Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.17.252007v1?rss=1 Authors: Misheva, M., Kotzamanis, K., Davies, L., Tyrrell, V., Rodrigues, P., Benavides, G., Christine, H., Murphy, R., Kennedy, P., Taylor, P., Rosas, M., Jones, S., Deshpande, S., Andrews, R., Czubala, M., Gurney, M., Aldrovandi, M., Meckelmann, S., Ghazal, P., Darley-Usmar, V., White, D., O'Donnell, V. Abstract: Oxylipins are potent mediators requiring strict control. How they are removed en masse during infection/inflammation is unknown. Herein, lipopolysaccharide (LPS) dynamically increased their mitochondrial b-oxidation, impacting leukocyte bioactivity. Genetic/pharmacological targeting of CPT1 showed <50 oxylipins were robustly removed by macrophage mitochondria during inflammation in vitro and in vivo. Stable isotope-lipidomics demonstrated secretion-reuptake recycling for 12-HETE and its intermediate metabolites. Oxylipin b-oxidation was uncoupled from oxidative phosphorylation. Transcriptional interrogation of human neonatal sepsis revealed significant upregulation of many candidates, encoding proteins for mitochondrial uptake and b- oxidation of long-chain fatty acyls (ACSL1,3,4, ACADVL, CPT1B, CPT2, HADHB). ACSL1/Acsl1 upregulation was a signature in multiple human/murine macrophage datasets. In summary, mitochondrial b-oxidation is a regulatory metabolic checkpoint for oxylipins during infection. This has implications for patients with CPT1 deficiency, at higher risk of mortality during respiratory infections. We propose that mitochondrial b-oxidation capacity to remove oxylipins during infection may directly influence development of inflammation. Copy rights belong to original authors. Visit the link for more info