Ischemic tolerance mediated by microglia-astrocytes communications
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1
University of Yamanashi, Interdisciplinary Graduate School of Medicine, Japan
A mild ischemic episode (preconditioning; PC) induces resistance to a subsequent severe ischemic injury. This phenomenon, known as ischemic tolerance, is an endogenous process that provides robust neuroprotection. We previously showed that astrocytes become a neuroprotective phenotype in response to PC, which was essential for induction of ischemic tolerance. Such an astrocyte-mediated ischemic tolerance requires activation of astrocytes and subsequent upregulation of P2X7 receptors in astrocytes. However, mechanisms underlying astrocytic activation, upregulation of P2X7 receptors in astrocytes, and the downstream signals of P2X7 receptors responsible for the ischemic tolerance remain unknown. Using in vivo middle cerebral artery occlusion (MCAO) model in mice, here, we show that microglia have an essential role in induction of such neuroprotective astrocytes. PC induced activation of microglia prior to activation of astrocytes. Inhibition of microglia by minocycline abolished the PC-evoked activation of astrocytes, upregulation of P2X7 receptors, and induction of ischemic tolerance. Microglia produced and released several proinflammatory cytokines in response to PC, and then caused phenotypical changes of astrocytes. As for the downstream signals, hypoxia inducible factor-1α (HIF-1α), a master molecule of oxygen homeostasis, has an indispensable role. Interestingly, unlike neurons, the increase in HIF-1α in astrocytes was not dependent on hypoxia, but rather dependent on activation of P2X7 receptors. Taken together, although astrocytes have a pivotal role in induction of ischemic tolerance, it is strongly suggested that the intimate communication between microglia and astrocytes should also be indispensable for the ischemic tolerance.
Keywords:
Astrocytes,
Ischemia,
hypoxia,
P2X7,
cerebral artery occlusion
Conference:
14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27 Aug - 30 Aug, 2016.
Presentation Type:
Symposium 10: Microglia: Immune Cells or Brain Cells?
Topic:
14th Meeting of the Asian-Pacific Society for Neurochemistry
Citation:
Koizumi
S
(2016). Ischemic tolerance mediated by microglia-astrocytes communications.
Conference Abstract:
14th Meeting of the Asian-Pacific Society for Neurochemistry.
doi: 10.3389/conf.fncel.2016.36.00043
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Received:
26 Jul 2016;
Published Online:
11 Aug 2016.
*
Correspondence:
Prof. Schuichi Koizumi, University of Yamanashi, Interdisciplinary Graduate School of Medicine, Yamanashi, Japan, skoizumi@yamanashi.ac.jp