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STEAP4 expression in CNS resident cells promotes Th17 cell-induced autoimmune encephalomyelitis.
- Source :
-
Journal of neuroinflammation [J Neuroinflammation] 2021 Apr 20; Vol. 18 (1), pp. 98. Date of Electronic Publication: 2021 Apr 20. - Publication Year :
- 2021
-
Abstract
- Background: Multiple 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.<br />Methods: By 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.<br />Results: Here, 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 STEAP4 <superscript>fl/fl</superscript> 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.<br />Conclusion: In 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.
- Subjects :
- Animals
Central Nervous System metabolism
Central Nervous System pathology
Central Nervous System physiopathology
Disease Models, Animal
Encephalomyelitis, Autoimmune, Experimental etiology
Encephalomyelitis, Autoimmune, Experimental pathology
Encephalomyelitis, Autoimmune, Experimental physiopathology
Interleukin-17 metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Multiple Sclerosis physiopathology
Th1 Cells immunology
Th1 Cells metabolism
Th17 Cells metabolism
Central Nervous System cytology
Encephalomyelitis, Autoimmune, Experimental immunology
Membrane Proteins genetics
Membrane Proteins metabolism
Th17 Cells immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1742-2094
- Volume :
- 18
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of neuroinflammation
- Publication Type :
- Academic Journal
- Accession number :
- 33879167
- Full Text :
- https://doi.org/10.1186/s12974-021-02146-7