Immune Proteins Play a Role in Neural Growth
Post by Anastasia Sares
What's the science?
The protein IL-33 is part of a large family of proteins related to immune function. Outside of the brain, it is mostly known for its role in inflammation, such as in asthma or auto-immune conditions. However, IL-33 also supports tissue repair and is necessary for proper neural development. In studies of brain injury and Alzheimer’s disease, IL-33 has been shown to increase plasticity and reverse memory deficits. But how can an immune system protein support memory? This week in Cell, Nguyen and colleagues examined IL-33’s role in memory formation in the hippocampus and showed that it involves the brain’s immune cells to clear a path for branching neurons.
How did they do it?
The research team employed a number of techniques for identifying cells producing IL-33 or its receptor, IL1RL1, in genetically modified mice. Some of the mice had a code for a fluorescent protein inserted right next to the IL-33 gene so that cells producing IL-33 could be seen with a fluorescent microscope. Others had genetic manipulations to knock out the IL-33 gene so that it no longer worked. The authors were also able to express extra IL-33 in mice using a lentivirus.
Their analyses of brain tissue included flow cytometry, which involves streaming a solution full of cell nuclei in a small tube one cell wide. As the nuclei passed one by one in front of a laser, they could measure many different properties of the scattered laser light to detect different proteins (including the fluorescence from the IL33 gene). The authors also raised mice in different conditions. Some of them experienced temporarily enriched environments, known for increasing neuronal growth and plasticity, while others experienced brief social isolation, which does the opposite. Still, others underwent fear conditioning to see how well they learned the association between a stimulus and a mild shock.
What did they find?
In the hippocampus, IL-33 was expressed primarily in neurons (and especially neurons in the dentate gyrus). This is different from elsewhere in the brain, where it is mostly found in astrocytes. The receptor, IL1RL1, was located in microglia, which are cells acting as the primary form of immune defense in the central nervous system.
IL-33 levels increased in the mice who had enriched environments and decreased in those undergoing social isolation. IL-33 also decreased with age and memory loss. Deleting IL-33 or its receptors on the microglia caused mice to have fewer dendritic spines on existing neurons, fewer new neurons, and less precise memory for fearful stimuli. Extensive testing indicated that IL-33 might induce the microglia to clear out the extracellular matrix (the web of structural proteins around the cells). This clearance would then pave the way for the growth and branching of new neurons.
What's the impact?
IL-33 may have neuroprotective benefits in diseases like stroke, traumatic brain injury, ALS, and even Alzheimer’s disease (which specifically affects memory and could be related to inflammation in the brain). Understanding the mechanisms behind synapse development and memory maintenance will help us to fight these diseases. This research also emphasizes and expands the role of immune cells like microglia in brain function.
Nguyen et al. Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity. Cell (2020). Access the original scientific publication here.