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Sci Immunol ; 9(95): eabq1558, 2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38701190

RESUMEN

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.


Asunto(s)
Dexametasona , Encefalomielitis Autoinmune Experimental , Interleucina-1beta , Factor de Transcripción STAT5 , Células Th17 , Animales , Células Th17/inmunología , Factor de Transcripción STAT5/metabolismo , Factor de Transcripción STAT5/inmunología , Ratones , Interleucina-1beta/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Dexametasona/farmacología , Dexametasona/uso terapéutico , Ratones Endogámicos C57BL , Resistencia a Medicamentos , Transducción de Señal/inmunología , Ratones Noqueados , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Femenino , Humanos
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