When pathogens invade peripheral tissues, they elicit an immune response that includes the production of cytokines and other inflammatory mediators. These mediators can enter the brain, where they alter neural activity to produce sickness behaviors, such as lethargy, loss of appetite, and social avoidance. Prolonged inflammation can cause cognitive deficits and depression of mood that persist after the peripheral infection is resolved. In severe cases, widespread hyperactivation of the immune

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... stem produces sepsis, which may lead to degeneration in the brain and peripheral organs and can ultimately result in death. Persistent CNS inflammation, whether from sepsis or neurodegenerative diseases, is typically accompanied by mitochondrial dysfunction, which may exacerbate neuronal damage. To investigate the consequences of neuronal mitochondrial dysfunction during sepsis in mice, Harland et al. overexpressed mitofusion 2 (Mfn2), a major regulator of mitochondrial function, selectively in neurons, then intraperitoneally injected the bacterial membrane component lipopolysaccharide (LPS) to induce sepsis. Wild-type and mutant mice showed similar spleen enlargement and elevation of proinflammatory cytokines IL-1␤ and TNF␣ in the blood, suggesting similar levels of peripheral immune-system activation. Peripheral tissue damage was also similar between genotypes. Despite this, neuronal Mfn2 overexpression increased survival: whereas most wild-type mice died within 1 week of infection, those overexpressing Mfn2 survived at least 2 weeks. Mfn2-overexpressing mice also exhibited less sickness behavior than wildtype mice. As expected, overexpressing Mfn2 reduced fragmentation of neuronal mitochondria after LPS injection. Although brain levels of several inflammatory molecules were comparable in wild-type and Mfn2-overexpressing mice, levels of IL-1␤ (the main inflammatory agent in the brain) were lower in mutants, suggesting reduced neuroinflammation. Correspondingly, microglia were less activated in Mfn2-overexpressing brains than in controls. This was attributable to elevated levels of the chemokine CX3CL1, which is produced by neurons and inhibits microglial activation. Indeed, knocking down CXC3L1 restored LPS-induced microglial activation in Mfn2-overexpressing mice. These results are remarkable for several reasons. First, they suggest that the mitochondrial protein Mfn2 can regulate neuronal gene expression; how this occurs is unknown. Furthermore, they show that improving mitochondrial health might reduce neuroinflammation. Finally, they suggest that improving mitochondrial health and/or reducing inflammation in the brain is sufficient to prevent the multiorgan failure that typically causes death in sepsis.