Distinguishing features of microglia- and monocyte-derived macrophages after stroke

Item Type:	Article
Title:	Distinguishing features of microglia- and monocyte-derived macrophages after stroke
Creators Name:	Kronenberg, G. and Uhlemann, R. and Richter, N. and Klempin, F. and Wegner, S. and Staerck, L. and Wolf, S. and Uckert, W. and Kettenmann, H. and Endres, M. and Gertz, K.
Abstract:	After stroke, macrophages in the ischemic brain may be derived from either resident microglia or infiltrating monocytes. Using bone marrow (BM)-chimerism and dual-reporter transgenic fate mapping, we here set out to delimit the responses of either cell type to mild brain ischemia in a mouse model of 30 min transient middle cerebral artery occlusion (MCAo). A discriminatory analysis of gene expression at 7 days post-event yielded 472 transcripts predominantly or exclusively expressed in blood-derived macrophages as well as 970 transcripts for microglia. The differentially regulated genes were further collated with oligodendrocyte, astrocyte, and neuron transcriptomes, resulting in a dataset of microglia- and monocyte-specific genes in the ischemic brain. Functional categories significantly enriched in monocytes included migration, proliferation, and calcium signaling, indicative of strong activation. Whole-cell patch-clamp analysis further confirmed this highly activated state by demonstrating delayed outward K(+) currents selectively in invading cells. Although both cell types displayed a mixture of known phenotypes pointing to the significance of 'intermediate states' in vivo, blood-derived macrophages were generally more skewed toward an M2 neuroprotective phenotype. Finally, we found that decreased engraftment of blood-borne cells in the ischemic brain of chimeras reconstituted with BM from Selplg(-/-) mice resulted in increased lesions at 7 days and worse post-stroke sensorimotor performance. In aggregate, our study establishes crucial differences in activation state between resident microglia and invading macrophages after stroke and identifies unique genomic signatures for either cell type.
Keywords:	Cerebral Ischemia, Bone-Marrow Chimera, Microglia, Macrophage, Middle Cerebral Artery Occlusion, Animals, Mice
Source:	Acta Neuropathologica
ISSN:	0001-6322
Publisher:	Springer
Volume:	135
Number:	4
Page Range:	551
Date:	April 2018
Official Publication:	https://doi.org/10.1007/s00401-017-1795-6
PubMed:	View item in PubMed

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