Transcription factor Nr4a1 couples sympathetic and inflammatory cues in CNS-recruited macrophages to limit neuroinflammation
| Autor: | Robert Tacke, Grzegorz Chodaczek, Shahram Salek-Ardakani, Helena Shaked, Amit Bar-Or, Minna U. Kaikkonen, Catherine C. Hedrick, Susan Togher, George Tweet, Alp Bugra Basat, Ayman Rezk, Christopher K. Glass, Graham D. Thomas, Amy Blatchley, Richard N. Hanna, Zbigniew Mikulski, Hozefa S. Bandukwala, Martin Darvas, Sonia Lai-Wing-Sun, Jacqueline Miller, Iftach Shaked, Heba Nowyhed |
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| Rok vydání: | 2015 |
| Předmět: |
Central Nervous System
Encephalomyelitis Autoimmune Experimental Multiple Sclerosis Sympathetic Nervous System Tyrosine 3-Monooxygenase Immunology Gene Expression Inflammation Biology Article Cell Line Norepinephrine medicine Nuclear Receptor Subfamily 4 Group A Member 1 Immunology and Allergy Animals Humans Myeloid Cells Transcription factor Neuroinflammation Cells Cultured Mice Knockout Microscopy Confocal Tyrosine hydroxylase Reverse Transcriptase Polymerase Chain Reaction Macrophages Experimental autoimmune encephalomyelitis medicine.disease Mice Inbred C57BL Disease Models Animal Neuroimmunology Catecholamine Rabbits medicine.symptom Corepressor medicine.drug |
| Zdroj: | Nature immunology. 16(12) |
| ISSN: | 1529-2916 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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