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Spinal cord injury (SCI) induces a glial response in which astrocytes become activated and produce inflammatory mediators. The molecular basis for regulation of glial–innate immune responses remains poorly understood. Here, we examined the activation of retinoic acid–inducible gene (RIG)–like receptors (RLRs) and their involvement in regulating inflammation after SCI. We show that astrocytes express two intracellular RLRs: RIG–I and melanoma differentiation–associated gene 5. SCI and stretch injury of cultured astrocytes stimulated RLR signaling as determined by phosphorylation of interferon regulatory factor 3 (IRF3) leading to production of type I interferons (IFNs). RLR signaling stimulation with synthetic ribonucleic acid resulted in RLR activation, phosphorylation of IRF3, and increased expression of glial fibrillary acidic protein (GFAP) and vimentin, two hallmarks of reactive astrocytes. Moreover, mitochondrial E3 ubiquitin protein ligase 1, an RLR inhibitor, decreased production of GFAP and vimentin after RIG–I signaling stimulation. Our findings identify a role for RLR signaling and type I IFN in regulating astrocyte innate immune responses after SCI. © 2011 Wiley Periodicals, Inc.