinetics; D008214:Lymphocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D015427:Reperfusion Injury / Q000276:immunology; D020521:Stroke / Q000276:immunology* / Q000473:pathology
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse