Type I interferon limits central nervous system autoimmunity by modulating the microRNA-21-FOXO1 axis in pathogenic T...

Area of Science:

• Immunology
• Neuroscience
• Molecular Biology

Background:

• Interferon-beta (IFN-β) is a first-line therapy for multiple sclerosis (MS).
• The precise cellular and molecular mechanisms underlying IFN-β's therapeutic effects in MS remain incompletely understood.
• Understanding these mechanisms is crucial for optimizing treatment strategies and identifying non-responders.

Purpose of the Study:

• To elucidate the molecular mechanisms by which IFN-β exerts its therapeutic effects in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS.
• To investigate the role of microRNA-21 (miR-21) and pathogenic T_H17 (pT_H17) cells in IFN-β's efficacy.
• To explore the potential of targeting miR-21 as a therapeutic strategy, particularly for IFN-β non-responders.

Main Methods:

• Utilized the EAE mouse model to study MS pathogenesis and IFN-β treatment effects.
• Performed in vitro experiments, including genetic knockout of miR-21, to assess its impact on pT_H17 cell differentiation.
• Analyzed cytokine profiles and cell populations in both mouse models and human patient samples (responders vs. non-responders to IFN-β).

Main Results:

• IFN-β treatment in EAE models was associated with decreased miR-21 and pT_H17 cells.
• Genetic deletion of miR-21 inhibited pT_H17 differentiation by upregulating the transcription factor Foxo1.
• IFN-β indirectly reduced miR-21 induction in T cells by modulating cytokine secretion from myeloid cells.
• Non-responders to IFN-β exhibited higher levels of miR-21-inducing cytokines and miR-21/pT_H17 cytokines compared to responders.
• Direct inhibition of miR-21 effectively reduced pT_H17 differentiation in non-responder T cells.

Conclusions:

• Type I interferon signaling, including IFN-β, limits central nervous system autoimmunity by suppressing miR-21-dependent pT_H17 cell development.
• miR-21 plays a critical role in promoting pT_H17 differentiation and driving autoimmunity.
• Targeting miR-21 presents a potential therapeutic avenue specifically for patients with MS who do not respond to IFN-β therapy.