Extracellular vesicles containing miR-146a attenuate experimental colitis by targeting TRAF6 and IRAK1

Area of Science:

• Immunology
• Molecular Biology
• Gastroenterology

Background:

• MicroRNA-146a (miR-146a) is an anti-inflammatory molecule with an unclear role in inflammatory bowel disease (IBD).
• The stability of exogenous miR-146a in circulation poses a challenge for therapeutic applications.

Purpose of the Study:

• To investigate the therapeutic potential of extracellular vesicles (EVs) as a delivery system for miR-146a in a rat model of colitis.
• To elucidate the underlying molecular mechanisms of miR-146a-mediated anti-inflammatory effects in IBD.

Main Methods:

• Bone-marrow mesenchymal stem cells (BMSCs) were engineered to overexpress miR-146a using lentiviral vectors.
• Extracellular vesicles (EVs) harvested from these engineered BMSCs were administered to rats with TNBS-induced colitis.
• Key inflammatory markers, including TRAF6, IRAK1, NF-κB signaling pathway components, and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), were assessed.

Main Results:

• EVs containing overexpressed miR-146a significantly reduced TNF receptor-associated factor 6 (TRAF6) and IL-1 receptor-associated kinase 1 (IRAK1) expression in the inflamed colon.
• Administration of miR-146a-loaded EVs downregulated the phosphorylation of NF-κB p65 and IκBα.
• Production of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), and Interleukin-1β was significantly suppressed.

Conclusions:

• Extracellular vesicles serve as a stable and effective delivery vehicle for miR-146a in treating experimental colitis.
• miR-146a ameliorates TNBS-induced colitis by targeting TRAF6 and IRAK1, thereby inhibiting the NF-κB signaling pathway.
• This study highlights a promising cell-free therapeutic strategy for inflammatory bowel disease.