A new Finnish-American study shows how the sympathetic nervous system participates in the regulation of neuroinflammation with help of immune system phagocytes. The transcription factor Nr4a1 was found to limit the production of norepinephrine in macrophages, thus reducing autoimmune neuroinflammation in an animal model of multiple sclerosis (MS). A lack of Nr4a1 led to enhanced norepinephrine production and worsening of the disease. The University of Eastern Finland contributed to the study, published online in Nature Immunology on 2 November.
The purpose of the inflammatory reaction is to protect the body against pathogens, among other things. However, inflammatory processes associated with autoimmune reactions can harm the body, as the immune system targets the body's own cells. Many brain-related diseases such as MS involve neuroinflammation.
Up until now, the molecular mechanisms linking the sympathetic nervous system and inflammation have been unknown. This new study now shows that the transcription factor Nr4a1 is a key regulator of norepinephrine, an important mediator of the sympathetic nervous system, in immune system macrophages. Nr4a1 prevented excessive production of norepinephrine and, in consequence, worsening of MS in an animal model. The effect was caused by the ability of Nr4a1 to regulate the production of tyrosine hydroxylase by recruiting the corepressor CoREST to the promoter of the gene in question. Tyrosine hydroxylase is an enzyme regulating norepinephrine levels in the body.
A lack of Nr4a1 in myeloid cells led to enhanced norepinephrine production, increased number of inflammatory leukocytes in the central nervous system, and worsening of the disease.
The study involved researchers from the La Jolla Institute for Allergy & Immunology, the University of Florida and the University of Washington in the US, McGill University in Canada, and the University of Eastern Finland. The main funders of the study are the Academy of Finland, the Sigrid Jusélius Foundation, Fondation Leducq, the La Jolla Institute for Allergy & Immunology, the American Heart Association, the Pacific Northwest Udall Center and the National Institutes of Health.
Source: University of Eastern Finland
- Academy Research Fellow Minna Kaikkonen, University of Eastern Finland, A.I. Virtanen Institute for Molecular Sciences, minna.kaikkonen(at)uef.fi, tel. +358 40 355 2413
- I Shaked, R N Hanna, H Shaked, G Chodaczek, H N Nowyhed, G Tweet, R Tacke, A B Basat, Z Mikulski, STogher, J Miller, A Blatchley, S Salek-Ardakani, M Darvas, M U Kaikkonen, G D Thomas, S Lai-Wing-Sun, A Rezk, A Bar-Or, C K Glass, H Bandukwala & C C Hedrick. Transcription factor Nr4a1 couples sympathetic and inflammatory cues in CNS-recruited macrophages to limit neuroinflammation. Nature Immunology, Advance Online Publication 2.11.2015. DOI: 10.1038/ni.3321.