Interleukin-10 (IL-10) is a key anti-inflammatory cytokine that limits immune cell activation and cytokine production in innate immune cells. Loss of IL-10 signaling leads to life-threatening inflammatory bowel disease in humans and mice, but the exact mechanism remains unclear. This study reveals that increased saturated very long-chain (VLC) ceramides are critical for the heightened inflammatory gene expression associated with IL-10 deficiency. Genetic deletion of ceramide synthase 2 (Cers2), which produces VLC ceramides, limits the exacerbated inflammatory gene expression program in vitro and in vivo. The accumulation of saturated VLC ceramides is regulated by a decrease in metabolic flux through the de novo mono-unsaturated fatty acid synthesis pathway. Restoring mono-unsaturated fatty acid availability in IL-10-deficient cells limits saturated VLC ceramide production and associated inflammation. Mechanistically, persistent inflammation mediated by VLC ceramides is dependent on sustained activity of REL, an immuno-modulatory transcription factor. These findings indicate that IL-10-driven fatty acid desaturation programs renew VLC ceramide accumulation and aberrant activation of REL, suggesting that 'metabolic correction' of VLC homeostasis could be a strategy to normalize dysregulated inflammation caused by IL-10 deficiency.Interleukin-10 (IL-10) is a key anti-inflammatory cytokine that limits immune cell activation and cytokine production in innate immune cells. Loss of IL-10 signaling leads to life-threatening inflammatory bowel disease in humans and mice, but the exact mechanism remains unclear. This study reveals that increased saturated very long-chain (VLC) ceramides are critical for the heightened inflammatory gene expression associated with IL-10 deficiency. Genetic deletion of ceramide synthase 2 (Cers2), which produces VLC ceramides, limits the exacerbated inflammatory gene expression program in vitro and in vivo. The accumulation of saturated VLC ceramides is regulated by a decrease in metabolic flux through the de novo mono-unsaturated fatty acid synthesis pathway. Restoring mono-unsaturated fatty acid availability in IL-10-deficient cells limits saturated VLC ceramide production and associated inflammation. Mechanistically, persistent inflammation mediated by VLC ceramides is dependent on sustained activity of REL, an immuno-modulatory transcription factor. These findings indicate that IL-10-driven fatty acid desaturation programs renew VLC ceramide accumulation and aberrant activation of REL, suggesting that 'metabolic correction' of VLC homeostasis could be a strategy to normalize dysregulated inflammation caused by IL-10 deficiency.