Retinoic Acid Abrogates Lps-Induced Inflammatory Response Via Negative Regulation Of Nf-Kappa B/Mir-21 Signaling

Context: Macrophages are essential components of the immune system, with significant roles in inflammation modulation. They can be activated into pro-inflammatory M1 or anti-inflammatory M2 phenotypes, depending on their micro-environment. Molecular factors that modulate macrophage polarization are hot targets for therapeutic strategies to counter chronic inflammatory pathological conditions.Objective: The current study aimed to elucidate the molecular mechanisms by which Retinoic acid (RA), a potent immunomodulator, suppresses LPS-induced inflammatory response in macrophages.Materials and methods: RAW 264.7 macrophages were treated with RA and/or LPS, and analyzed for inflammatory genes and miR-21 by PCR. The roles of miR-21 and NF-kappa B signaling pathway were also assessed by knock-down experiments, immunofluorescence, and ChIP assays.Results: Pretreatment with RA quenched the LPS-induced inflammatory responses, including phagocytosis, ROS generation, and NO production. RA shifted the polarization away from the M1 state by negative regulation of IKK alpha/beta, p65, and miR-21. RA hindered the phosphorylation of IKK alpha/beta, translocation of p65 into the nucleus, and the subsequent upregulation of miR-21. Knock-in and knock-down experiments showed that miR-21 is central for the polarization shift toward the pro-inflammatory M1 state.Conclusion: miR-21 is involved in the LPS-induced pro-inflammatory profile of macrophages and that RA negatively regulates the inflammatory response by targeting NF-kappa B/miR-21 signaling. Our data exposes RA's potential as a pharmacological agent to manipulate miR-21 and counteract hyper-inflammatory response.