Relapse in neuroinflammatory disease : studies into events at the blood-brain barrier

Abstract

Prostaglandin E₂ (PGE₂) is considered to be the inflammatory mediator responsible for various CNS responses to systemic inflammation such as fever and sickness behaviour. Whether it plays a role in the induction of cytokine expression within the brain was unknown. De novo cytokine transcription within the brain occurs during systemic inflammation and is thought to be one of the mechanisms underlying exacerbation of neuroinflammatory disease. It is shown that intraperitoneal administration of indomethacin, which inhibits PGE₂ synthesis, did not prevent the upregulation of TNFα, IL1β and IL6 mRNA which occurs in the brain during systemic inflammation and is thought to be one of the mechanisms underlying exacerbation of neuroinflammatory disease. It is shown that intraperitoneal administration of indomethacin, which inhibits PGE₂ synthesis, did not prevent the upregulation of TNFα, IL1β and IL6 mRNA which occurs in the brain during systemic endotoxin challenge in rats. This suggests that exacerbation of neuroinflammatory disease following a systemic infection occurs via a prostaglandin-independent pathway. Future research efforts are therefore needed to identify the humoral mediator(s) signalling CNS cytokine induction during systemic inflammation.

Cerebral CD16 3-positive macrophages and endothelial cells are the cellular constituents of the BBB which are activated during systemic inflammation. However their relative contribution to immune-to-brain signalling was not known. Therefore, cerebral CD163-positive macrophages were selectively depleted using an intracerebroventricular infusion of clodronate liposomes. This technique was optimized in order to preserve the peripheral immune system’s response to systemic inflammatory challenge. It was observed that depletion of cerebral CD163-positive macrophages did not affect immune-to-brain signalling after a systemic endotoxin challenge as assessed by studying several events which are considered to reflect the brain’s response to systemic inflammation: fever, de novo transcription of the cytokines TNFα, IL1β and IL6, IL1β protein expression and upregulation of microglial phosphorylated ERK ½. This shows that the role of cerebral CD163-positive macrophages in immune-to-brain signalling is not essential. Therefore the cerebral endothelium is mainly responsible for the inflammatory pathway across the BBB, and represents a potential therapeutic target.

The role of CD8 T cells in neuroinflammatory disease is increasingly being recognized. IN order to initiate inflammation, neuroantigen-specific CD8 T cells need to infiltrate the brain. Here, a novel route whereby CD8 T cells gain access to the CNS in an antigen-dependent manner is described. An in vivo model of antigen-specific CD8 T cell recruitment was developed by injecting cognate antigen in the striatum of CD8 TCR-transgenic mice using a minimally invasive technique cognate antigen in the striatum of CD8 TCR-transgenic mice using a minimally invasive technique. Luminal MHC Class I expression by cerebral endothelium directs antigen-specific CD8 T cell traffic into the brain in vivo and represents a novel therapeutic target in inflammatory neurological diseases.

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