Researchers find molecular trigger for brain inflammation

April 27, 2017 by Mark Derewicz
Researchers find molecular trigger for brain inflammation
The green represents glial fibrillary acidic proteins in a mouse astrocyte. Credit: Ting Lab

Brain inflammation is a key component of multiple sclerosis, Alzheimer's, Parkinson's, ALS, and most other major neurodegenerative diseases. How inflammation starts, how it's sustained, and how it contributes to these diseases is not well understood, but scientists from the University of North Carolina School of Medicine have just found some important clues.

In a study published in the Journal of Experimental Medicine, UNC researchers led by Jenny Ting, PhD, the William R. Kenan Distinguished Professor of Genetics, identified key molecules that drive brain in a mouse model of multiple sclerosis – molecules that are present at abnormally high levels in the brains of humans with the disease.

The findings show that these inflammatory molecules are ripe targets for further study and potential targets for future multiple sclerosis treatments. The research may also lead to a better understanding of Alzheimer's, , stroke and other diseases that involve neuroinflammation.

"We need to better understand brain inflammation at the molecular level in order to treat neurodegenerative conditions," said Ting, who is also a member of the UNC Lineberger Comprehensive Cancer Center. "Our study shows how two proteins that control inflammation are crucial to a particular kind of brain inflammation."

The study began as an investigation of LPC (lysophosphatidylcholine), a fat-related signaling molecule that researchers have suspected stokes harmful brain inflammation in multiple sclerosis and other central nervous system diseases.

In initial experiments, study co-lead authors – UNC postdoctoral researcher Haitao Guo, PhD, graduate student Leslie Freeman, and former graduate student Sushmita Jha, PhD (now an assistant professor at the Indian Institute of Technology Jodhpur) – found evidence that LPC triggers the inflammatory activation of mouse immune cells through two proteins called NLRP3 and NLRC4.

NLRP3 and NLRC4 are components of the so-called innate immune system – a network of infection-fighting molecules and cells evolutionarily older than the better-known adaptive immune system's T-cells, B-cells, and antibodies. Like other NLR-family proteins, NLRP3 and NLRC4 appear to have evolved to detect molecular patterns associated with certain microbes. The two proteins trigger inflammation in response to these microbes.

There is evidence, too, that NLR-family proteins can trigger inflammation in response to non-microbial signals related to tissue damage. LPC is suspected to be one such kind of signal, and it is this sort of non-microbial tissue inflammation that researchers think is involved in neurodegenerative diseases.

In previous studies, NLRP3 was shown to be a factor in brain inflammation in multiple sclerosis and Alzheimer's disease. But no one had reported a brain inflammation role for NLRC4 in neurodegenerative diseases involving animal models.

To investigate that possibility, Freeman, Guo, and Jha examined mouse astrocytes and microglia – resident brain cells that can perform immune functions in the nervous system. These cells are usually the main sources of inflammation in . Ting's team found that LPC could induce an inflammatory response in these brain cells, as well, in a way dependent on NLRP3 and NLRC4.

The researchers then worked with a mouse model of multiple sclerosis. They used a chemical called cuprizone to induce . This chemical also helped them strip the fatty layer surrounding nerve fibers. They found that the usual inflammatory activation of astrocytes and microglia, along with the stripping of nerve fibers, was greatly reduced when the mice lacked the genes for both NLRP3 and NLRC4.

"Essentially, we saw a profound reduction of the inflammatory disease in these mice," Guo said. "And where just one of those genes was absent, we didn't see as pronounced a reduction of inflammation."

Underscoring the likely clinical relevance of these findings, the group found high levels of NLRC4 in astrocytes and microglia from the brain-inflamed mice, as well as in biopsied brain tissue from patients. Affected mouse and human tissue also showed abnormally high levels of an LPC cell receptor protein called G2A.

"This is direct evidence of the importance of NLRC4 and NLRP3 in astrocytic and microglial inflammation, and we showed that this damage-associated molecule called LPC triggers the inflammation," said Guo.

Explore further: Researchers identify how inflammation spreads through the brain after injury

More information: Leslie Freeman et al. NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes, The Journal of Experimental Medicine (2017). DOI: 10.1084/jem.20150237

Related Stories

Researchers identify how inflammation spreads through the brain after injury

March 8, 2017
Researchers have identified a new mechanism by which inflammation can spread throughout the brain after injury. This mechanism may explain the widespread and long-lasting inflammation that occurs after traumatic brain injury, ...

Scientists make surprising finding in stroke research

March 16, 2015
Scientists at The University of Manchester have made an important new discovery about the brain's immune system that could lead to potential new treatments for stroke and other related conditions.

The brain may show signs of aging earlier than old age

March 18, 2016
A new study published in Physiological Genomics suggests that the brain shows signs of aging earlier than old age. The study found that the microglia cells—the immune cells of the brain—in middle-aged mice already showed ...

The Japanese traditional therapy, honokiol, blocks key protein in inflammatory brain damage

March 19, 2012
Microglia are the first line defence of the brain and are constantly looking for infections to fight off. Overactive microglia can cause uncontrolled inflammation within the brain, which can in turn lead to neuronal damage. ...

Experimental drug shows promise in treating Alzheimer's disease

October 25, 2016
An experimental drug shows promise in treating Alzheimer's disease by preventing inflammation and removing abnormal protein clumps in the brain that are associated with the disease, suggests a study in mice presented at the ...

Exploring the gut-brain connection for insights into multiple sclerosis

May 9, 2016
New research by investigators at Brigham and Women's Hospital (BWH) suggests that bacteria living in the gut may remotely influence the activity of cells in the brain that are involved in controlling inflammation and neurodegeneration. ...

Recommended for you

New insights into protein's role in inflammatory response

July 28, 2017
A protein called POP2 inhibits a key inflammatory pathway, calming the body's inflammatory response before it can become destructive, Northwestern Medicine scientists have demonstrated in mouse models.

Targeting 'broken' metabolism in immune cells reduces inflammatory disease

July 12, 2017
The team, led by researchers at Imperial College London, Queen Mary University of London and Ergon Pharmaceuticals, believes the approach could offer new hope in the treatment of inflammatory conditions like arthritis, autoimmune ...

A perturbed skin microbiome can be 'contagious' and promote inflammation, study finds

June 29, 2017
Even in healthy individuals, the skin plays host to a menagerie of bacteria, fungi and viruses. Growing scientific evidence suggests that this lively community, collectively known as the skin microbiome, serves an important ...

Inflammatory bowel disease: Scientists zoom in on genetic culprits

June 28, 2017
Scientists have closed in on specific genes responsible for Inflammatory Bowel Disease (IBD) from a list of over 600 genes that were suspects for the disease. The team from the Wellcome Trust Sanger Institute and their collaborators ...

Trials show unique stem cells a potential asthma treatment

June 28, 2017
A study led by scientists at Monash University has shown that a new therapy developed through stem cell technology holds promise as a treatment for chronic asthma.

Researchers find piece in inflammatory disease puzzle

May 23, 2017
Inflammation is the process by which the body responds to injury or infection but when this process becomes out of control it can cause disease. Monash Biomedicine Discovery Institute (BDI) researchers, in collaboration with ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.