miPEP31 alleviates sepsis development by regulating Chi3l1-dependent macrophage polarization

Background: Sepsis is a severe condition characterized by multiple organ dysfunction resulting from an imbalanced host immune response to infections. miRNAs play a crucial role in regulating various biological processes. However, the precise role of miR-31 in the immunopathology of sepsis remains poorly understood.

Methods: The concentration of hsa-miR-31-5p in patients with sepsis (both survivors and non-survivors) and healthy individuals was assayed. Using an experimental sepsis model of caecal ligation and puncture (CLP), the impact of mmu-miR-31-5p on survival, organ injury, and inflammation was evaluated. Additionally, the effect of mmu-miR-31-5p on macrophage polarization through Chi3l1 was investigated. Lastly, the therapeutic effects of miPEP31 on experimental sepsis were examined.

Results: The results of miRNA sequencing (miRNA-seq) and quantitative polymerase chain reaction (q-PCR) analyses identified hsa-miR-31-5p as a potential biomarker for patients with sepsis, with non-survivors showing higher levels of hsa-miR-31-5p in peripheral blood mononuclear cells (PBMCs) compared to survivors. Functional studies conducted on peritoneal elucidated macrophages (PEMs) demonstrated that mmu-miR-31-5p inhibits M2 polarization in macrophages by downregulating Chi3l1. The utilization of miPEP31 as a therapeutic intervention had a substantial impact on reducing mortality rates, mitigating organ damage, inducing macrophage polarization towards the M2 phenotype, and suppressing the inflammatory response in murine models of severe sepsis.

Conclusions: The suppression of miR-31 in sepsis plays a protective role in the host defense response by upregulating Chi3l1, highlighting the potential therapeutic efficacy of miPEP31 in sepsis treatment.