STAT1 Inhibitor Selectively Targets Inflammatory Cells
Yongfang Zhao, Cheng Ma, Caixia Chen, Sicheng Li, Yangfan Wang, et al.
(see pages 7466–7481)
After traumatic brain injury, microglia become activated and the blood–brain barrier ruptures, allowing peripheral macrophages to enter the brain. Both microglia and macrophages assume a range of phenotypes to promote inflammation and tissue repair. Although initially beneficial, proinflammatory cells can ultimately cause secondary tissue damage, worsening prospects for recovery. Outcomes might be improved by selectively reducing the number of proinflammatory cells while sparing repair cells. Zhao, Ma, et al. have found a way to do this.
The authors focused on signal transducer and activator of transcription 1 (STAT1), a transcription factor previously shown to promote proinflammatory phenotypes in peripheral macrophages and to be upregulated in the brain after traumatic injury. Although STAT1 was expressed in multiple glial types in baseline conditions, its expression increased only in microglia and macrophages after moderate-to-severe brain injury in mice. Knocking out STAT1 selectively in microglia and macrophages of adults reduced the total number of peripheral macrophages and the number of proinflammatory microglia in the subsequently injured brain, but it did not affect the number of prorepair microglia. Moreover, the volume of tissue lost and the extent of axonal damage after injury were lower in mice lacking STAT1 in microglia and macrophages than in control mice, and the STAT1-deficient mice regained more motor function over the next month.
Importantly, administering fludarabine, a selective STAT1 inhibitor currently used in chemotherapy, after traumatic brain injury not only reduced the number of proinflammatory microglia and macrophages, but also increased the number of prorepair cells. Moreover, fludarabine reduced brain levels of several inflammatory cytokines that are upregulated after injury. It also reduced tissue loss and axonal damage and sped recovery of sensorimotor function. Finally, in cultures of wild-type (but not STAT1-deficient) microglia treated with inflammatory agents, fludarabine reduced production of nitric oxide and the inflammatory cytokine TNF-α.
These results suggest that inhibiting STAT1 with fludarabine limits damage and enhances recovery after traumatic brain injury by selectively reducing the numbers of proinflammatory microglia and macrophages in the brain. Notably, beneficial effects were obtained when fludarabine treatment began 2 h after injury—a time frame that is possible for human patients. Therefore, fludarabine may improve functional recovery in these patients.
A STAT1 inhibitor (bottom) increases the number of prorepair (indicated by Arg1 labeling, green) microglia and macrophages (red) in the striatum after brain injury. See Zhao, Ma, et al. for details.
Furin Is Required for Habituation in Flies
Kyriaki Foka, Eirini-Maria Georganta, Ourania Semelidou, and Efthimios M. C. Skoulakis
(see pages 7496–7511)
Furin has received much attention recently as the endoprotease that cleaves the spike protein of SARS-CoV-2, allowing the virus to enter cells; but furin has many endogenous roles as well. It is highly expressed in the brain, where it is required for generation or activation of brain-derived neurotrophic factor, several peptidases, Notch receptors, and an orphan G-protein-coupled receptor involved in dopaminergic signaling. Furthermore, people with Alzheimer's disease or schizophrenia have reduced levels of furin, and polymorphisms in the furin gene have been linked to schizophrenia, major depression, and bipolar disorder (Zhang et al., 2022, Transl Neurodegener 11:39).
To better understand furin's role in the brain, Foka et al. expressed mutant forms of the Drosophila ortholog, furin1, in adult flies. They examined the effect of this manipulation on habituation—the suppression of behavioral responses to repeated, insignificant stimuli—because habituation is impaired in several human diseases, including schizophrenia. In flies, habituation occurs when mild footshocks are delivered repeatedly in one part of an enclosure. Although flies initially avoid the shock-paired area, they become habituated to the shocks and suppress avoidance. Compared with wild-type flies, those expressing mutant furin1 required more shock exposures to become habituated. Similar delays in habituation occurred when furin1 was knocked down selectively in α′/β′ mushroom body neurons, which were previously shown to be involved in habituation, or in γ neurons, which were newly discovered to be required for habituation. Importantly, expressing either human furin or wild-type furin1 selectively in α′/β′ neurons rescued habituation in flies expressing mutant furin1, indicating that Drosophila and human furin function similarly in these neurons. Remarkably, haloperidol, an antipsychotic drug that antagonizes D2 dopamine receptors, and clozapine, an antipsychotic drug that antagonizes HTR2A serotonin receptors, both rescued habituation after furin1 was knocked down in α′/β′ neurons.
These results indicate that furin1 expression in particular neurons is required for habituation in Drosophila. The finding that habituation is restored by antipsychotic drugs is consistent with a role for furin in schizophrenia and suggests that studies of habituation in Drosophila can provide insight into disease mechanisms. Thus, future work should determine which targets of furin are required for habituation and how failure to cleave these targets disrupts habituation.
Footnotes
This Week in The Journal was written by Teresa Esch, Ph.D.
