title: Transcription factor Nr4a1 couples sympathetic and inflammatory cues in CNS-recruited macrophages to limit neuroinflammation.
abstract: 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.
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Iftach
authors.initials: I
authors.lastname: Shaked
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Hanna
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Helena
authors.initials: H
authors.lastname: Shaked
authors.affiliation: Microscopy Core, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Chodaczek
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Heba N
authors.initials: HN
authors.lastname: Nowyhed
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: George
authors.initials: G
authors.lastname: Tweet
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Tacke
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Alp Bugra
authors.initials: AB
authors.lastname: Basat
authors.affiliation: Microscopy Core, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Zbigniew
authors.identifier: http://orcid.org/0000-0002-1918-9216
authors.initials: Z
authors.lastname: Mikulski
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Togher
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Miller
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Blatchley
authors.affiliation: Department of Pathology, Immunology &Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.
authors.forename: Shahram
authors.initials: S
authors.lastname: Salek-Ardakani
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Darvas
authors.affiliation: Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Minna U
authors.initials: MU
authors.lastname: Kaikkonen
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Graham D
authors.initials: GD
authors.lastname: Thomas
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, Canada.
authors.forename: Sonia
authors.initials: S
authors.lastname: Lai-Wing-Sun
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, Canada.
authors.forename: Ayman
authors.initials: A
authors.lastname: Rezk
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, Canada.
authors.forename: Amit
authors.initials: A
authors.lastname: Bar-Or
authors.affiliation: Department of Cellular &Molecular Medicine, University of California San Diego, San Diego, California, USA.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Hozefa
authors.initials: H
authors.lastname: Bandukwala
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Hedrick
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D009638:Norepinephrine / Q000276:immunology / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013564:Sympathetic Nervous System / Q000276:immunology* / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D014446:Tyrosine 3-Monooxygenase; D009638:Norepinephrine