Chronic interleukin-1β expression in mouse brain leads to leukocyte infiltration and neutrophil-independent blood brain barrier permeability without overt neurodegeneration

The proinflammatory cytokine interleukin-1 beta( IL-1 beta) plays a significant role in leukocyte recruitment to the CNS. Although acute effects of IL-1 beta 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-1 beta(XAT) transgenic mouse model, we triggered sustained unilateral hippocampal overexpression of IL-1 beta. 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.