Transcription factor Nr4a1 couples sympathetic and inflammatory cues in CNS-recruited macrophages to limit neuroinflammation.
Shaked I, Hanna RN, Shaked H, Chodaczek G, Nowyhed HN, Tweet G, Tacke R, Basat AB, Mikulski Z, Togher S, Miller J, Blatchley A, Salek-Ardakani S, Darvas M, Kaikkonen MU, Thomas GD, Lai-Wing-Sun S, Rezk A, Bar-Or A, Glass CK, Bandukwala H, Hedrick CC.
Nat Immunol. 2015 Nov 2. doi: 10.1038/ni.3321. [Epub ahead of print]
The molecular mechanisms that link the sympathetic stress response and inflammation remain obscure. Here we found that the transcription factor Nr4a1 regulated the production of norepinephrine (NE)/adrenaline in macrophages and thereby limited experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Lack of Nr4a1 in macrophages led to enhanced NE production, accelerated infiltration of leucocytes into the central nervous system (CNS) and disease exacerbation in vivo. In contrast, macrophage-specific deletion of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, protected mice against EAE. Furthermore, we found that Nr4a1 repressed autocrine NE production in macrophages by recruiting the corepressor CoREST to the Th promoter. Our data reveal a new role for macrophages in neuroinflammation and identify Nr4a1 as a key regulator of catecholamine production by macrophages.
Catecholamines are water-soluble and are 50%-bound to plasma proteins in circulation. Included among catecholamines are: epinephrine (adrenaline), norepinephrine (noradrenaline) and dopamine; all of which are produced from phenylalanine and tyrosine. In this study they find that regulation of a transcription factor in macrophages limited their ability to be involved in neuroinflammation and their production of adrenaline. This is the hormone involved in the fight or flight response. Is this the link with stress you have been asking about?
A corepressor does not directly bind to DNA, but instead indirectly regulates gene expression by binding to repressors.The repressor in turn binds to a gene promoter (a sequence of DNAadjacent to the regulated gene), thereby blocking transcription of that gene.
Control group = abit of a limp tail…so according to Jaz “The only way is up”