Myeloid-specific deletion of the mineralocorticoid receptor reduces infarct volume and alters inflammation during cerebral ischemia.
OBJECTIVE
mineralocorticoid receptor (MR) antagonists have protective effects in rodent models of ischemic stroke, but the cell type-specific actions of these drugs are unknown. In the present study, we examined the contribution of myeloid cell MR during focal cerebral ischemia using myeloid-specific MR knockout mice.


METHODS
myeloid-specific MR knockout mice were subjected to transient (90 minutes) middle cerebral artery occlusion followed by 24 hours reperfusion (n=5 to 7 per group). Ischemic cerebral infarcts were identified by hematoxylin and eosin staining and quantified with image analysis software. Immunohistochemical localization of microglia and macrophages was performed using Iba1 staining, and the expression of inflammatory markers was measured after 24 hours of reperfusion by quantitative reverse transcription-polymerase chain reaction.


RESULTS
myeloid-specific MR knockout resulted in a 65% reduction in infarct volume (P=0.005) after middle cerebral artery occlusion. This was accompanied by a significant reduction in activated microglia and macrophages in the ischemic core. Furthermore, myeloid-specific MR knockout suppressed classically activated M1 macrophage markers tumor necrosis factor-α, interleukin-1β, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and interleukin-6 at the same time as partially preserving the induction of alternatively activated, M2, markers Arg1, and Ym1.


CONCLUSIONS
these data demonstrate that myeloid MR activation exacerbates stroke and identify myeloid MR as a critical target for MR antagonists. Furthermore, these data indicate that MR activation has an important role in controlling immune cell function during the inflammatory response to stroke.
Department of Internal Medicine, Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Mich. 48109, USA.
Ryan A
RA
Frieler
He
H
Meng
Sheng Zhong
SZ
Duan
Stefan
S
Berger
Günther
G
Schütz
Yangdong
Y
He
Guohua
G
Xi
Michael M
MM
Wang
Richard M
RM
Mortensen
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002545:Brain Ischemia / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D017628:Microglia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
C491049:Aif1 protein, mouse; D000943:Antigens, Differentiation; D002135:Calcium-Binding Proteins; D018836:Inflammation Mediators; D008840:Microfilament Proteins; D018161:Receptors, Mineralocorticoid