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MicroRNA-33 regulates the innate immune response via ATP Binding Cassette transporter-mediated remodeling of membrane microdomains

Lai, L;Azzam, KM;Lin, WC;Rai, P;Lowe, JM;Gabor, KA;Madenspacher, JH;Aloor, JJ;Parks, JS;Nr, AM;Fessler, MB;

MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression by promoting degradation and/or repressing translation of specific target mRNAs. Several miRNAs have been identified that regulate the amplitude of the innate immune response by directly targeting Toll-like Receptor (TLR) pathway members and/or cytokines. miR-33a and miR-33b (the latter present in primates, but absent in rodents and lower species) are located in introns of the sterol regulatory element-binding protein (SREBP)-encoding genes and control cholesterol/lipid homeostasis in concert with their host gene products. These miRNAs regulate macrophage cholesterol by targeting the lipid efflux transporters ATP Binding Cassette (ABC)A1 and ABCG1. We and others have previously reported that Abca1-/- and Abcg1-/- macrophages have increased TLR pro-inflammatory responses due to augmented lipid raft cholesterol. Given this, we hypothesized that miR-33 would augment TLR signaling in macrophages via a raft cholesterol-dependent mechanism. Herein, we report that multiple TLR ligands downregulate miR-33 in murine macrophages. In the case of lipopolysaccharide, this is a delayed, TIR-domain-containing adapter-inducing interferon--dependent response that also downregulates Srebf-2, the host gene for miR-33. miR-33 augments macrophage lipid rafts and enhances pro-inflammatory cytokine induction and NF-B activation by LPS. This occurs through an ABCA1- and ABCG1-dependent mechanism, and is reversible by interventions upon raft cholesterol and by ABC transporter-inducing liver X receptor agonists. Taken together, these findings extend the purview of miR-33, identifying it as an indirect regulator of innate immunity that mediates bidirectional crosstalk between lipid homeostasis and inflammation.