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Innate Response to Focal Necrotic Injury Inside the Blood-Brain Barrier¹

Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, Department of Pathology, New York University School of Medicine, New York, NY 10016

We have studied the initial innate immune response to focal necrotic injury on different sides of the mouse blood-brain barrier by two-photon intravital microscopy. Transgenic mice in which the promoter of the myeloid isoform of lysozyme drives GFP were used to track granulocytes and monocytes. Necrotic injury in the meninges, but not the brain parenchyma, recruited GFP⁺ cells within minutes that fully surrounded the necrotic site within a day. Recently, it has been suggested that microglial cells and astrocytes cooperate to mount a distinct response to laser injury behind the blood-brain barrier. We followed the microglial response in heterozygous knockin mice in which GFP replaces CX₃CR1 coding sequence. Prior to injury, microglial cell bodies were immobile over days, but moved to the laser injury site within 1 day. We followed astrocytes, which have been proposed to cooperate with microglial cells in response to focal injury, using transgenic mice in which glial fibrillary acidic protein promoter drives GFP expression. Before injury fine astrocyte processes permeate the parenchyma. Astrocytes polarized toward the injury in an ATP, connexin hemichannels, and intracellular Ca²⁺-dependent process. The astrocytes network established a cytoplasmic Ca²⁺ gradient that preceded the microglial response. This is consistent with astrocyte-microglial collaboration to mount this innate response that excludes blood leukocytes.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health and Dana Foundation grants (to M.L.D.), Irene Diamond Foundation (to M.L.D.), and National Cancer Institute Training Fellowship Grant CA009161-31 (to J.V.K.).

² Address correspondence and reprint requests to Dr. Michael L. Dustin, Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, Department of Pathology, New York University School of Medicine, 540 First Ave, New York, NY 10016. E-mail address: dustin{at}saturn.med.nyu.edu

³ Abbreviations used in this paper: BBB, blood-brain barrier; YFP, yellow fluorescent protein; FFA, flufenamic acid.

⁴ The online version of this article contains supplemental material.

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