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

Wendy L. Thompson, William J. Karpus, Linda J. Van Eldik

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

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.

Original languageEnglish
Article number35
JournalJournal of Neuroinflammation
Volume5
DOIs
StatePublished - Aug 15 2008

Bibliographical note

Funding Information:
These studies were supported in part by NIH grant R37 AG013939 (LVE) and NS34510 (WK). WT was a predoctoral trainee on NIH T32 AG000260 and is currently supported by NIH F31 NS055471 predoctoral fellowship. We thank Marina Yasvoina and Peizhen Shao for performing tissue sectioning and immunohistochemistry.

ASJC Scopus subject areas

  • Neuroscience (all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

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