Symptoms associated with infection are orchestrated by the brain in response to circulating cytokines, the signaling molecules of the immune system. But just how cytokines cross the almost impenetrable blood-brain barrier has been the topic of much dispute.
Now, Salk scientists have described how resident macrophages lined up along the blood-brain barrier play opposing roles in the transmission of immune signals into the brain. Their findings may pave the way for novel therapies for sufferers of chronic neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS), Parkinson's, Alzheimer's and prion diseases, in which central inflammatory mechanisms play an important role.
Earlier research by Paul E. Sawchenko, a professor in the Neuronal Structure and Function Laboratory and the study's senior author, and others suggested a vascular route whereby cytokines interact with vessel walls to generate secondary messengers, which then engage the relevant circuitry in the brain. Tightly packed endothelial cells, which line almost 400 miles of narrow capillaries throughout the brain, are perfectly positioned to record circulating immune signals but they require a very strong signal to become activated. Perivascular macrophages, on the other hand, are more sensitive but don't have direct access to the bloodstream.
To disentangle the exact role of these two cell types, the researchers took advantage of the macrophages' ability to engulf and ingest solid particles. They injected liposomes containing clodronate, a drug that can cause cell death, into the lateral cerebral ventricle. The liposomes were taken up by the macrophages, which were selectively killed off.
Without perivascular macrophages, the animals were unable to respond to blood-borne interleukin-1, an inflammatory cytokine, and initiate the brain's so-called acute phase responses, which help the body deal with the challenge at hand but also cause the familiar feeling of "being sick." But to their surprise, the Salk researchers found that the same cells put a damper on the pro-inflammatory activities of endothelial cells, which form the lining of blood vessels and are only stirred to action when they encounter lipopolysaccharide, a key component of the cell wall of certain bacteria.
"Many neurodegenerative diseases are worsened by systemic inflammation or infections," says Sawchenko. "Once we identify the molecules that mediate the two-way communication between perivascular macrophages and endothelial cells, we can develop strategies for managing the adverse health consequences of central inflammatory responses."