MS-linked Molecule IL-17 Impaired Immune Cells in Mice’s Brains

MS-linked Molecule IL-17 Impaired Immune Cells in Mice’s Brains
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Sustained, excessive levels of interleukin 17A (IL-17A) — a pro-inflammatory molecule linked to multiple sclerosis (MS) and other autoimmune diseases — reduce the number and activity of the brain’s immune cells in the dentate gyrus, according to a study in mice.

The dentate gyrus is part of the hippocampus, a brain region with a well-established role in memory.

However, no other significant changes were observed in hippocampal cells and function in the mice with chronically high IL-17 levels.

Further studies are needed to better characterize the consequences of IL-17A-induced chronic inflammation and to clarify the underlying mechanism of the drop in immune cells’ activity in the brain, the researchers noted.

“These mutant mice can be used in future studies as a model for chronic IL-17A-related inflammation,” Yosuke Takei, MD, PhD, said in a press release. Takei is the study’s senior author and professor at the University of Tsukuba in Japan.

“Further neuronal and behavioral testing will help us begin to understand IL-17A’s role in a range of debilitating neurological disorders,” Takei said.

The study, “Effects of RORγt overexpression on the murine central nervous system,” was published in the journal Neuropsychopharmacology Reports.

T-helper 17 (Th17) cells are a population of Th cells mainly located in the gut that produce the pro-inflammatory molecule IL-17A. Both Th17 cells and IL-17A are considered to play a key role in MS and other autoimmune and neurological disorders.Tetsuya Sasaki, PhD, an author of the study and assistant professor at the University of Tsukuba, said that in addition to MS, “recent reports show that IL-17A is also a factor in Alzheimer’s disease, schizophrenia, and autism spectrum disorder.”Notably, a previous study showed that a gut Th17-derived increase in IL‐17A levels in the blood leads to cognitive dysfunction in mice, but how excessive IL-17A affects the brain remains unclear.Now, Takei’s team evaluated how chronically high levels of IL-17A in the blood affected the brain’s cells and function by using mice genetically modified to overly produce the retinoic acid receptor-related-orphan-receptor-gamma t (ROR-gamma t), a key molecule for Th17 cells maturation and IL-17A production.

“Our strategy,” said Sasaki, “was to induce more generic helper T-cells to become the kind that produce IL-17A.”

The researchers found that their strategy worked, as higher ROR-gamma t levels increased the production of IL-17A in the mice’s gut and excessive IL-17A levels in the blood, compared with normal mice.

The team then analyzed the effects of these high levels of IL-17A in microglia (brain’s immune cells) and astrocytes (nerve cell-supporting cells) in the hippocampus, a brain area involved in learning and memory and that is affected in MS.

Results showed that mice with excessive IL-17A had reduced activity and numbers of microglia in a specific region of the hippocampus (the dentate gyrus) compared with normal mice. However, no changes in astrocytes were observed between the two types of mice.

Further analyses in the hippocampus revealed that high IL-17A levels did not affect nerve cell formation and levels of molecules involved in nerve cell communication. Notably, mice with chronic IL-17A-derived inflammation had no major defects in spatial memory, compared with normal mice.

“These results suggest that the level of inflammation induced by elevation of IL‐17A was not enough to cause robust changes in [nerve cell communication] in the hippocampus,” the researchers wrote.

The team also hypothesized that the IL-17A-associated drop in microglia’s activity may be due to immunoregulatory mechanisms. Th17 cells are known to also produce high levels of the pro-inflammatory molecule TNF that activates regulatory T-cells, a type of immune cell that works to dampen immune and inflammatory responses.

“A continuous excess of Th17 cells caused by [ROR-gamma t] overexpression might potentiate these inhibitory systems,” and the production of anti-inflammatory molecules, the team wrote.

Future research using these genetically altered mice may help to clarify how IL-17A affects the brain, the researchers noted.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.
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Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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