Research

MCP-1-deficient mice show reduced neuroinflammatory responses and increased peripheral inflammatory responses to peripheral endotoxin insult

Wendy L Thompson^1,3 , William J Karpus^2,3 and Linda J Van Eldik^1,3

¹  Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611, USA

²  Department of Pathology, Northwestern University, Chicago, IL 60611, USA

³  Center for Drug Discovery and Chemical Biology, Northwestern University, Chicago, IL 60611, USA

author email corresponding author email

Journal of Neuroinflammation 2008, 5:35doi:10.1186/1742-2094-5-35

Published:	15 August 2008

Abstract

Background

An endotoxin insult mimics a severe peripheral infection and recent evidence suggests that a single exposure can cause long-term cognitive deficits. A peripheral injection of LPS results in production of pro-inflammatory cytokines, such as IL-1β and TNF-α, in the brain and periphery and these cytokines mediate many effects of the acute phase response including activation of the HPA axis. The chemokine MCP-1 is highly expressed during endotoxemia and although much is known about the importance of MCP-1 in peripheral inflammatory responses to LPS, information about MCP-1 and CNS responses to peripheral LPS is lacking.

Methods

C57Bl/6 mice were administered LPS by intraperitoneal (i.p.) injection, serum and brains were collected at several time points, and the time course of MCP-1 protein up-regulation was measured. To examine the role of MCP-1 in activation of the brain during acute systemic inflammation, we injected MCP-1 knockout (MCP-1^-/-) or control C57Bl/6 (MCP-1^+/+) mice with LPS i.p. and measured the levels of selected cytokines and chemokines in serum and brain extracts 6 hours later. Activated microglia were examined by CD45 immunohistochemistry, and serum corticosterone and ACTH levels were measured by enzyme immunoassay.

Results

We report that LPS injection induces a robust increase in MCP-1 protein levels in serum and brain, with peak brain levels reached at 6 hrs after LPS administration. MCP-1^-/- mice injected with LPS showed higher levels of serum IL-1β and TNF-α compared to LPS-treated MCP-1^+/+ mice. In contrast, these MCP-1^-/- mice showed significantly lower inductions of brain pro-inflammatory cytokines and chemokines, fewer activated microglia, and a reduction in serum corticosterone levels.

Conclusion

MCP-1^-/- mice have decreased brain inflammation after a peripheral LPS insult, despite an exaggerated peripheral response. These data demonstrate an important role for MCP-1 in regulation of brain inflammation after peripheral endotoxemia.