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MicroRNAs play pivotal roles in the regulation of both innate and adaptive immune responses.In this study, we found that activation of tolllike receptor 4 (TLR4) rapidly increased the level of microRNA124 (miR124) in lipopolysaccharide (LPS)treated macrophages and mice.MiR124 knockdown significantly increased the production of the proinflammatory cytokine TNFα at the posttranscriptional level in LPStriggered macrophages.Furthermore, miR124 knockdown or overexpression siguificanly increased or decreased the protein stability of TNFα.We found miR124 directly targeted ubiquitinspecific proteases 2 (USP2) and 14 (USP14), two components of deubiquitinating enzymes.Knockdown of USP2 and USP14 attenuated the miR124mediated protein degradation of TNFα.Together, our data identify miR124 as an important feedback negative regulator for LPSinduced production of TNFα by targeting USP2 and USP14, thus outlining new mechanisms for finetuning the TLRtriggered inflammatory response.