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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.

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Figure 1: High expression of Nr4a1 in myeloid cells in the CNS at the onset of EAE.
Figure 2: Loss of Nr4a1 leads to accelerated and exacerbated EAE.
Figure 3: Essential role for NE-producing macrophages in EAE.
Figure 4: Nr4a1 directly suppresses TH expression in macrophages.
Figure 5: Increased abundance of TH protein in monocytes of patients with MS.

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References

  1. Cosentino, M. & Marino, F. Adrenergic and dopaminergic modulation of immunity in multiple sclerosis: teaching old drugs new tricks? J. Neuroimmune Pharmacol. 8, 163–179 (2013).

    PubMed  Google Scholar 

  2. Gold, S.M. et al. The role of stress-response systems for the pathogenesis and progression of MS. Trends Immunol. 26, 644–652 (2005).

    CAS  PubMed  Google Scholar 

  3. Arima, Y. et al. Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier. Cell 148, 447–457 (2012).

    CAS  PubMed  Google Scholar 

  4. Brosnan, C.F. et al. Prazosin, an alpha 1-adrenergic receptor antagonist, suppresses experimental autoimmune encephalomyelitis in the Lewis rat. Proc. Natl. Acad. Sci. USA 82, 5915–5919 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Brosnan, C.F., Sacks, H.J., Goldschmidt, R.C., Goldmuntz, E.A. & Norton, W.T. Prazosin treatment during the effector stage of disease suppresses experimental autoimmune encephalomyelitis in the Lewis rat. J. Immunol. 137, 3451–3456 (1986).

    CAS  PubMed  Google Scholar 

  6. Dimitrijević, M. et al. Beta-adrenoceptor blockade ameliorates the clinical course of experimental allergic encephalomyelitis and diminishes its aggravation in adrenalectomized rats. Eur. J. Pharmacol. 577, 170–182 (2007).

    PubMed  Google Scholar 

  7. Maxwell, M.A. & Muscat, G.E. The NR4A subgroup: immediate early response genes with pleiotropic physiological roles. Nucl. Recept. Signal. 4, e002 (2006).

    PubMed  PubMed Central  Google Scholar 

  8. Campos-Melo, D. et al. Repeated immobilization stress increases nur77 expression in the bed nucleus of the stria terminalis. Neurotox. Res. 20, 289–300 (2011).

    CAS  PubMed  Google Scholar 

  9. Chan, R.K., Brown, E.R., Ericsson, A., Kovacs, K.J. & Sawchenko, P.E. A comparison of two immediate-early genes, c-fos and NGFI-B, as markers for functional activation in stress-related neuroendocrine circuitry. J. Neurosci. 13, 5126–5138 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Helbling, J.C., Minni, A.M., Pallet, V. & Moisan, M.P. Stress and glucocorticoid regulation of NR4A genes in mice. J. Neurosci. Res. 92, 825–834 (2014).

    CAS  PubMed  Google Scholar 

  11. Malkani, S. & Rosen, J.B. Induction of NGFI-B mRNA following contextual fear conditioning and its blockade by diazepam. Brain Res. Mol. Brain Res. 80, 153–165 (2000).

    CAS  PubMed  Google Scholar 

  12. Hamers, A.A. et al. Bone marrow-specific deficiency of nuclear receptor Nur77 enhances atherosclerosis. Circ. Res. 110, 428–438 (2012).

    CAS  PubMed  Google Scholar 

  13. Hanna, R.N. et al. NR4A1 (Nur77) deletion polarizes macrophages toward an inflammatory phenotype and increases atherosclerosis. Circ. Res. 110, 416–427 (2012).

    CAS  PubMed  Google Scholar 

  14. Carlin, L.M. et al. Nr4a1-dependent Ly6Clow monocytes monitor endothelial cells and orchestrate their disposal. Cell 153, 362–375 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Hanna, R.N. et al. The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C- monocytes. Nat. Immunol. 12, 778–785 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Moran, A.E. et al. T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J. Exp. Med. 208, 1279–1289 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Kaufman, S. Tyrosine hydroxylase. Adv. Enzymol. Relat. Areas Mol. Biol. 70, 103–220 (1995).

    CAS  PubMed  Google Scholar 

  18. Bettelli, E. et al. Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis. J. Exp. Med. 197, 1073–1081 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Sedgwick, J.D. et al. Isolation and direct characterization of resident microglial cells from the normal and inflamed central nervous system. Proc. Natl. Acad. Sci. USA 88, 7438–7442 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Gautier, E.L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118–1128 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Jakubzick, C. et al. Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity 39, 599–610 (2013).

    CAS  PubMed  Google Scholar 

  22. Lee, S.L. et al. Unimpaired thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B (Nur77). Science 269, 532–535 (1995).

    CAS  PubMed  Google Scholar 

  23. Ajami, B., Bennett, J.L., Krieger, C., McNagny, K.M. & Rossi, F.M. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat. Neurosci. 14, 1142–1149 (2011).

    CAS  PubMed  Google Scholar 

  24. Geissmann, F., Jung, S. & Littman, D.R. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82 (2003).

    CAS  PubMed  Google Scholar 

  25. Jung, S. et al. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol. Cell. Biol. 20, 4106–4114 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Saederup, N. et al. Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice. PLoS ONE 5, e13693 (2010).

    PubMed  PubMed Central  Google Scholar 

  27. Fan, Z. et al. In vivo tracking of 'color-coded' effector, natural and induced regulatory T cells in the allograft response. Nat. Med. 16, 718–722 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. King, I.L., Dickendesher, T.L. & Segal, B.M. Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. Blood 113, 3190–3197 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Mildner, A. et al. CCR2+Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain 132, 2487–2500 (2009).

    PubMed  Google Scholar 

  30. Yamasaki, R. et al. Differential roles of microglia and monocytes in the inflamed central nervous system. J. Exp. Med. 211, 1533–1549 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Aloisi, F. Immune function of microglia. Glia 36, 165–179 (2001).

    CAS  PubMed  Google Scholar 

  32. Gilbert, F. et al. Nur77 gene knockout alters dopamine neuron biochemical activity and dopamine turnover. Biol. Psychiatry 60, 538–547 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Hnasko, T.S. et al. Cre recombinase-mediated restoration of nigrostriatal dopamine in dopamine-deficient mice reverses hypophagia and bradykinesia. Proc. Natl. Acad. Sci. USA 103, 8858–8863 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Nguyen, K.D. et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480, 104–108 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Brown, S.W. et al. Catecholamines in a macrophage cell line. J. Neuroimmunol. 135, 47–55 (2003).

    CAS  PubMed  Google Scholar 

  37. He, X.B. et al. Prolonged membrane depolarization enhances midbrain dopamine neuron differentiation via epigenetic histone modifications. Stem Cells 29, 1861–1873 (2011).

    CAS  PubMed  Google Scholar 

  38. Sakurada, K., Ohshima-Sakurada, M., Palmer, T.D. & Gage, F.H. Nurr1, an orphan nuclear receptor, is a transcriptional activator of endogenous tyrosine hydroxylase in neural progenitor cells derived from the adult brain. Development 126, 4017–4026 (1999).

    CAS  PubMed  Google Scholar 

  39. Yi, S.H. et al. Foxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulation. Development 141, 761–772 (2014).

    CAS  PubMed  Google Scholar 

  40. Andrés, M.E. et al. CoREST: a functional corepressor required for regulation of neural-specific gene expression. Proc. Natl. Acad. Sci. USA 96, 9873–9878 (1999).

    PubMed  PubMed Central  Google Scholar 

  41. Ballas, N. et al. Regulation of neuronal traits by a novel transcriptional complex. Neuron 31, 353–365 (2001).

    CAS  PubMed  Google Scholar 

  42. Nowyhed, H.N. et al. The nuclear receptor nr4a1 controls CD8 T cell development through transcriptional suppression of runx3. Sci. Rep. 5, 9059 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Palumbo-Zerr, K. et al. Orphan nuclear receptor NR4A1 regulates transforming growth factor-beta signaling and fibrosis. Nat. Med. 21, 150–158 (2015).

    CAS  PubMed  Google Scholar 

  44. Gaskill, P.J., Carvallo, L., Eugenin, E.A. & Berman, J.W. Characterization and function of the human macrophage dopaminergic system: implications for CNS disease and drug abuse. J. Neuroinflammation 9, 203 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Qiu, Y. et al. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157, 1292–1308 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Claudio, L. & Brosnan, C.F. Effects of prazosin on the blood-brain barrier during experimental autoimmune encephalomyelitis. Brain Res. 594, 233–243 (1992).

    CAS  PubMed  Google Scholar 

  47. Goldmuntz, E.A., Brosnan, C.F. & Norton, W.T. Prazosin treatment suppresses increased vascular permeability in both acute and passively transferred experimental autoimmune encephalomyelitis in the Lewis rat. J. Immunol. 137, 3444–3450 (1986).

    CAS  PubMed  Google Scholar 

  48. Flierl, M.A. et al. Phagocyte-derived catecholamines enhance acute inflammatory injury. Nature 449, 721–725 (2007).

    CAS  PubMed  Google Scholar 

  49. Li, L. et al. Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation. Nat. Chem. Biol. 11, 339–346 (2015).

    CAS  PubMed  Google Scholar 

  50. McMorrow, J.P. & Murphy, E.P. Inflammation: a role for NR4A orphan nuclear receptors? Biochem. Soc. Trans. 39, 688–693 (2011).

    CAS  PubMed  Google Scholar 

  51. Saijo, K. et al. A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137, 47–59 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Achiron, A., Feldman, A. & Gurevich, M. Characterization of multiple sclerosis traits: nuclear receptors (NR) impaired apoptosis pathway and the role of 1-alpha 25-dihydroxyvitamin D3. J. Neurol. Sci. 311, 9–14 (2011).

    CAS  PubMed  Google Scholar 

  53. Achiron, A. et al. Microarray analysis identifies altered regulation of nuclear receptor family members in the pre-disease state of multiple sclerosis. Neurobiol. Dis. 38, 201–209 (2010).

    CAS  PubMed  Google Scholar 

  54. Riol-Blanco, L. et al. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature 510, 157–161 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Sekiya, T. et al. The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells. Nat. Commun. 2, 269 (2011).

    PubMed  Google Scholar 

  56. Jackson, C.R. et al. Retinal dopamine mediates multiple dimensions of light-adapted vision. J. Neurosci. 32, 9359–9368 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Bandukwala, H.S. et al. Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors. Proc. Natl. Acad. Sci. USA 109, 14532–14537 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Shaked, H. et al. Chronic epithelial NF-κB activation accelerates APC loss and intestinal tumor initiation through iNOS up-regulation. Proc. Natl. Acad. Sci. USA 109, 14007–14012 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Davalos, D. et al. Stable in vivo imaging of densely populated glia, axons and blood vessels in the mouse spinal cord using two-photon microscopy. J. Neurosci. Methods 169, 1–7 (2008).

    PubMed  Google Scholar 

  60. Farrar, M.J. et al. Chronic in vivo imaging in the mouse spinal cord using an implanted chamber. Nat. Methods 9, 297–302 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Thornton, E.E., Krummel, M.F. & Looney, M.R. Live imaging of the lung. Curr. Protoc. Cytom. 60, 12.28.1–12.28.12 (2012).

    Google Scholar 

  62. Baxter, C.S., Andringa, A., Chalfin, K . & Miller, M.L. Effect of tumor-promoting agents on density and morphometric parameters of mouse epidermal Langerhans and Thy-1+ cells. Carcinogenesis 12, 1017–1021 (1991).

    CAS  PubMed  Google Scholar 

  63. Wallace, K.L. & Linden, J. Adenosine A2A receptors induced on iNKT and NK cells reduce pulmonary inflammation and injury in mice with sickle cell disease. Blood 116, 5010–5020 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank D. Metzger (Institut Génétique Biologie Moléculaire Cellulaire) and H. Ichinose (Tokyo Institute of Technology) for Nr4a1fl/fl mice; K. Ley for discussions; A. Rao for guidance in composing the manuscript; A. Crotti for guidance on microglia culture; and D. Yoakum for assistance with mouse colony management. Supported by the American Heart Association (13SDG17060117 to I.S. and 12SDG12070005 to R.N.H.), the La Jolla Institute Board of Directors (R.N.H.), Fondation Leducq (M.U.K.), the Sigrid Juselius Foundation (M.U.K.), the Academy of Finland (M.U.K.), the Pacific Northwest Udall Center (P50-NS062684 to M.D.) and the US National Institutes of Health (R01 DK091183-21 to C.K.G. and R01 HL118765 to C.C.H.).

Author information

Authors and Affiliations

Authors

Contributions

I.S., R.N.H. and H.S. designed, performed and analyzed the experiments; G.C., H.N.N. and R.T. designed and preformed the experiments; G.T., R.T., A.B.B., Z.M., S.T., J.M., A.B., M.U.K., S.L.-W.-S. and A.R. performed the experiments; S.S.-A., M.D., G.D.T., A.B.-O., C.K.G., H.B. and C.C.H. designed the experiments; and I.S., R.N.H., H.S. and C.C.H. wrote the manuscript.

Corresponding authors

Correspondence to Iftach Shaked or Catherine C Hedrick.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 EAE induction.

(a) Schematic of autoreactive 2D2 T cell stimulation, adoptive transfer and EAE disease induction in WT and Nr4a1–/– mice. (b) Flow cytometry analysis of TNFα and IFN-γ production in expanded and stimulated autoreactive 2D2 T cells prior to transfer. (c) CD64 and MerTK expression on macrophages and monocytes gated as in Main Fig. 1b.

Supplementary Figure 2 Loss of Nr4a1 leads to accelerated and exacerbated EAE.

(a) EAE progression following transfer of 0.5, 1 or 2 million autoreactive 2D2 T cells. Note that regardless of the number of injected cells, all mice eventually develop disease while Nr4a1–/– mice develop accelerated and worsened disease compared to their WT counterparts. p<0.01, p<0.001, p<0.001, respectively. (b) EAE progression following transfer of 1 million 2D2 T cells, monitored till the end point; note that WT mice eventually exhibit full disease progression, but in a significantly longer time compared to Nr4a1–/– mice. p<0.001. (c) Change in body mass percentage in WT and Nr4a1–/– mice with EAE progression following transfer of 0.5, 1 or 2 million 2D2 T cells. p<0.01, p<0.05, p<0.01, respectively. (d) EAE disease progression in WT and Nr4a1–/– mice after active immunization with MOG in complete Freund’s adjuvant. p<0.001. (e) Change in body mass percentage following (left) transfer of 1 million 2D2 cells into Nr4a1fl/fl (WT) or LysM-Cre;Nr4a1fl/fl (Nr4a1ΔLysM) and (right) transfer of 0.5 million 2D2 cells into Nr4a1fl/fl (WT) or Csfr-Cre;Nr4a1fl/fl (Nr4a1ΔCsfr) recipients. p<0.05, p<0.001, respectively. (f) One million 2D2 cells derived on Nr4a1–/– or WT backgrounds were transferred into WT mice and disease progression was scored. p>0.05. Two way-ANOVA test; error bars, s.e.m. (n = 5/group in each experiment).

Supplementary Figure 3 Infiltration of monocytes and their Nr4a1 expression by subset.

(a) Numbers of Ly6C+ and Ly6C monocyte subsets isolated from diseased CNS, gated from the total number of infiltrating monocyte as described in Main Fig. 2e. (b) Nr4a1-GFP expression in monocyte subsets isolated from diseased CNS, as described in Main Fig. 1b.

Supplementary Figure 4 Early T cell infiltration, but similar blood-brain-barrier permeability, in Nr4a1–/– mice.

(a-b) Quantification of 2D2 T cell infiltration on day 4 (a) or 7 (b), as described in Main Fig. 2f. (c) Evans Blue concentration in the brain following i.v. injection; 3 mice in each group; unpaired Student’s t-test (p>0.05); error bars, s.e.m.

Supplementary Figure 5 Early microglial activation in Nr4a1–/– mice at the induction of EAE.

(a) Quantification of microglia dendricity (top) as a measure of microglia activation; representative images (bottom) on day 7 of disease onset as described in Main Fig. 2f. (b-c) A representative flow cytometry plot (b), and quantification (c) of MHC class II and CD44 expression in microglia analyzed by flow cytometry upon EAE onset. Four mice per group were analyzed.

Supplementary Figure 6 Greater infiltration of 2D2 T cells and microglial activation in the brain of Nr4a1–/– mice than in Nr4a1+/+ mice at 7 d after transfer.

Confocal imaging of DsRed 2D2 T cell infiltrate (red), Cx3cr1-GFP+ microglia/ monocytes (green) and vasculature (blue) in the brain (cerebral cortex) of WT and Nr4a1–/– mice 7 days after the transfer of 1 million 2D2 T cell transfer.

Supplementary Figure 7 NE-producing macrophages have an essential role in EAE.

(a,b) The β1 (atenolol) (a) and the β2 (butaxamine) (b) blockers were administered (250 μg i.p. twice a day) and compared to untreated (UN) WT or Nr4a1–/– mice after the transfer of 1 million 2D2 cells; EAE was scored over 12 days (n = 5/group). (c) TH mRNA in BMM from WT or DDfs mice. Expression relative to WT is shown. (d) To confirm TH deletion in ThΔLysM mice, the cells were freshly isolated from the CNS at day 15 post EAE induction and analyzed via flow cytometry; 3 animals were analyzed in each group; gating scheme as in Fig. 1b (middle lower panel). (e) NE blood concentration in WT and ThΔLysM mice at day 15 post EAE induction, 3 animals in each group. *** p<0.001, ** p<0.01, * p<0.05 (unpaired Student’s t-test and 2-way Anova test); error bars, s.e.m.

Supplementary Figure 8 Nr4a1 is a negative regulator of TH in vitro.

(a) Nr4a1 mRNA expression in BMM following treatment with IFN-γ or with NE. (b, c) Flow cytometry of BMM shows Nr4a1-GFP induction following IFN-γ (b) or NE (c) treatment. A representative of 2 experiments is shown. (d) NE concentration in the conditioned media of BMM, untreated (CTL) or treated with IFN-γ, with or without 100 μM AMPT, a TH inhibitor, or 100 μM 6-OHDA, a toxin inducing chemical sympathectomy, analyzed by ELISA, 4 replicates in each group. (e) TH-luciferase reporter assay in macrophages. RAW or BMM cells were transfected with β-gal construct and TH-luciferase reporter construct; luciferase activity was measured and normalized to β-gal activity and to the activity in cells without IFN-γ treatment. BMM were derived from WT or Nr4a1–/– mice. RAW cells were transfected with either control or Nr4a1 siRNA. Three replicates in each group, a representative of 2 experiments shown. *** p<0.001, ** p<0.01, * p<0.05 (unpaired Student’s t-test and 2-way Anova test); error bars, s.e.m.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 (PDF 1427 kb)

Autoreactive T cell infiltration into CNS

Two million DsRed-2D2 T cells were transferred into WT and Nr4a1–/– mice on CX3CR1-GFP background, and Ly6G-APC was injected just before imaging to visualize neutrophils and blood vessels (blue). The imaging was performed in the naïve animal. Representative results of three separate experiments are showing in vivo confocal imaging of the spinal cord adjacent to the posterior spinal vein (PSV). (MOV 25393 kb)

Autoreactive T cell infiltration into CNS

Two million DsRed-2D2 T cells were transferred into WT and Nr4a1–/– mice on CX3CR1-GFP background, and Ly6G-APC was injected just before imaging to visualize neutrophils and blood vessels (blue). The imaging was performed in the animal at score 1.5 (limp tail) o Representative results of three separate experiments are showing in vivo confocal imaging of the spinal cord adjacent to the posterior spinal vein (PSV).f the EAE. (MOV 15293 kb)

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Shaked, I., Hanna, R., Shaked, H. et al. Transcription factor Nr4a1 couples sympathetic and inflammatory cues in CNS-recruited macrophages to limit neuroinflammation. Nat Immunol 16, 1228–1234 (2015). https://doi.org/10.1038/ni.3321

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