Abstract
BackgroundAn 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.MethodsC57Bl/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.ResultsWe 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.ConclusionMCP-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.
Highlights
An endotoxin insult mimics a severe peripheral infection and recent evidence suggests that a single exposure can cause long-term cognitive deficits
Six hours after LPS treatment represents a point of robust production of monocyte chemoattractant protein (MCP)-1 protein in the brain and at this time point we were able to measure significant levels of the cytokines IL-1β and tumor necrosis factor-α (TNF-α) in both the brain and serum
Since there was a decrease in IL-1β and tumor necrosis factor (TNF)-α in the brains of the monocyte chemoattractant protein-1 (MCP-1)-/- mice, we investigated whether this corresponded to a decrease in activated microglia in these mice
Summary
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. Systemic LPS causes an increase in production of pro-inflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6, in the periphery by immune cells such as monocytes and tissue macrophages [6] These peripherally produced cytokines may transfer an inflammatory signal to the brain in several ways: activation in areas of the brain with a leaky blood brain barrier (BBB), direct transport of cytokines across the BBB, or a neural route [6]. Evidence that innate immune cells of the brain can be activated by these cytokines is demonstrated by the observation that a single injection of IL-1β or TNF-α into selected regions of the brain results in sickness behaviors or activation of the HPA axis, and receptors for these cytokines are expressed in several brain regions [2,12]
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