An interferon-β-resistant and NLRP3 inflammasome-independent subtype of EAE with neuronal damage.
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.
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.
Makoto
M
Inoue
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA.
Po-Han
PH
Chen
Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA.
Stephen
S
Siecinski
Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA.
Qi-Jing
QJ
Li
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.
Chunlei
C
Liu
Department of Neurology and Neurological Sciences, Stanford University, Beckman Center for Molecular Medicine, Stanford, California, USA.
Lawrence
L
Steinman
Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA.
Simon G
SG
Gregory
Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.
Eric
E
Benner
Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA.|Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA.
Mari L
0000-0002-6808-9844
ML
Shinohara
D000818:Animals; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology*; D053259:Lymphotoxin beta Receptor / Q000235:genetics*; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics*; D023063:Receptors, Interleukin-8B / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology
D058847:Inflammasomes; C505697:LTBR protein, human; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D023063:Receptors, Interleukin-8B; D016899:Interferon-beta