Activating group 2 innate lymphoid cells in aging brains helps improve memory


Researchers at Albany Medical College in New York have discovered that a specific type of immune cell accumulates in older brains, and that activating these cells improves the memory of aged mice.

The study, which will be published February 5 in the Journal of Experimental Medicine (JEM), suggests that targeting these cells might reduce age-related cognitive decline and combat aging-associated neurodegenerative disease in humans.

The brain is highly susceptible to aging, with cognitive functions, such as learning and memory, gradually declining as we get older.

Much of the body’s immune system also deteriorates with age, resulting in increased susceptibility to infection and higher levels of inflammation.

In their new JEM study, however, a team of researchers led by Qi Yang and Kristen L. Zuloaga at Albany Medical College reveal that aging-related changes in a class of immune cell known as group 2 innate lymphoid cells (ILC2s) could allow doctors to combat the effects of aging on the brain.

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.

“However, whether ILC2s also reside in other parts of the central nervous system, and how they respond to aging, was unknown,” Yang says.

The 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.

Remarkably, 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. “This suggested that activated ILC2 can improve the cognitive function of aged mice,” says Zuloaga.

This shows the immune cells

Staining for immune cells shows that the number of ILC2 cells (white arrows) are increased in the choroid plexus of old mice (right) compared with young mice (left). Other types of immune cells are indicated by blue arrows. Image is credited to Fung et al., 2020.

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.

“Our work has thus revealed the accumulation of tissue-resident ILC2 cells in the choroid plexus of aged brains and demonstrated that their activation may revitalize the aged brain and alleviate aging-associated cognitive decline,” says Yang.

“Aging is the major risk factor for a variety of neurocognitive and neurodegenerative diseases,” says Zuloaga. “Targeting ILC2 cells in the aged brain may provide new avenues to combat these diseases in humans.”

Aging is a complex process in which an organism progressively loses physiologic function leading to increased vulnerability to diseases and death. Aging is associated with various metabolic, genomic, proteostatic, and intercellular changes in many different organs and systems (Lopez‐Otin, Blasco, Partridge, Serrano, & Kroemer, 2013).

A prominent manifestation of aging is enhanced susceptibility to infectious diseases and the underlying deterioration of the immune system, termed immunosenescence (Goronzy & Weyand, 2013; Nikolich‐Zugich, 2018).

Mechanisms of immunosenescence remain unclear. Aging‐induced changes to adaptive immune cells and the resulting impacts on immunosenescence are well recognized (Goronzy & Weyand, 2013; Nikolich‐Zugich, 2018). However, the effects of aging on the development and function of innate immune cells remain largely unknown.

Aging is associated with diverse and intricate physiologic changes in multiple organs and cellular systems. Lymphoid tissues, such as bone marrow (BM), thymus, and lymph nodes, are highly susceptible to the impacts of aging (Chinn, Blackburn, Manley, & Sempowski, 2012). Aging‐induced BM stromal cell failure and thymus involution result in diminished production of naïve T and B lymphocytes (Chinn et al., 2012).

The maintenance and maturation of adaptive lymphocytes are further impaired by age‐related structural and functional changes to the lymph nodes, leading to increased vulnerability to pathogens and poor responses to vaccination (Thompson, Smithey, Surh, & Nikolich‐Zugich, 2017; Turner & Mabbott, 2017).

Aging is also associated with changes to nonlymphoid tissues such as the lungs (Lowery, Brubaker, Kuhlmann, & Kovacs, 2013); however, how aging influences tissue immunity remains very poorly understood.

Innate lymphoid cells (ILCs) are a unique family of innate lymphocytes that lack clonally distributed antigen receptors but functionally and molecularly resemble T cells (Vivier et al., 2018). GATA3‐expressing group 2 innate lymphoid cells (ILC2) are the predominant ILC subset in the lung.

Lung‐resident ILC2 are implicated in pulmonary homeostasis, epithelial repair, and lung remodeling (Vivier et al., 2018). ILC2 are seeded into the lungs during prenatal or perinatal stages (Gasteiger, Fan, Dikiy, Lee, & Rudensky, 2015; Nussbaum et al., 2013).

Mature lung ILC2 in adult young mice are noncirculating tissue‐resident cells, and their local proliferation, but not recruitment from the BM, is a signature of activation (Gasteiger et al., 2015). Nevertheless, BM lLC lymphopoiesis remains active in adult mice (Yang & Bhandoola, 2016). Various ILC and ILC2 precursors have been identified in the BM of adult mice (Yang & Bhandoola, 2016).

When transferred to irradiated recipients, these BM ILC/ILC2 precursors efficiently give rise to mature ILC2 in the lungs of recipient mice (Yang & Bhandoola, 2016).

However, it remains unknown whether BM precursors may home into the lungs to replenish mature lung ILC2 in physiologic and pathologic conditions other than irradiation. Very little is known about whether and how aging may impact ILC development or function.

In this study, we have explored the effects of aging on ILC2 development and function. Interestingly, our data reveal highly compartmentalized effects of aging on ILC2. Specifically, aging is paradoxically associated with increased early ILC2 development in the BM, but reduced maintenance and function of mature ILC2 in the lungs.

Aging leads to a drastic increase in the numbers of BM ILC2 precursors (ILC2P) through Notch signaling‐dependent mechanisms. However, this increase is not sufficient to replenish the concomitant decline in mature ILC2 in the lungs of aged mice.

Mature lung ILC2 in aged mice are numerically and functionally compromised, failing to produce cytokines both at homeostasis and during influenza infection. Aged lung ILC2 have reduced fatty acid uptake and decreased expression of peroxisomal and cytochrome p450 (CYP) enzymes that are required for optimal ILC2 function.

Transfer of activated ILC2 purified from the lungs of young mice enhances resistance to influenza infection in old mice.

Together, these data highlight highly tissue‐specific effects of aging on innate lymphoid cell development and function, and indicate that targeting tissue‐resident ILC might unlock new therapies to enhance resistance to infectious diseases in the elderly.

Rockefeller University Press


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