People & Ideas
The roles of microglia and ApoE in tauopathies, such as Alzheimer’s disease, remain elusive. In this issue of JEM, Shi et al. demonstrate that microglia-mediated innate immunity collaborates with ApoE to drive neurodegeneration and disease progression in a mouse model of tauopathy.
Pyroptosis is an important component of the innate immune system. Gasdermin D, the mediator of pyroptosis, has been shown to be crucial for optimal defense against microbial infection. In this review, the authors discuss gasdermin D and its role in disease.
Brief Definitive Reports
A small population of self-reactive CD4SP thymocytes promotes thymic T reg cell development by provision of the niche factor IL-2, thereby scaling the size of the T reg cell compartment to appropriately match the self-reactive T cell pool.
A high-affinity monoclonal antibody (CTRND05) targeting corticotropin-releasing factor (CRF) blocks stress-induced corticosterone increases, counteracts effects of chronic variable stress, and induces other phenotypes consistent with suppression of the HPA axis.
Using a tracer-based approach with near-infrared fluorescence and magnetic resonance imaging in mice, the authors establish the concept of a cranial-to-caudal circulation of cerebrospinal fluid within the spinal column, with clearance to lymphatic vessels at the sacral terminus.
Corticospinal circuit remodeling after central nervous system injury is dependent on neuronal activity
This study investigates the principles of target selection during the remodeling of neuronal circuits following spinal cord injury. It demonstrates that remodeling axons select their postsynaptic partners in an activity-dependent competitive process that is critical for functional recovery after injury.
Technical Advances and Resources
Antibody-mediated long-lasting protection from harmful pathogens depends on collaboration of immune cells within immunological niches. Stoler-Barak et al. introduce an approach that enables the visualization of all the germinal center niches and activated B cells within intact lymph nodes.
GCs are polarized into LZ and DZ to allow for the spatial separation of selection and proliferation. In this study, we describe the previously unknown function of TGFβ in promoting the transition of GCBs from LZ to DZ.
Shi et al. find that microglia, instead of tau-induced direct neurotoxicity, are the driving force of neurodegeneration in a tauopathy mouse model. Microglia are also required for tau pathogenesis. In addition, apoE strongly regulates neurodegeneration in the setting of tauopathy predominantly by modulating microglial function.
Gasdermin D in peripheral myeloid cells drives neuroinflammation in experimental autoimmune encephalomyelitis
In this study, Li et al. demonstrate that gasdermin D in peripheral myeloid cells promotes the activation and differentiation of T cell in the secondary lymphoid organs, thus driving T cell–mediated neuroinflammation and demyelination in the CNS of EAE mice.
Endothelial IQGAP1 regulates leukocyte transmigration by directing the LBRC to the site of diapedesis
The function of endothelial cell IQGAP1 during diapedesis requires its actin-binding domain and IQ motifs to recruit the lateral border recycling compartment. Genetic ablation of endothelial cell IQGAP1 expression in vivo causes significant disruption of diapedesis in two models of inflammation.
It is thought that the Nlrp6 inflammasome regulates formation of the inner mucus layer (IML) barrier that prohibits contact between the microbiota and colonic epithelial cells. Using microbiota-controlled mice and combined ex vivo/in vivo IML analytical approaches, Volk et al. delineate the relative roles of the inflammasome and microbiota in shaping IML formation and function.
Lee et al. reveal that administration of IL-1β can alter the host environment to augment the magnitude and functionality of CD8+ T cells, thereby improving the efficacy of adoptively transferred tumor-reactive T cells in treating large, established tumors in mice.
Tuberous sclerosis complex (TSC) is a genetic disorder in which tumors develop due to TSC1/TSC2 loss and activation of mTORC1. Zarei et al. show that TSC tumors are sensitive to CDK7 inhibition, which reduces expression of NRF2 and glutathione synthetic genes, leading to glutathione depletion and ROS-mediated cell death.
Liu et al. show that Yeats4 recruits the Dot1l–RNA Pol II complex onto the Lmo4 promoter by recognizing H3K27ac modification to initiate Lmo4 transcription in α4β7+ CLPs, leading to ILC lineage commitment.
This study describes a novel function of cytosolic proliferating cell nuclear antigen (PCNA) in the control of neutrophil NADPH oxidase, a complex pivotal for ROS generation in inflammation. Inhibition of neutrophil PCNA results in a potent antiinflammatory effect in colitis.