Regulating Microglia Functions May Reduce Inflammation in Neurological Disorders

Targeting and activating immune checkpoints in immune cells called microglia could be a potential therapeutic strategy for neurodegenerative diseases, such as Alzheimer disease and amyotrophic lateral sclerosis (ALS), according to a new study.

The study, published in Nature Neuroscience, examines the effect of uncontrolled activity in microglia on neurodegeneration in several neurological disorders. The Massachusetts General Hospital (MGH) researchers indicated that the proposed strategy could reduce the inflammatory components of these diseases.

According to senior study author Joseph El Khoury, MD, of the MGH Center for Immunology and Inflammatory Diseases and the Division of Infectious Diseases, the 3 essential functions of microglia include:

• A “sentinel” function that surveys and senses changes within the brain.
• A “nurturer” function that promotes neuronal wellbeing through actions such as removing dying cells and debris.
• A “warrior” function that defends the brain against infection and toxins.

For the study, the researchers analyzed gene patterns to examine how the microglia carry out these functions and how disrupting them affects the progression of several neurodegenerative disorders. According to their findings, the researchers determined the potential role of microglia in diseases such as Alzheimer disease, Parkinson disease, and ALS, and identified 3 potential immune checkpoints that could be potential therapeutic targets.

“Analyzing patterns of microglial gene transcription and regulation in several disease states, understanding how those patterns may be altered by aging and disease progression, and correlating those changes to microglial behavior is essential,” Dr El Khoury said in a press release about the findings.

Although microglia initially have a neuroprotective role, specific stimuli or neuroinflammation can cause these cells to damage and kill neurons, the researchers reported. The study found that injury to neurons in several neurodegenerative diseases results from disruption of the “sentinel” and “nurturer” function and dysregulation of the defense function and neuroinflammation.

According to the researchers, immune checkpoints called Trem2, Cx3cr1, and progranulin pathways typically keep the microglial inflammatory response under control. However, dysregulation of these pathways can lead to progression of neurodegeneration and alter the course of disease.

In Alzheimer disease, the researchers wrote that microglia interaction is a “double-edged sword.” Persistent, damaging neuroinflammation is induced when microglia are unable to keep up with the production of amyloid-beta, further compromising the cells’ “nurturer” functions. Initially protective, the microglia progress into a dysfunction cell later in the disease, which ultimately becomes deleterious, the researchers wrote.

Additionally, the researchers propose that several genes with ALS-associated mutations regulate microglial host defense functions, including the production of ROS (mutant SOD1), cytokines, and phagocytosis. They noted that the findings suggest targeting microglia for potential ALS therapy should be tailored to the specific pathways affected.

“Initiation or exacerbation of neurodegeneration results form an imbalance between these microglial functions,” the researchers concluded. “Correcting such imbalances may be a potential mode for therapy.”

References

Hickman S, Izzy S, Sen P, et al. Microglia in neurodegeneration. Nature Neuroscience. 2018. https://www.nature.com/articles/s41593-018-0242-x#Sec37.

Regulating microglial activity may reduce damaging inflammation in neurodegenerative diseases [news release]. MGH’s website. https://www.massgeneral.org/about/pressrelease.aspx?id=2306. Accessed October 17, 2018.