Acta Neuropathologica

, Volume 126, Issue 5, pp 711–724 | Cite as

Astrocytic A20 ameliorates experimental autoimmune encephalomyelitis by inhibiting NF-κB- and STAT1-dependent chemokine production in astrocytes

  • Xu Wang
  • Martina Deckert
  • Nguyen Thi Xuan
  • Gopala Nishanth
  • Sissy Just
  • Ari Waisman
  • Michael Naumann
  • Dirk Schlüter
Original Paper


Single-nucleotide polymorphisms in the tumor necrosis factor, alpha-induced protein 3 gene, which encodes the ubiquitin-modifying protein A20, are linked to susceptibility to multiple sclerosis (MS), a demyelinating autoimmune disease of the central nervous system (CNS). Since it is unresolved how A20 regulates MS pathogenesis, we examined its function in a murine model of MS, namely experimental autoimmune encephalomyelitis (EAE). Deletion of A20 in neuroectodermal cells (astrocytes, neurons, and oligodendrocytes; Nestin-Cre A20fl/fl mice) or selectively in astrocytes (GFAP-Cre A20fl/fl mice) resulted in more severe EAE as compared to control animals. In Nestin-Cre A20fl/fl and GFAP-Cre A20fl/fl mice demyelination and recruitment of inflammatory leukocytes were increased as compared to A20fl/fl control mice. Importantly, numbers of encephalitogenic CD4+ T cells producing interferon (IFN)-γ, interleukin (IL)-17, and granulocyte–macrophage colony-stimulating factor (GM-CSF), respectively, as well as mRNA production of IFN-γ, IL-17, tumor necrosis factor (TNF), GM-CSF, IL-6, CXCL1, CCL2, and CXCL10 were significantly increased in spinal cords of Nestin-Cre A20fl/fl and GFAP-Cre A20fl/fl mice, respectively. Compared to A20-sufficient astrocytes, A20-deficient astrocytes displayed stronger activation of nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) in response to TNF, IL-17, and GM-CSF, and of signal transducer and activator of transcription 1 (STAT1) upon IFN-γ stimulation. Due to NF-κB and STAT1 hyperactivation, A20-deficient astrocytes produced significantly more chemokines in response to these key encephalitogenic cytokines of autoimmune CD4+ T cells resulting in an amplification of CD4+ T cell recruitment to the CNS. Thus, astrocytic A20 is an important inhibitor of autoimmune-mediated demyelination in the CNS.


A20 Astrocytes Autoimmunity EAE 



The authors thank Elena Fischer, Nadja Schlüter, and Annette Sohnekind for technical assistance. This work was supported by grants of the Deutsche Forschungsgemeinschaft (GRK 1167 to DS; SFB 854/TP5 to DS and MN).

Supplementary material

401_2013_1183_MOESM1_ESM.tif (118 kb)
Online Resource 1 Upregulation of A20 in the spinal cord during EAE mRNA transcription of A20 in the spinal cord was evaluated by quantitative RT-PCR in untreated and MOG35-55-immunized C57BL/6 mice at day 15 and 22 p.i (n = 3). Data are expressed as the increase of A20 mRNA of immunized over unimmunized mice normalized to HPRT (mean + SEM * p < 0.05) (TIFF 118 kb)
401_2013_1183_MOESM2_ESM.tif (195 kb)
Online Resource 2 EAE was not aggravated in Nestin-Cre A20wt/wt mice Clinical scores of Nestin-Cre A20wt/wt (n = 12) and A20wt/wt (n = 11) mice after active immunization with MOG35-55 peptide. Data show the mean clinical scores + SEM (TIFF 195 kb)
401_2013_1183_MOESM3_ESM.tif (1013 kb)
Online Resource 3 EAE was not aggravated in GFAP-Cre A20wt/wt mice and Synapsin-Cre A20fl/fl mice a WB analysis for A20 expression in FACS-sorted microglia and cultured neurons from GFAP-Cre A20fl/fl and A20fl/fl mice. b Clinical scores of EAE in GFAP-Cre A20wt/wt (n = 5) and A20wt/wt (n = 5) mice induced by MOG35-55-immunization. Data show the mean clinical scores + SEM. c WB analysis for A20 expression in cultured neurons from neuron-restricted A20 deficient (Synapsin-Cre A20fl/fl) and control (A20fl/fl) mice. The right panel shows the relative quantification of A20 normalized to GAPDH. Data show the mean + SEM. d Clinical scores of EAE in Synapsin-Cre A20fl/fl (n = 8) and A20fl/fl (n = 6) mice induced by MOG35-55-immunization. Data show the mean clinical scores + SEM (TIFF 1013 kb)
401_2013_1183_MOESM4_ESM.tif (583 kb)
Online Resource 4 Normal apoptosis of A20-deficient and -sufficient astrocytes after TNF stimulation Astrocytes isolated from GFAP-Cre A20fl/fl and A20fl/fl mice were treated with 20 or 100 ng/ml TNF, respectively, for 24 h. Apoptosis was detected by PI and Annexin staining (TIFF 583 kb)
401_2013_1183_MOESM5_ESM.tif (246 kb)
Online Resource 5 STAT1 expression was upregulated in astrocytes after A20 siRNA treatment a Astrocytes derived from C57BL/6 mice were transfected with siRNA targeting A20 or nonsense siRNA. Sixty hours later, WB analysis was performed on total cell lysates for A20, STAT1 and GAPDH. b Relative quantification of A20 normalized to GAPDH. Data show the mean + SEM. c Relative quantification of STAT1 normalized to GAPDH. Data show the mean + SEM (TIFF 246 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Xu Wang
    • 1
  • Martina Deckert
    • 2
  • Nguyen Thi Xuan
    • 1
  • Gopala Nishanth
    • 1
  • Sissy Just
    • 1
  • Ari Waisman
    • 3
  • Michael Naumann
    • 4
  • Dirk Schlüter
    • 1
    • 5
  1. 1.Institute of Medical MicrobiologyOtto-von-Guericke University MagdeburgMagdeburgGermany
  2. 2.Department of NeuropathologyUniversity Hospital CologneCologneGermany
  3. 3.Institute for Molecular MedicineUniversity Medical Center of the Johannes-Gutenberg University of MainzMainzGermany
  4. 4.Institute of Experimental Internal MedicineOtto-von-Guericke University MagdeburgMagdeburgGermany
  5. 5.Helmholtz Centre for Infection ResearchBraunschweigGermany

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