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  • Title: Suppression of TLR4 by miR-448 is involved in Diabetic development via regulating Macrophage polarization.
    Author: Zhao Q, Wang X, Hu Q, Zhang R, Yin Y.
    Journal: J Pharm Pharmacol; 2019 May; 71(5):806-815. PubMed ID: 30536833.
    Abstract:
    OBJECTIVES: Lipopolysaccharide (LPS) contributed to the development and progression of type 2 diabetes mellitus (T2D), while TLR4 is reported to mediate the LPS-induced inflammation in macrophages. However, the potential molecular mechanisms for TLR4-mediated macrophages activation in T2D have not yet to be fully clarified. METHODS: Type 2 diabetes models in C57BL/6J mice were generated by a combination administration of streptozotocin (STZ) and a high-fat diet (HFD). Cell proportions of M1 and M2 macrophages were analyzed using flow cytometry. Expression profiles of miR-448 and TLR 4 were determined by qRT-PCR and Western blot. KEY FINDINGS: LPS/IFN-γ significantly induced M1 polarization in macrophages characterized by the increased levels of TNF-α, IL-6, IL-12, iNOS and decreased levels of TNF-β, CCL-22, IL-10 and Arg-1, with a higher expression of toll-like receptor 4 (TLR4) in vitro. Consistently, T2D mice-derived macrophages had a significantly elevated expression of TLR4 mRNA and decreased expression of miR-448. We further confirmed that miR-448 could inhibit TLR4 expression by targeting the 3'-UTR of TLR4, rescuing the LPS/IFN-γ-induced M1 macrophage polarization. CONCLUSIONS: Taken together, our results indicated that decreased miR-448 in diabetic macrophages may contribute to LPS-induced M1 polarization by targeting TLR4, thereby modulating T2D development.
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