MicroRNA-9 Inhibits NLRP3 Inflammasome Activation in Human Atherosclerosis Inflammation Cell Models through the JAK1/STAT Signaling Pathway

Abstract

Background/Aims: MicroRNA-9 (miR-9) is involved in inflammatory reaction in atherosclerosis; however, its function and regulatory mechanisms remain unclear. We aimed to uncover the exact roles of miR-9 and downstream signaling pathways using in vitro human atherosclerosis models. Methods: We used oxidized low-density lipoprotein (oxLDL)-stimulated human THP-1 derived macrophages, oxLDL-stimulated human primary peripheral blood monocytes and lipopolysaccharides (LPS) or Alum-stimulated human THP-1 derived macrophages as in vitro atherosclerosis inflammation models. Transient transfection of over-expression vectors, small interference RNAs (siRNAs) or antisense oligonucleotides was used to regulate intracellular protein or miR-9 levels. Cell responses and signal transduction were detected by multiple assays including Western blotting, enzyme-linked immunosorbent assay (ELISA) and luciferase reporter assay. Results: MiR-9 inhibited while anti-miR-9 antisense oligonucleotides induced interleukin-1 beta (IL-1β) and NLRP3 inflammasome activation in all in vitro models. Janus kinase 1 (JAK1) and matrix metalloproteinase 13 (MMP-13) were identified as the target genes of miR-9. In oxLDL-stimulated human THP-1 derived macrophages, knockdown of JAK1 by siRNA blocked the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and mimicked the effects of miR-9. In the same model, JAK1 knockdown blocked the phosphorylation of NF-κB p65 in the nuclei and the phosphorylation of NF-κB IκBα in the cytoplasm. Conclusions: Our study demonstrated that miR-9 could inhibit activation of the NLRP3 inflammasome and attenuate atherosclerosis-related inflammation, likely through the JAK1/STAT1 signaling pathway. Therefore, miR-9 may serve as a potential therapeutic target for atherosclerosis.

NEAT1 contributes to ox‐LDL‐induced inflammation and oxidative stress in macrophages through inhibiting miR‐128

“…miR‐134 promotes AS development via the ANGPTL4/LPL pathway in apolipoprotein E knockout mice . miR‐9 represses NLRP3 inflammasome activation in AS inflammation cell models through the JAK1/STAT pathway . Numerous studies have reported that miR‐128 is involved in different cellular processes including differentiation, apoptosis and metabolism .…”

“…NEAT1 can contribute to hepatocellular carcinoma development through sponging miR‐485 and activating STAT3 . Knockdown of NEAT1 inhibits osteosarcoma progression by sponging miR‐194 …”

Apigenin Retards Atherogenesis by Promoting ABCA1-Mediated Cholesterol Efflux and Suppressing Inflammation

“…Chronic vascular inflammation is closely related to AS development [36]. Previous studies have revealed that apigenin can protect against inflammation [22,23].…”

Mitochondria Targeted Peptide Attenuates Mitochondrial Dysfunction, Controls Inflammation and Protects Against Spinal Cord Injury-Induced Lung Injury

“…NLRP3 inflammasome is assembled by NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1 released after an endogenous ‘‘danger signal” and exogenous infection, comprise an important cytosolic protein complex [34]; this provides a caspase-1-activation platform to promote the maturation and release of proinflammatory cytokines, including IL-1β and IL-18 [35]. NLRP3 inflammasome plays a critical role in lung injury in diverse models [34, 36].…”