Transcription factor Nr4a1 couples sympathetic and inflammatory cues in CNS-recruited macrophages to limit neuroinflammation

• Published in: Nature immunology Vol. 16; no. 12; pp. 1228 - 1234
• Main Authors: Shaked, Iftach, Hanna, Richard N, Shaked, Helena, Chodaczek, Grzegorz, Nowyhed, Heba N, Tweet, George, Tacke, Robert, Basat, Alp Bugra, Mikulski, Zbigniew, Togher, Susan, Miller, Jacqueline, Blatchley, Amy, Salek-Ardakani, Shahram, Darvas, Martin, Kaikkonen, Minna U, Thomas, Graham D, Lai-Wing-Sun, Sonia, Rezk, Ayman, Bar-Or, Amit, Glass, Christopher K, Bandukwala, Hozefa, Hedrick, Catherine C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2015; Nature Publishing Group
• Subjects: 13/31; 38/1; 38/77; 631/250/371; 631/250/38; 64/60; 692/699/249/1313/1666; Animals; Biomedicine; Biosynthesis; Cell Line; Cells, Cultured; Central nervous system; Central Nervous System - immunology; Central Nervous System - metabolism; Development and progression; Disease Models, Animal; Diseases; Encephalomyelitis; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Enzymes; Gene Expression - immunology; Genetic aspects; Humans; Hydroxylases; Immune response; Immunology; Infectious Diseases; Inflammation; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Macrophages; Macrophages - immunology; Macrophages - metabolism; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Confocal; Multiple sclerosis; Multiple Sclerosis - immunology; Multiple Sclerosis - pathology; Myeloid Cells - immunology; Myeloid Cells - metabolism; Noradrenaline; Norepinephrine - immunology; Norepinephrine - metabolism; Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics; Nuclear Receptor Subfamily 4, Group A, Member 1 - immunology; Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism; Phenols (Class of compounds); Physiological aspects; Properties; Rabbits; Reverse Transcriptase Polymerase Chain Reaction; Sympathetic Nervous System - immunology; Sympathetic Nervous System - metabolism; Transcription factors; Tyrosine; Tyrosine 3-Monooxygenase - genetics; Tyrosine 3-Monooxygenase - immunology; Tyrosine 3-Monooxygenase - metabolism
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.3321

Stress can induce expression of norepinephrine, which can enhance neuroinflammation. Shaked, Hedrick and colleagues show that the transcriptional repressor Nr4a1 limits this stress-induced response by suppressing expression of tyrosine hydroxylase required for the synthesis of norepinephrine. 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) in macrophages and thereby limited experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Lack of Nr4a1 in myeloid cells led to enhanced NE production, accelerated infiltration of leukocytes into the central nervous system (CNS) and disease exacerbation in vivo . In contrast, myeloid-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.