Evidence that Ly6C(hi) monocytes are protective in acute ischemic stroke by promoting M2 macrophage polarization

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Abstract

BACKGROUND AND PURPOSE: Ly6Chi monocytes are generally thought to exert a proinflammatory role in acute tissue injury, although their impact after injuries to the central nervous system is poorly defined. CC chemokine receptor 2 is expressed on Ly6Chi monocytes and plays an essential role in their extravasation and transmigration into the brain after cerebral ischemia. We used a selective CC chemokine receptor 2 antagonist, INCB3344, to assess the effect of Ly6Chi monocytes recruited into the brain early after ischemic stroke. METHODS: Male C57Bl/6J mice underwent occlusion of the middle cerebral artery for 1 hour followed by 23 hours of reperfusion. Mice were administered either vehicle (dimethyl sulfoxide/carboxymethylcellulose) or INCB3344 (10, 30 or 100 mg/kg IP) 1 hour before ischemia and at 2 and 6 hours after ischemia. At 24 hours, we assessed functional outcomes, infarct volume, and quantified the immune cells in blood and brain by flow cytometry or immunofluorescence. Gene expression of selected inflammatory markers was assessed by quantitative polymerase chain reaction. RESULTS: Ly6Chi monocytes were increased 3-fold in the blood and 10-fold in the brain after stroke, and these increases were selectively prevented by INCB3344 in a dose-dependent manner. Mice treated with INCB3344 exhibited markedly worse functional outcomes and larger infarct volumes, in association with reduced M2 polarization and increased peroxynitrite production in macrophages, compared with vehicle-treated mice. CONCLUSIONS: Our data suggest that Ly6Chi monocytes exert an acute protective effect after ischemic stroke to limit brain injury and functional deficit that involves promotion of M2 macrophage polarization.
Original languageEnglish
Pages (from-to)1929 - 1937
Number of pages9
JournalStroke
Volume46
Issue number7
DOIs
Publication statusPublished - 2015

Cite this

@article{ba0081cbc9394796a766d0c2a6f7fb70,
title = "Evidence that Ly6C(hi) monocytes are protective in acute ischemic stroke by promoting M2 macrophage polarization",
abstract = "BACKGROUND AND PURPOSE: Ly6Chi monocytes are generally thought to exert a proinflammatory role in acute tissue injury, although their impact after injuries to the central nervous system is poorly defined. CC chemokine receptor 2 is expressed on Ly6Chi monocytes and plays an essential role in their extravasation and transmigration into the brain after cerebral ischemia. We used a selective CC chemokine receptor 2 antagonist, INCB3344, to assess the effect of Ly6Chi monocytes recruited into the brain early after ischemic stroke. METHODS: Male C57Bl/6J mice underwent occlusion of the middle cerebral artery for 1 hour followed by 23 hours of reperfusion. Mice were administered either vehicle (dimethyl sulfoxide/carboxymethylcellulose) or INCB3344 (10, 30 or 100 mg/kg IP) 1 hour before ischemia and at 2 and 6 hours after ischemia. At 24 hours, we assessed functional outcomes, infarct volume, and quantified the immune cells in blood and brain by flow cytometry or immunofluorescence. Gene expression of selected inflammatory markers was assessed by quantitative polymerase chain reaction. RESULTS: Ly6Chi monocytes were increased 3-fold in the blood and 10-fold in the brain after stroke, and these increases were selectively prevented by INCB3344 in a dose-dependent manner. Mice treated with INCB3344 exhibited markedly worse functional outcomes and larger infarct volumes, in association with reduced M2 polarization and increased peroxynitrite production in macrophages, compared with vehicle-treated mice. CONCLUSIONS: Our data suggest that Ly6Chi monocytes exert an acute protective effect after ischemic stroke to limit brain injury and functional deficit that involves promotion of M2 macrophage polarization.",
author = "Chu, {Hannah X} and Broughton, {Bradley R S} and Kim, {Helena Hyun Ah} and Lee, {Seyoung Sandy} and Drummond, {Grant R} and Sobey, {Christopher G}",
year = "2015",
doi = "10.1161/STROKEAHA.115.009426",
language = "English",
volume = "46",
pages = "1929 -- 1937",
journal = "Stroke",
issn = "0039-2499",
publisher = "American Heart Association",
number = "7",

}

Evidence that Ly6C(hi) monocytes are protective in acute ischemic stroke by promoting M2 macrophage polarization. / Chu, Hannah X; Broughton, Bradley R S; Kim, Helena Hyun Ah; Lee, Seyoung Sandy; Drummond, Grant R; Sobey, Christopher G.

In: Stroke, Vol. 46, No. 7, 2015, p. 1929 - 1937.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Evidence that Ly6C(hi) monocytes are protective in acute ischemic stroke by promoting M2 macrophage polarization

AU - Chu, Hannah X

AU - Broughton, Bradley R S

AU - Kim, Helena Hyun Ah

AU - Lee, Seyoung Sandy

AU - Drummond, Grant R

AU - Sobey, Christopher G

PY - 2015

Y1 - 2015

N2 - BACKGROUND AND PURPOSE: Ly6Chi monocytes are generally thought to exert a proinflammatory role in acute tissue injury, although their impact after injuries to the central nervous system is poorly defined. CC chemokine receptor 2 is expressed on Ly6Chi monocytes and plays an essential role in their extravasation and transmigration into the brain after cerebral ischemia. We used a selective CC chemokine receptor 2 antagonist, INCB3344, to assess the effect of Ly6Chi monocytes recruited into the brain early after ischemic stroke. METHODS: Male C57Bl/6J mice underwent occlusion of the middle cerebral artery for 1 hour followed by 23 hours of reperfusion. Mice were administered either vehicle (dimethyl sulfoxide/carboxymethylcellulose) or INCB3344 (10, 30 or 100 mg/kg IP) 1 hour before ischemia and at 2 and 6 hours after ischemia. At 24 hours, we assessed functional outcomes, infarct volume, and quantified the immune cells in blood and brain by flow cytometry or immunofluorescence. Gene expression of selected inflammatory markers was assessed by quantitative polymerase chain reaction. RESULTS: Ly6Chi monocytes were increased 3-fold in the blood and 10-fold in the brain after stroke, and these increases were selectively prevented by INCB3344 in a dose-dependent manner. Mice treated with INCB3344 exhibited markedly worse functional outcomes and larger infarct volumes, in association with reduced M2 polarization and increased peroxynitrite production in macrophages, compared with vehicle-treated mice. CONCLUSIONS: Our data suggest that Ly6Chi monocytes exert an acute protective effect after ischemic stroke to limit brain injury and functional deficit that involves promotion of M2 macrophage polarization.

AB - BACKGROUND AND PURPOSE: Ly6Chi monocytes are generally thought to exert a proinflammatory role in acute tissue injury, although their impact after injuries to the central nervous system is poorly defined. CC chemokine receptor 2 is expressed on Ly6Chi monocytes and plays an essential role in their extravasation and transmigration into the brain after cerebral ischemia. We used a selective CC chemokine receptor 2 antagonist, INCB3344, to assess the effect of Ly6Chi monocytes recruited into the brain early after ischemic stroke. METHODS: Male C57Bl/6J mice underwent occlusion of the middle cerebral artery for 1 hour followed by 23 hours of reperfusion. Mice were administered either vehicle (dimethyl sulfoxide/carboxymethylcellulose) or INCB3344 (10, 30 or 100 mg/kg IP) 1 hour before ischemia and at 2 and 6 hours after ischemia. At 24 hours, we assessed functional outcomes, infarct volume, and quantified the immune cells in blood and brain by flow cytometry or immunofluorescence. Gene expression of selected inflammatory markers was assessed by quantitative polymerase chain reaction. RESULTS: Ly6Chi monocytes were increased 3-fold in the blood and 10-fold in the brain after stroke, and these increases were selectively prevented by INCB3344 in a dose-dependent manner. Mice treated with INCB3344 exhibited markedly worse functional outcomes and larger infarct volumes, in association with reduced M2 polarization and increased peroxynitrite production in macrophages, compared with vehicle-treated mice. CONCLUSIONS: Our data suggest that Ly6Chi monocytes exert an acute protective effect after ischemic stroke to limit brain injury and functional deficit that involves promotion of M2 macrophage polarization.

UR - http://stroke.ahajournals.org/content/46/7/1929.full.pdf+html

U2 - 10.1161/STROKEAHA.115.009426

DO - 10.1161/STROKEAHA.115.009426

M3 - Article

VL - 46

SP - 1929

EP - 1937

JO - Stroke

JF - Stroke

SN - 0039-2499

IS - 7

ER -