The central nervous system is separated from the rest of the body by the blood-brain barrier, a layer of specialized cells wrapping blood vessels in the brain. These only allow certain molecules and cells to cross back and forth, and so the biochemical and cellular environment of the brain can be quite different from that of tissues it interacts with connected to. The brain even has its own distinct immune system: microglia, for example, are innate immune cells analogous to macrophages elsewhere in the body. Microglia are involved in an arguably broader range of activities than is the case for macrophages. They support core functions in the brain, such as via participation in the processes of synaptic remodeling.
A great deal of evidence points towards chronic inflammation as an important contributing cause of neurodegenerative conditions. Inflammation is beneficial when temporary, a necessary part of the immune response, but chronic inflammation that fails to resolve is a dysfunction of the immune system. Inflammatory microglia are a part of this chronic inflammation, and consequently they are also implicated in neurodegenerative conditions.
In all of this, there is a little of microglia being led into bad behavior by a preexisting inflammatory environment, joining in to make it worse, and a little of microglia becoming inflammatory (or even senescent and thus highly inflammatory) as a result of processes of damage in the brain, and thereby generating an inflammatory environment. Either will lead to the results observed in today's open access research, in which microglia are shown to contribute to dysfunction of the blood-brain barrier. This is one of the early features of neurodegeneration. When the blood-brain barrier leaks, inappropriate cells and molecules cross into the brain, causing disruption and adding to the burden of inflammation as immune cells respond to the invasion.
A new study shows that microglia - the resident immune cells of the brain - initially protect the blood-brain barrier from damage due to "systemic inflammation," a condition of chronic inflammation associated with factors like smoking, ageing, and diabetes, and leading to an increased risk of neurodegenerative disorders. However, these same microglia can change their behavior and increase the blood-brain barrier permeability, thereby damaging it.
A key point of interest was the systemic inflammation induced by injecting the mice with an inflammation-inducing substance. Such injections resulted in the movement of microglia to the blood vessels and increased the permeability of the blood-brain barrier within a few days. Then, the microglia initially acted to protect the blood-brain barrier and limit increases in permeability, but as inflammation progressed, the microglia reversed their behavior by attacking the components of the blood-brain barrier, thus increasing the barrier's permeability. The subsequent leakage of molecules into the brain had the potential to cause widespread inflammation in the brain and consequent damage to neurons.
Uncontrolled inflammatory responses in the brain can cause a range of cognitive disorders and adverse neurological effects, and drugs that target microglia may help patients avoid such problems by preserving the integrity of the blood-brain barrier. More studies are required to understand more about the processes underlying the microglial behaviors observed in this study. Nevertheless, the study's results offer hope for the development of therapies that could "force" microglia to promote blood-brain barrier integrity and prevent microglia from transitioning to behaviors that damage the barrier.
Microglia are active surveyors of brain parenchyma with important roles in sculpting and coordinating neural circuits in healthy brains that respond rapidly to form a range of reactive phenotypes in brain infection and damage. Activated microglia play roles in a range of acute and neurodegenerative diseases, where they can help clear neuronal damage by phagocytosis, but can also contribute to disease progression by releasing molecules that can initiate a neuroinflammatory states. Microglia can also respond to peripheral inflammatory diseases.
A key question is how microglia change phenotypes when the primary pathological insult resides in the peripheral organs and systemic circulation. Determining how these systemic and neuronal inflammatory responses are linked may help reduce the deleterious impact of systemic immune activation and inflammation on cognitive function and susceptibility to brain disease. The blood-brain barrier (BBB) represents a major pathway by which systemic inflammation and immune responses potentially interact with the brain microenvironment.
The goal of this study was to examine the role of microglia in responding to systemic infection and inflammation, and its contribution to BBB integrity. Using two different models of peripheral inflammation, MRL/lpr mice and mice treated for 7 days with lipopolysaccharide, we demonstrated that resident brain microglia migrate to cerebral vessels during systemic inflammation in response to the release of the chemokine CCL5 from endothelial cells. This triggers microglial cells to express CLDN5 and to infiltrate through the neurovascular unit, thus contacting endothelial cells and forming tight junctions to maintain BBB integrity. Consistently, partial microglial ablation or blocking CCL5 signaling, actually increased BBB permeability during the early stages of inflammation.