Purinergic receptor P2RY12-dependent microglial closure of the injured blood-brain barrier

TY - JOUR

T1 - Purinergic receptor P2RY12-dependent microglial closure of the injured blood-brain barrier

AU - Lou, Nanhong

AU - Takano, Takahiro

AU - Pei, Yong

AU - Xavier, Anna L.

AU - Goldman, Steven A.

AU - Nedergaard, Maiken

PY - 2016/1/26

Y1 - 2016/1/26

N2 - Microglia are integral functional elements of the central nervous system, but the contribution of these cells to the structural integrity of the neurovascular unit has not hitherto been assessed. We show here that following blood-brain barrier (BBB) breakdown, P2RY12 (purinergic receptor P2Y, G-protein coupled, 12)-mediated chemotaxis of microglia processes is required for the rapid closure of the BBB. Mice treated with the P2RY12 inhibitor clopidogrel, as well as those in which P2RY12 was genetically ablated, exhibited significantly diminished movement of juxtavascular microglial processes and failed to close laser-induced openings of the BBB. Thus, microglial cells play a previously unrecognized protective role in the maintenance of BBB integrity following cerebrovascular damage. Because clopidogrel antagonizes the platelet P2Y12 receptor, it is widely prescribed for patients with coronary artery and cerebrovascular disease. As such, these observations suggest the need for caution in the postincident continuation of P2RY12-targeted platelet inhibition.

AB - Microglia are integral functional elements of the central nervous system, but the contribution of these cells to the structural integrity of the neurovascular unit has not hitherto been assessed. We show here that following blood-brain barrier (BBB) breakdown, P2RY12 (purinergic receptor P2Y, G-protein coupled, 12)-mediated chemotaxis of microglia processes is required for the rapid closure of the BBB. Mice treated with the P2RY12 inhibitor clopidogrel, as well as those in which P2RY12 was genetically ablated, exhibited significantly diminished movement of juxtavascular microglial processes and failed to close laser-induced openings of the BBB. Thus, microglial cells play a previously unrecognized protective role in the maintenance of BBB integrity following cerebrovascular damage. Because clopidogrel antagonizes the platelet P2Y12 receptor, it is widely prescribed for patients with coronary artery and cerebrovascular disease. As such, these observations suggest the need for caution in the postincident continuation of P2RY12-targeted platelet inhibition.

KW - Animals

KW - Blood-Brain Barrier

KW - Cell Movement

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Microglia

KW - Platelet Aggregation Inhibitors

KW - Receptors, Purinergic P2Y12

KW - Ticlopidine

KW - Journal Article

KW - Research Support, N.I.H., Extramural

U2 - 10.1073/pnas.1520398113

DO - 10.1073/pnas.1520398113

M3 - Journal article

C2 - 26755608

SN - 0027-8424

VL - 113

SP - 1074

EP - 1079

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 4

ER -