Chronic interleukin-1β expression in mouse brain leads to leukocyte infiltration and neutrophil-independent blood-brain barrier permeability without overt neurodegeneration
- Solomon S. Shaftela(Author),
- Thaddeus J. Carlsona(Author),
- John A. Olschowkaa(Author),
- Stephanos Kyrkanidesa(Author),
- ,
- M. Kerry O'Baniona, b(Author)
- aUniversity of Rochester School of Medicine and Dentistry,
- bUniversity of Rochester Medical Center
Open access
Abstract
The proinflammatory cytokine interleukin-1β (IL-1β) plays a significant role in leukocyte recruitment to the CNS. Although acute effects of IL-1β 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-1βXAT transgenic mouse model, we triggered sustained unilateral hippocampal overexpression of IL-1β. 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.