Fluoxetine promotes immunometabolic defenses to mediate host-pathogen cooperation during sepsis.

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.

A Subset of Oligodendrocyte Lineage Cells Interact With the Developing Dorsal Root Entry Zone During Its Genesis.

Oligodendrocytes are the myelinating cell of the CNS and are critical for the functionality of the nervous system. In the packed CNS, we know distinct profiles of oligodendrocytes are present. Here, we used intravital imaging in zebrafish to identify a distinct oligodendrocyte lineage cell (OLC) that resides on the dorsal root ganglia sensory neurons in the spinal cord. Our profiling of OLC cellular dynamics revealed a distinct cell cluster that interacts with peripheral sensory neurons at the dorsal root entry zone (DREZ). With pharmacological, physical and genetic manipulations, we show that the entry of dorsal root ganglia pioneer axons across the DREZ is important to produce sensory located oligodendrocyte lineage cells. These oligodendrocyte lineage cells on peripherally derived sensory neurons display distinct processes that are stable and do not express mbpa. Upon their removal, sensory behavior related to the DRG neurons is abolished. Together, these data support the hypothesis that peripheral neurons at the DREZ can also impact oligodendrocyte development.