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Abstract
Ischemic brain injury causes local inflammation, which involves activation of resident
microglia, leukocyte, and monocyte infiltration. Involvement of peripheral immune
cells in ischemia-induced damage and repair is debatable. Using flow cytometry, gene
expression profiling, and immunocytochemistry, we show that microglia predominate
in the ischemic brain and express inflammation mediators at Day 1 after transient
middle cerebral artery occlusion (MCAo) in rats. At Day 3, both resident microglia
and bone marrow (BM)-derived macrophages are detected in the ischemic hemispheres
and display unique transcriptomic profiles. Functional groups enriched in BM-macrophages
are indicative of the pro-regenerative, immunosuppressive phenotype. Transient depletion
of peripheral macrophages with clodronate-filled liposomes reduced the number of Arg1+
Iba1+ expressing cells in the ischemic brain. The analysis of microglia and macrophage
signature genes shows that each cell type maintains the expression of their identity
genes, even if gene expression is modified in a response to environmental clues. At
Day 7, infiltrating BM-macrophages exhibit the reduced expression of Arg1, the elevated
expression of iNos and many inflammatory genes, as shown by RNA sequencing. This is
consistent with their switch toward a pro-inflammatory phenotype. We propose that
BM-macrophages recruited to the injured brain early after ischemia could contribute
to functional recovery after stroke, but they switch toward a pro-inflammatory phenotype
in the ischemic parenchyma. Our results point to the detrimental role of microglia
in an ischemic brain and the primarily pro-regenerative role of infiltrating BM-macrophages.
[1
]Laboratory of Molecular Neurobiology, Neurobiology Center; The Nencki Institute of
Experimental Biology of the Polish Academy of Sciences; Warsaw Poland