Astrocytes are very sensitive to develop innate immune responses to lipid-carried short interfering RNA

Glia
Roser GorinaAnna M Planas

Abstract

Short interfering RNA (siRNA) inhibits the synthesis of specific proteins through RNA interference (RNAi). However, siRNA can induce innate immune responses that are mediated by toll-like receptors (TLRs) in cells of the immune system. Here, we sought to evaluate whether siRNA can induce such responses in glial cells. We examined the effects of various siRNA sequences prepared with lipids (oligofectamine). Lipid-siRNA induced variable degrees of silencing-independent nonspecific effects, e.g. increased Stat1 and Cox-2 expression and release of IL-6 and IP-10 in primary astroglia. This was prevented through chemical modification of siRNA by nucleoside 2'-O-methylation, without impairing specific gene silencing. Lipid-siRNA also induced nonspecific responses in purified astroglia, but not in microglia, or 3T3 cells. The highest TLR7 and TLR3 mRNA expression was found in microglia and purified astroglia, respectively. Accordingly, the TLR3 agonist poly(I:C) (PIC) induced higher release of IFN-beta in primary and purified astroglia than in microglia. As siRNA, PIC induced IP-10, Stat1, VCAM-1, and Cox-2 and increased TLR3 mRNA expression. The effects of lipid-siRNA in purified astrocytes were attenuated after silencing TLR3 or TLR7...Continue Reading

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