Plasma Exosomal miR-17-5p Regulates Macrophage Polarization by Targeting Bcl11b in Sepsis-Induced Lung Injury.

Background: Sepsis is a life-threatening syndrome characterized by overwhelming inflammation and immune dysregulation, commonly complicated by acute lung injury. Patients with underlying conditions such as diabetes, malignancy, and chronic liver disease are particularly vulnerable. Dysregulated macrophage polarization plays a pivotal role in sepsis progression. Although exosomal microRNAs (miRNAs) have emerged as key immune modulators, the precise role of plasma-derived exosomal miR-17-5p in this process remains poorly defined. The transcription factor Bcl11b, previously linked to immune cell regulation, has not yet been studied in the context of sepsis-associated macrophage reprogramming.

Methods: Extracellular vehicles (EVs) were isolated from the plasma of sepsis patients and healthy controls. A series of in vitro and in vivo experiments were conducted to investigate the effect of exosomal miR-17-5p on macrophage polarization, using qRT-PCR, flow cytometry, ELISA, and Western blot analyses. Transcriptome sequencing and dual-luciferase reporter assays were used to explore the regulatory relationship between miR-17-5p and Bcl11b.

Results: Plasma exosomes derived from sepsis patients exhibited reduced levels of miR-17-5p and promoted M1 macrophage polarization, characterized by increased iNOS and pro-inflammatory cytokines. Overexpression of miR-17-5p inhibited M1 polarization and alleviated inflammatory injury both in LPS-treated macrophages and in a CLP-induced mouse model. Mechanistically, miR-17-5p directly targeted the 3'UTR of Bcl11b, suppressing its expression. Restoration of Bcl11b reversed the anti-inflammatory effects of miR-17-5p, reinforcing M1 polarization and exacerbating lung injury.

Conclusion: Plasma exosomal miR-17-5p promotes macrophage M1 polarization by targeting Bcl11b and contributes to sepsis-induced lung injury. These findings highlight a previously unrecognized miR-17-5p-Bcl11b regulatory axis and suggest a potential biomarker and therapeutic target for sepsis.