Chronic interleukin-1beta expression in mouse brain leads to leukocyte infiltration and neutrophil-independent blood brain barrier permeability without overt neurodegeneration.
The proinflammatory cytokine interleukin-1beta (IL-1beta) plays a significant role in leukocyte recruitment to the CNS. Although acute effects of IL-1beta 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-1beta(XAT) transgenic mouse model, we triggered sustained unilateral hippocampal overexpression of IL-1beta. 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.
Shaftel
Solomon S
SS
Department of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
Carlson
Thaddeus J
TJ
Olschowka
John A
JA
Kyrkanides
Stephanos
S
Matousek
Sarah B
SB
O'Banion
M Kerry
MK
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D018932:Chemokine CCL2 / Q000378:metabolism; D054426:Chemokine CXCL2; D006624:Hippocampus / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015846:Monokines / Q000172:deficiency / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*
D018932:Chemokine CCL2; D054426:Chemokine CXCL2; D053583:Interleukin-1beta; D015846:Monokines; D018799:Intercellular Adhesion Molecule-1; D017493:Leukocyte Common Antigens