Systemic infection and inflammation lead to release of cytokines, such as IL-1, which activate the brain’s stress response mechanisms, producing typical symptoms such as lethargy, fever, and lack of appetite. In response to inflammation or infection, the hypothalamus releases corticotropin-releasing factor which, in turn, stimulates the pituitary gland to secrete adrenocorticotropic hormone. This then causes the adrenal glands to increase production of glucocorticoids, which both mobilise energy reserves to cope with the inflammatory insult and also act as powerful immunosuppressants, preventing excessive cytokine production and immune cell proliferation. Since cytokines are not able to freely cross the blood-brain barrier, exactly how they initiate this cascade of events has not been clear but researchers at the Salk Institute for Biological Studies have now begun to unravel the process.
It had been suggested that cytokines might interact with epithelial cells in the brain’s vasculature to produce prostanoids which act as secondary messengers transmitting the signal onwards. Epithelial cells are ideally positioned to receive inflammatory signals from circulating blood but need a very strong signal to become activated. In contrast, perivascular macrophages, a subset of brain-resident macrophages, are much more sensitive to cytokines but are not in direct contact with the bloodstream. To clarify the roles of both cell types, liposomes containing clodronate, which specifically deplete macrophages, were injected into the lateral cerebral ventricles of rats. This procedure abolished responses to IL-1 which activates prostanoid synthesis only in perivascular cells, but enhanced responses to LPS which stimulates prostanoid synthesis by both perivascular cells and endothelial cells. Resident macrophages lined up along the blood-brain barrier thus play opposing roles in the transmission of immune signals to the brain depending on the nature of the stimulus.
As well as clarifying the cellular mechanisms of CNS responses to inflammatory insults, the team hope that a better understanding of how immune signals are transmitted across the blood-brain barrier may also lead ultimately to new treatments for chronic neurodegenerative diseases such as Amyotrophic Lateral Sclerosis, Parkinson’s disease, Alzheimer’s disease and prion diseases, in which inflammation is believed to play an important role.
The study is published in the January 14th issue of Neuron.