| Autor: |
Gallant RM; Molecular and Systems Physiology Lab, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.; Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92037, USA.; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA.; Gene Expression Lab, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA., Snyder JM; Department of Comparative Medicine, School of Medicine, University of Washington, Seattle WA., Ayres JS; Molecular and Systems Physiology Lab, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA.; Gene Expression Lab, Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.; Lead contact. |
| Abstrakt: |
Selective serotonin reuptake inhibitors (SSRIs) are some of the most prescribed drugs in the world. While they are used for their ability to increase serotonergic signaling in the brain, SSRIs are also known to have a broad range of effects beyond the brain, including immune and metabolic effects. Recent studies have demonstrated that SSRIs are protective in animal models and humans against several infections, including sepsis and COVID-19, however the mechanisms underlying this protection are largely unknown. Here we mechanistically link two previously described effects of the SSRI fluoxetine in mediating protection against sepsis. We show that fluoxetine-mediated protection is independent of peripheral serotonin, and instead increases levels of circulating IL-10. IL-10 is necessary for protection from sepsis-induced hypertriglyceridemia and cardiac triglyceride accumulation, allowing for metabolic reprogramming of the heart. Our work reveals a beneficial "off-target" effect of fluoxetine, and reveals a protective immunometabolic defense mechanism with therapeutic potential. |
