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STEAP4 expression in CNS resident cells promotes Th17 cell-induced autoimmune encephalomyelitis

Authors
  • Zhao, Junjie1
  • Liao, Yun1
  • Miller-Little, William1
  • Xiao, Jianxing1
  • Liu, Caini1
  • Li, Xiaoxia1
  • Li, Xiao2
  • Kang, Zizhen1, 3
  • 1 Lerner Research Institute, Cleveland, OH, USA , Cleveland (United States)
  • 2 Case Western Reserve University, Cleveland, OH, USA , Cleveland (United States)
  • 3 University of Iowa, Iowa City, IA, 52242, USA , Iowa City (United States)
Type
Published Article
Journal
Journal of Neuroinflammation
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Apr 20, 2021
Volume
18
Issue
1
Identifiers
DOI: 10.1186/s12974-021-02146-7
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundMultiple sclerosis (MS) is a debilitating neurological disease caused by autoimmune destruction of the myelin sheath. Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model for the pathogenesis of MS. We and others have previously demonstrated that IL-17 is critical for the pathogenesis of EAE. The concentration of IL-17 is significantly higher in the sera of MS patients than in healthy controls and correlates with disease activity. Moreover, anti-IL-17 neutralizing antibody demonstrated promising efficacy in a phase II trial in MS patients, further substantiating a key pathogenic role for IL-17 in MS. While Th17 and IL-17 are emerging as a bona fide drivers for neuroinflammation, it remains unclear what effector molecule executes the inflammatory tissue destruction in Th17-driven EAE.MethodsBy microarray analysis, we found STEAP4 is a downstream molecule of IL-17 signaling in EAE. We then used STEAP4 global knockout mice and STEAP4 conditional knockout mice to test its role in the pathogenesis of EAE.ResultsHere, we report that the metalloreductase, STEAP4, is a key effector molecule that participates and contributes to the pathogenesis of Th17-mediated neuroinflammation in experimental autoimmune encephalomyelitis. STEAP4 knockout mice displayed delayed onset and reduced severity of EAE induced by active immunization. The reduced disease phenotype was not due to any impact of STEAP4 deficiency on myelin reactive T cells. In contrast, STEAP4 knockout mice were resistant to passively induced EAE, pointing to a role for STEAP4 in the effector stage of EAE. Notably, STEAP4 was only induced the spinal cord of EAE mice that received Th17 cells but not Th1 cells. Consistently, STEAP4 deficiency protected from only Th17 but not Th1-induced EAE. Finally, using Nestin-Cre STEAP4fl/fl mice, we showed that ablation of STEAP4 expression in the resident cells in the central nervous system attenuated disease severity in both active immunization and passive Th17 transfer-induced EAE.ConclusionIn this study, we identified STEAP4 as a Th17-specific effector molecule that participates and contributes to the pathogenesis of neuroinflammation, thus potentially provide a novel target for MS therapy.

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