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Peli1 promotes microglia-mediated CNS inflammation by regulating Traf3 degradation

Nature Medicine volume 19, pages 595–602 (2013)Cite this article

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Abstract

Microglia are crucial for the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Here we show that the E3 ubiquitin ligase Peli1 is abundantly expressed in microglia and promotes microglial activation during the course of EAE induction. Peli1 mediates the induction of chemokines and proinflammatory cytokines in microglia and thereby promotes recruitment of T cells into the central nervous system. The severity of EAE is reduced in Peli1-deficient mice despite their competent induction of inflammatory T cells in the peripheral lymphoid organs. Notably, Peli1 regulates Toll-like receptor (TLR) pathway signaling by promoting degradation of TNF receptor–associated factor 3 (Traf3), a potent inhibitor of mitogen-activated protein kinase (MAPK) activation and gene induction. Ablation of Traf3 restores microglial activation and CNS inflammation after the induction of EAE in Peli1-deficient mice. These findings establish Peli1 as a microglia-specific mediator of autoimmune neuroinflammation and suggest a previously unknown signaling mechanism of Peli1 function.

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Figure 1: Disease severity is reduced in Peli1 knockout mice after the induction of EAE.
Figure 2: Peli1 deficiency in radioresistant cells inhibits immune-cell recruitment into the CNS and reduces the severity of EAE.
Figure 3: Peli1-mediated microglial activation contributes to EAE pathogenesis.
Figure 4: Peli1 mediates TLR-stimulated gene expression and MAPK activation in microglia.
Figure 5: Peli1 regulates TLR-stimulated c-IAP2 ubiquitination and Traf3 degradation.
Figure 6: Traf3 ablation restores proinflammatory gene induction in Peli1-deficient microglia and increases EAE disease severity in Peli1-deficient mice.

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Acknowledgements

We thank the Centenary Institute of Cancer Medicine and Cell Biology for Traf3-floxed mice; the Texas A&M Institute for Genomic Medicine for Peli1 knockout mice; S.H. Park (Sungkyunkwan University) for hemagglutinin (HA)-tagged Peli1 and Peli1ΔC; R. Beyaert (Ghent University) for E-tag–Peli1; Z. Chen (University of Texas Southwestern Medical Center) for HA-tagged K63 ubiquitin; C. Du (University of Cincinnati College of Medicine) for Flag–c-IAP2; S. Akira (Osaka University) for Flag-IKKi; and X. Qin (Sun Yat-Sen University) for lentiviral packing plasmids. We also thank the personnel from the flow cytometry, DNA analysis, animal and histology core facilities at MD Anderson Cancer Center for technical assistance. This research was supported by grants from the US National Institutes of Health (AI057555, AI064639 and GM84459 to S.-C.S. and T32CA009598 to G.C.B.).

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Authors and Affiliations

  1. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Yichuan Xiao, Jin Jin, Mikyoung Chang, Jae-Hoon Chang, Hongbo Hu, Xiaofei Zhou, George C Brittain, Xuhong Cheng & Shao-Cong Sun

  2. Department of Clinical Medicine, Dr E. Martens Research Group for Biological Psychiatry, University of Bergen, Bergen, Norway

    Christine Stansberg

  3. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway

    Christine Stansberg

  4. Department of Neurology, Norwegian Multiple Sclerosis Competence Center, Haukeland University Hospital, Bergen, Norway

    Øivind Torkildsen

  5. Department of Clinical Medicine, Kristian Gerhard Jebsen Mississippi Research Center, University of Bergen, Bergen, Norway

    Øivind Torkildsen

  6. National Institute of Biological Sciences, Zhongguancun Life Science Park, Beijing, China

    Xiaodong Wang

  7. Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

    Robert Brink

  8. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA

    Shao-Cong Sun

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  1. Yichuan Xiao
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Contributions

Y.X. designed and did the research, prepared the figures and wrote the manuscript. J.J., M.C., J.-H.C., H.H., X.Z., G.C.B. and X.C. contributed experiments. C.S. and Ø.T. performed the human microarray experiments. X.W. and R.B. contributed reagents. S.-C.S. supervised the research and wrote the manuscript.

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Correspondence to Shao-Cong Sun.

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Xiao, Y., Jin, J., Chang, M. et al. Peli1 promotes microglia-mediated CNS inflammation by regulating Traf3 degradation. Nat Med 19, 595–602 (2013). https://doi.org/10.1038/nm.3111

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