Journal Articles

An interferon-β-resistant and NLRP3 inflammasome–independent subtype of EAE with neuronal damage

November 17, 2016

Makoto Inoue, Po-han Chen, Stephen Siecinski, Qi-jing Li, Chunlei Liu, Lawrence Steinman, Simon G. Gregory, Eric Benner, Mari L Shinohara (2016). An interferon-β-resistant and NLRP3 inflammasome–independent subtype of EAE with neuronal damage. Nature Neuroscience.

Author Affiliations

Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA.
Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA.
Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA.
Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, California, USA.
Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California, USA.
Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.

Abstract

Inflammation induced by innate immunity influences the development of T cell–mediated autoimmunity in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). We found that strong activation of innate immunity induced Nod-like receptor protein 3 (NLRP3) inflammasome–independent and interferon-β (IFNβ)-resistant EAE (termed type B EAE), whereas EAE induced by weak activation of innate immunity requires the NLRP3 inflammasome and is sensitive to IFNβ treatment. Instead, an alternative inflammatory mechanism, including membrane-bound lymphotoxin-β receptor (LTβR) and CXC chemokine receptor 2 (CXCR2), is involved in type B EAE development, and type B EAE is ameliorated by antagonizing these receptors. Relative expression of Ltbr and Cxcr2 genes was indeed enhanced in patients with IFNβ-resistant multiple sclerosis. Remission was minimal in type B EAE due to neuronal damages induced by semaphorin 6B upregulation on CD4+ T cells. Our data reveal a new inflammatory mechanism by which an IFNβ-resistant EAE subtype develops.

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