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The Journal of Neuroscience, August 29, 2007, 27(35):9301-9309; doi:10.1523/JNEUROSCI.1418-07.2007

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Cellular/Molecular
Chronic Interleukin-1ß Expression in Mouse Brain Leads to Leukocyte Infiltration and Neutrophil-Independent Blood–Brain Barrier Permeability without Overt Neurodegeneration

Solomon S. Shaftel,¹ Thaddeus J. Carlson,² John A. Olschowka,¹ Stephanos Kyrkanides,^1,3 Sarah B. Matousek,¹ and M. Kerry O'Banion^1,4

Departments of ¹Neurobiology and Anatomy, ²Microbiology and Immunology, ³Dentistry, and ⁴Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Correspondence should be addressed to Dr. M. Kerry O'Banion, University of Rochester Medical Center, 601 Elmwood Avenue, Box 603, Rochester, NY 14642. Email: kerry_obanion{at}urmc.rochester.edu

The proinflammatory cytokine interleukin-1ß (IL-1ß) plays a significant role in leukocyte recruitment to the CNS. Although acute effects of IL-1ß signaling in the mouse brain have been well described, studies elucidating the downstream effects of sustained upregulation have been lacking. Using the recently described IL-1ß^XAT transgenic mouse model, we triggered sustained unilateral hippocampal overexpression of IL-1ß. Transgene induction led to blood–brain barrier leakage, induction of MCP-1 (monocyte chemoattractant protein 1) (CCL2), ICAM-1 (intercellular adhesion molecule 1), and dramatic infiltration of CD45-positive leukocytes comprised of neutrophils, T-cells, macrophages, and dendritic cells. Despite prolonged cellular infiltration of the hippocampus, there was no evidence of neuronal degeneration. Surprisingly, neutrophils were observed in the hippocampal parenchyma as late as 1 year after transgene induction. Their presence was coincident with upregulation of the potent neutrophil chemotactic chemokines KC (keratinocyte-derived chemokine) (CXCL1) and MIP-2 (macrophage inflammatory protein 2) (CXCL2). Knock-out of their sole receptor CXCR2 abrogated neutrophil infiltration but failed to reduce leakage of the blood–brain barrier.

Key words: interleukin-1ß; blood–brain barrier; CXCR2; hippocampus; neurotoxicity; neutrophils

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Received March 29, 2007; revised June 26, 2007; accepted July 7, 2007.

Correspondence should be addressed to Dr. M. Kerry O'Banion, University of Rochester Medical Center, 601 Elmwood Avenue, Box 603, Rochester, NY 14642. Email: kerry_obanion{at}urmc.rochester.edu

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