Nr4a1: Is it the Link Between Stress & MS?

The Background

Many studies have highlighted a link between stress and multiple sclerosis (MS), including research that has shown that norepinephrine (a regulator of stress) is implicated in the mouse model of MS (EAE).  However, the mechanism behind how stress may be linked to neuroinflammation is unclear.

One particular protein that provides an interesting target for research is a transcription factor known as Nr4a1.  Transcription factors are proteins that bind to DNA and help regulate the expression of other genes.  Nr4a1 has been shown to have a role in both the stress response and the immune system, thus making it potentially important in the link between the two.

The Study

The role of Nr4a1 was analysed in a recent publication in Nature Immunology from collaborators at the La Jolla Institute for Allergy and Immunology (pictured), The University of Florida, The University of Washington, The University of Eastern Finland, McGill University and The University of California San Diego.  To determine the role that Nr4a1 might play in MS, the researchers used an EAE model.  The mice were divided into two groups – those with Nr4a1 and those which were lacking that protein.  The researchers then looked at various aspects of the disease, including:

• The effect on EAE disease severity
• Where the protein was expressed
• Which cells were expressing it
• How it was linked to norepinephrine

The Findings

It was found that removing Nr4a1 from mice led to an acceleration and worsening of the disease, which indicated that this protein might have a protective effect in MS.  The protein was found to be expressed in macrophages and monocytes (collectively termed myeloid cells), as well as T cells.  When the protein was deleted specifically from the T cells, no change in disease severity was observed.  This suggested that the protective effect is due to the expression in myeloid cells. The worsening of disease was linked to increased levels of norepinephrine and interleukin-6, a cytokine that is involved in the recruitment of T cells to the Central Nervous System (CNS).   It was also found that blocking norepinephrine could reduce the disease progression in the mice.

The Outcomes

This study provides a possible mechanism for neurological and immunological communication, which may explain why stress has been linked to MS.  Other studies have shown that Nr4a1 is decreased in immune cells in MS patients before the onset of disease, which supports the findings of this article.  Further studies should be done to confirm this association in people with MS.  This has potential to provide a novel avenue for treatment of MS via the manipulation of the amount or activity of NR4a1.

Learn More

The abstract for this article can be viewed here.