Uncontrolled microglial activation may lead to development of inflammation-induced brain damage. Here we uncover a ribosome-based mechanism/check point involved in control of the innate immune response and microglial activation. Using an in vivo model-system for analysis of the dynamic translational state of microglial ribosomes with mRNAs as input and newly synthesized peptides as an output, we find a marked dissociation of microglia mRNA and protein networks following innate immune challenge. Highly up-regulated and ribosome-associated mRNAs were not translated resulting in two distinct microglial molecular signatures, a highly specialized pro-inflammatory mRNA and immunomodulatory/homeostatic protein signature. We find that this is due to specific translational suppression of highly expressed mRNAs through a 3’UTR-mediated mechanism involving the RNA binding protein SRSF3. This discovery suggests avenues for therapeutic modulation of innate immune response in resident microglia. Overall design: Transgenic mice expressing Flag/EGFP-RPL10a under the control of CD11b promoter were used to perform transcriptomic analysis in the baseline and following Lipopolysaccharide (LPS) injection (5mg/kg; for 24 hrs). RNA was extracted according to the TRAP protocol and hybridized on Affymetrix microarrays (MoGene-2_0-st). The mice were used at the age of 2-3 months with an equal ratio of male/female. Array data was processed by Transcriptome Analysis Console 3.0 (TAC). Three biological replicates were performed for each condition.