Activating Quiescent ILC2 Immune Cells in the Aging Mouse Brain Improves Cognitive Function

Immune cells play a wide variety of important roles in the normal function of tissues throughout the body. The more familiar tasks, such as chasing down pathogens and clearing up metabolic waste and other debris, are just one slice of a much broader spectrum. Many of the other activities undertaken by immune cells are poorly catalogued and understood, particularly in the brain, where resident immune cells appear critical to the fine details of neural function. As is often the case in cellular interactions, many of the distinct contributions of immune cells to tissue function take the form of secreted molecules (or extracellular vesicles) that act upon other cell types to change their behavior.

In today's open access research, scientists identify a population of immune cells, ILC2 cells, largely concentrated in the choroid plexus in the aging brain, that could be helpful were they not largely quiescent. Given suitable signals to override their quiescence, these cells act to improve cognitive function. This is likely achieved via signal molecules secreted by ILC2 cells when active. The researchers identify IL-5 as an important signal, but it will no doubt be the work of years to more completely understand how benefits are produced in this case.

Activating Immune Cells Could Revitalize the Aging Brain

Group 2 innate lymphoid cells (ILC2s) reside in specific tissues of the body and help to repair them when they are damaged. Recently, for example, ILC2s in the spinal cord were shown to promote healing after spinal cord injury. Researchers examined the brains of both young and old mice and found that ILC2s accumulated with age in a structure called the choroid plexus. This structure produces cerebrospinal fluid and is close to the hippocampus, a region of the brain that plays a key role in learning and memory. Older mouse brains had up to five times as many ILC2 cells as younger brains. Crucially, the researchers also saw large numbers of ILC2s in the choroid plexus of elderly humans.

The ILC2s in old mouse brains were largely in an inactive, or quiescent, state, but the researchers were able to activate them by treating the animals with a cell signaling molecule called IL-33, causing the cells to proliferate and produce proteins that stimulate the formation and survival of neurons. Compared with ILC2s from younger animals, ILC2s from older mice were able to live longer and produce more ILC2 upon activation, the researchers found. Additionally, treating old mice with IL-33, or injecting them with ILC2 cells pre-activated in the lab, improved the animals' performance in a series of cognitive tests designed to measure their learning and memory.

One of the proteins produced by activated ILC2s is the signaling molecule IL-5. The research team found that treating old mice with IL-5 increased the formation of new nerve cells in the hippocampus and reduced the amount of potentially damaging inflammation in the brain. Again, IL-5 treatment improved the cognitive performance of aged mice in a number of tests.

Activation of group 2 innate lymphoid cells alleviates aging-associated cognitive decline

In this study, we report the accumulation of tissue-resident ILC2 in the choroid plexus of the aged brain, with ILC2 comprising a major subset of lymphocytes in the choroid plexus of aged mice and humans. ILC2 in the aged brain are long-lived and capable of reversibly switching between cell cycle dormancy and proliferation. They are relatively resistant to cellular senescence and exhaustion under replication stress, leading to enhanced self-renewal capability. They are functionally quiescent at homeostasis but can be activated by exogenous IL-33 to produce large amounts of IL-5 and IL-13 as well as a variety of other effector molecules in vitro and in vivo.

When activated in vitro and transferred intracerebroventricularly, they revitalized the aged brains and enhanced cognitive function of aged mice. Administration of IL-5, a major ILC2 product, repressed aging-associated neuroinflammation and alleviated aging-associated cognitive decline. Together, these results suggest that aging may expand a unique population of brain-resident ILC2 with enhanced cellular fitness and potent neuroprotective capability. Targeting ILC2 in the aged brain may unlock therapies to combat aging-related neurodegenerative disorders.

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