Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells.

Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells1,2. Genetic variants that are associated with the function of DCs have been linked to autoimmune disorders3,4, and DCs are therefore attractive therapeutic targets for such diseases. However, developing DC-targeted therapies for autoimmunity requires identification of the mechanisms that regulate DC function. Here, using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies, we identify a regulatory loop of negative feedback that operates in DCs to limit immunopathology. Specifically, we find that lactate, produced by activated DCs and other immune cells, boosts the expression of NDUFA4L2 through a mechanism mediated by hypoxia-inducible factor 1α (HIF-1α). NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs that are involved in the control of pathogenic autoimmune T cells. We also engineer a probiotic that produces lactate and suppresses T cell autoimmunity through the activation of HIF-1α-NDUFA4L2 signalling in DCs. In summary, we identify an immunometabolic pathway that regulates DC function, and develop a synthetic probiotic for its therapeutic activation.

Engineered probiotics limit CNS autoimmunity by stabilizing HIF-1α in dendritic cells.

Dendritic cells (DCs) control the generation of self-reactive pathogenic T cells. Thus, DCs are considered attractive therapeutic targets for autoimmune diseases. Using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies we identified a negative feedback regulatory pathway that operates in DCs to limit immunopathology. Specifically, we found that lactate, produced by activated DCs and other immune cells, boosts NDUFA4L2 expression through a mechanism mediated by HIF-1α. NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs involved in the control of pathogenic autoimmune T cells. Moreover, we engineered a probiotic that produces lactate and suppresses T-cell autoimmunity in the central nervous system via the activation of HIF-1α/NDUFA4L2 signaling in DCs. In summary, we identified an immunometabolic pathway that regulates DC function, and developed a synthetic probiotic for its therapeutic activation.

Evoked Frontal and Parietal Field Potential Signatures of Target Detection and Response Inhibition in Rats Performing an Equiprobable Auditory Go/No-Go Task.

To characterize the rat as a potential model of frontal-parietal auditory processing during sustained attention, target detection, and response inhibition, we recorded field potentials (FPs) at multiple sites in medial-dorsal frontal and posterior parietal cortex simultaneously while rats performed an equiprobable auditory go/no-go discrimination task. Event-related potentials (ERPs) were calculated by averaging tone-triggered FPs across hit, miss, false alarm (FA), and correct rejection (CR) trials separately for each recording session, and five peak amplitudes (termed N1, P2, N2, P3E, and P3L) were extracted from the individual-session ERPs. Comparing peak amplitudes across different trials types indicated a statistically significant amplification of the P2 peak on hit trials that accompanies detection of the target tone prior to the behavioral go response. This result appears analogous to human ERP phenomena during auditory target discrimination. Conversely, the rat P3 responses were not associated with target detection as in the human ERP literature. Likewise, we did not observe the "no-go N2" or "no-go P3" responses reported in the human literature in association with response inhibition, which might reflect differences in task context or a difference in auditory processing between rats and humans. We also present analyses of stimulus-induced spectral power and interarea coherence to characterize oscillatory synchronization which may contribute to ERPs, and discuss possible error-related processing at the N2, P3E, and P3L peaks.