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Inhibition of transcription factor NF-κB in the central nervous system ameliorates autoimmune encephalomyelitis in mice

Abstract

Activation of transcription factor NF-κB in the central nervous system (CNS) has been linked to autoimmune demyelinating disease; however, it remains unclear whether its function is protective or pathogenic. Here we show that CNS-restricted ablation of 'upstream' NF-κB activators NEMO or IKK2 but not IKK1 ameliorated disease pathology in a mouse model of multiple sclerosis, suggesting that 'canonical' NF-κB activation in cells of the CNS has a mainly pathogenic function in autoimmune demyelinating disease. NF-κB inhibition prevented the expression of proinflammatory cytokines, chemokines and the adhesion molecule VCAM-1 from CNS-resident cells. Thus, NF-κB-dependent gene expression in non–microglial cells of the CNS provides a permissive proinflammatory milieu that is critical for CNS inflammation and tissue damage in autoimmune demyelinating disease.

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Figure 1: CNS-restricted ablation of NEMO and IKK2 but not of IKK1 ameliorates EAE.
Figure 2: Impaired infiltration of inflammatory cells into the CNS of NEMOCNS-KO mice.
Figure 3: Ablation of NEMO in the CNS inhibits the expression of proinflammatory mediators during EAE.
Figure 4: Impaired VCAM-1 induction in astrocytes in the CNS of NEMOCNS-KO mice with EAE at 14 d after immunization with MOG(35–55).
Figure 5: Primary astrocytes but not microglia from NEMOCNS-KO mice show impaired NF-κB activation and proinflammatory gene expression.

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Acknowledgements

We thank W. Brück for scientific discussions; R. Klein for Nes-Cre mice; and O. Kowatsch and S. Zischkau for technical assistance. Supported by the European Molecular Biology Laboratory, European Union (QLG1-CT-1999-00202, LSHG-CT-2005-005203 and MRTN-CT-2004-005632 to M.P.), Gemeinnützige Hertie-Stiftung (M.R.P. and M.P.), Deutsche Forschungsgemeinschaft and Deutsche Forschungsgemeinschaft Research Center for Molecular Physiology of the Brain (M.R.P.), Gertrud-Reemtsma-Stiftung (H.S.) and a Marie Curie Fellowship (FP6-EIF-LIF-2002-Mobility 5 to G.v.L.).

Author information

Authors and Affiliations

Authors

Contributions

G.v.L. in collaboration with R.D.L., H.S. and A.M. did all the experiments; M.H., M.S.-S. and M.P. generated the loxP-flanked IKK mouse lines; H.S., A.M., H.L. and M.R.P. did the immunohistopathological analysis; G.v.L., M.R.P. and M.P. wrote the paper; and M.P. was responsible for planning and supervising the project.

Note: Supplementary information is available on the Nature Immunology website.

Corresponding author

Correspondence to Manolis Pasparakis.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Tissue specificity of NEMO inactivation. (PDF 1080 kb)

Supplementary Fig. 2

Maximal clinical scores of all individual NEMOCNS-KO, IKK2CNS-KO and IKK1CNS-KO mice and their respective wild-type control mice during the course of the disease as shown in Fig. 1 b-d. (PDF 441 kb)

Supplementary Fig. 3

No clinical differences between Nes-Cre transgenic mice (n=9) and transgene negative (WT) littermates (n=9) after EAE induction (PDF 425 kb)

Supplementary Fig. 4

Histological profiles of spinal cords from wild-type, NEMOCNS-KO, IKK2CNS-KO and IKK1CNS-KO mice 25 days after EAE induction. (PDF 2891 kb)

Supplementary Fig. 5

Perivascular and parenchymal distribution of CD3-positive T cells in the CNS of MOG-immunized wild-type (n=6) and NEMOCNS-KO (n=6) mice. (PDF 383 kb)

Supplementary Fig. 6

Deletion of NEMO in the CNS does not affect the peripheral T cell response of mice to MOG peptide. (PDF 432 kb)

Supplementary Fig. 7

Impaired NF-κB activation in primary astrocytes, but normal NF-κB activation in primary microglial cells from NEMOCNS-KO mice. (PDF 758 kb)

Supplementary Fig. 8

IFN-γ-induced expression of C2ta (a) and IL-1β-induced expression of Tgfb1 (b) in primary astrocytes from NEMOCNS-KO (KO) or wild-type (WT) mice. (PDF 422 kb)

Supplementary Table 1

Primer-sequences used for quantitative real-time PCR. (PDF 38 kb)

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van Loo, G., De Lorenzi, R., Schmidt, H. et al. Inhibition of transcription factor NF-κB in the central nervous system ameliorates autoimmune encephalomyelitis in mice. Nat Immunol 7, 954–961 (2006). https://doi.org/10.1038/ni1372

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