A TH17-intrinsic IL-1ß-STAT5 axis drives steroid resistance in autoimmune neuroinflammation.
Sci Immunol
; 9(95): eabq1558, 2024 May 03.
Article
en En
| MEDLINE
| ID: mdl-38701190
ABSTRACT
Steroid resistance poses a major challenge for the management of autoimmune neuroinflammation. T helper 17 (TH17) cells are widely implicated in the pathology of steroid resistance; however, the underlying mechanisms are unknown. In this study, we identified that interleukin-1 receptor (IL-1R) blockade rendered experimental autoimmune encephalomyelitis (EAE) mice sensitive to dexamethasone (Dex) treatment. Interleukin-1ß (IL-1ß) induced a signal transducer and activator of transcription 5 (STAT5)-mediated steroid-resistant transcriptional program in TH17 cells, which promoted inflammatory cytokine production and suppressed Dex-induced anti-inflammatory genes. TH17-specific deletion of STAT5 ablated the IL-1ß-induced steroid-resistant transcriptional program and rendered EAE mice sensitive to Dex treatment. IL-1ß synergized with Dex to promote the STAT5-dependent expression of CD69 and the development of central nervous system (CNS)-resident CD69+ TH17 cells. Combined IL-1R blockade and Dex treatment ablated CNS-resident TH17 cells, reduced EAE severity, and prevented relapse. CD69+ tissue-resident TH17 cells were also detected in brain lesions of patients with multiple sclerosis. These findings (i) demonstrate that IL-1ß-STAT5 signaling in TH17 cells mediates steroid resistance and (ii) identify a therapeutic strategy for reversing steroid resistance in TH17-mediated CNS autoimmunity.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Dexametasona
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Encefalomielitis Autoinmune Experimental
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Factor de Transcripción STAT5
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Interleucina-1beta
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Células Th17
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Sci Immunol
/
Sci. immunol
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Science immunology
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos