Ifi27l2a acts as a cytokine that promotes a pro-inflammatory phenotype in microglia and enhances neuroinflammation

Interferon alpha-inducible protein 27 like 2A (Ifi27l2a) was initially identified as an interferon-stimulated gene (Isg) involved in host-dependent mechanisms during viral invasion. We have recently shown that the Ifi27l2a protein also plays a critical role in microglia and the spreading of neuroinflammation. However, the detailed mechanisms of action of intracellular and extracellular Ifi27l2a in glial cells, particularly in inflammatory and neurodegenerative diseases, are not yet defined. We now report that systemic inflammation leads to an elevated level of circulating Ifi27l2a in the plasma of lipopolysaccharide (LPS)-treated mice, which is associated with elevated Il1b mRNA expression in the brain. Elevated IFI27L2 (human isoform) was also found in plasma of human stroke patients. To test whether extracellular (e.g. secreted) Ifi27l2a can contribute as an autocrine or paracrine inducer of microglial activation and inflammation, we treated microglial cells with recombinant Ifi27l2a (rIfi27l2a). Treatment with rIfi27l2a led to increased expression of proinflammatory cytokines and elevated reactive oxygen species (ROS) levels in microglial cells. These effects resulted from alterations in mitochondrial function and a metabolic shift from oxidative phosphorylation toward glycolysis for ATP synthesis. Additionally, Ifi27l2a led to increased caspase-1 activity, demonstrating that Ifi27l2a causes Nlrp3 inflammasome activation. RNA sequencing revealed that Ifi27l2a mediates transcriptional changes reflecting activated microglia. These data support an extracellular role of Ifi27l2a as a novel cytokine, in which it promotes a phenotypic shift in microglia toward a proinflammatory phenotype. Targeting Ifi27l2a may therefore provide an additional strategy to reduce microglia-mediated inflammation in the brain.