The equilibrium of signaling through activating and inhibitory receptors dictates whether a given NK cell will execute cellular cytotoxicity. In this issue of the JCI, Kamiya et al. describe a novel approach to efficiently inhibiting surface expression of the inhibitory receptor CD94/NK group 2 member A (NKG2A) through retention of the protein in the endoplasmic reticulum. In adoptive transfer experiments into tumor-bearing immunodeficient mice, NKG2Anull NK cells were significantly more effective at eliminating HLA-E–expressing tumor cells than NKG2A+ NK cells. This study provides proof of concept for a new immunotherapeutic approach using NKG2Anull NK cells.
Frank Cichocki, Jeffrey S. Miller
Cancer stem cells sustain propagation of the deadly primary brain cancer glioblastoma. Glioblastoma stem cells (GSCs) characterized by a mesenchymal phenotype are aggressive and resistant to therapies and represent a crucial therapeutic target. In this issue of the JCI, Chen et al. show that the intracellular levels of aldehyde dehydrogenase 1A3 (ALDH1A3), known as a functional marker of mesenchymal GSCs, are regulated posttranslationally by ubiquitin-specific protease 9X–mediated (USP9X-mediated) deubiquitination. Increased expression of USP9X stabilizes ALDH1A3, enabling GSCs to exhibit mesenchymal traits and the malignant phenotype. Thus, the USP9X-ALDH1A3 axis may offer a novel therapeutic target in glioblastoma.
Eosinophilic esophagitis (EoE) is a recently described disease in which exposure to specific foods and allergens leads to type 2 inflammation, epithelial barrier dysfunction, and difficulty in swallowing. In the current issue of the JCI, Wen and colleagues investigate tissue T cell heterogeneity in patients with EoE using single-cell RNA sequencing (scRNA-seq). Esophageal epithelium from individuals with EoE convtained a prominent population of Th2 cells not seen in controls. The short-chain fatty acid (SCFA) receptor FFAR3 was found to be highly expressed in EoE Th2 cells. Experiments presented here provide evidence that SCFAs may promote type 2 inflammation in allergic diseases such as EoE and asthma. This study provides an early example of scRNA-seq for identifying relevant cell populations and mechanisms underlying allergic diseases.
Walter L. Eckalbar, David J. Erle
The role of urokinase-type plasminogen activator receptor (uPAR) in kidney physiology and pathology has attracted considerable attention. The protein uPAR has dual functions: as a key regulator of plasmin generation and a component of the innate immune system. In the current issue, Wei and colleagues describe a transgenic mouse expressing Plaur RNA in glomerular podocytes. The mice manifested podocyte injury, including c-Src phosphorylation, proteinuria, and focal segmental glomerulosclerosis (FSGS). Plaur-transgenic mice on a β3 integrin–deficient background were protected from podocyte injury. Renal biopsies from subjects with FSGS, but not those with other glomerular diseases, manifested increased c-Src phosphorylation in podocytes. These findings suggest a novel injury mechanism in FSGS, with possible implications for new treatment strategies.
Jeffrey B. Kopp, Jurgen Heymann
In this issue of the JCI, Casas et al. define a previously unknown role of the NADPH oxidase catalytic subunit NOX5 in cerebral infarction. Using a mouse expressing human NOX5 in the endothelium, the investigators show that NOX5 is activated and plays a deleterious role in promoting edema, infarction, and ultimately, worsened neurological function following cerebral ischemia. They provide evidence that this is due to the breakdown of the blood-brain barrier (BBB) and that a unique pharmacological inhibitor of NOX5, ML090, if given early, around the time of reoxygenation, can maintain BBB integrity. Future studies of NOX5 inhibition in humans, particularly in the setting of thrombolysis, are warranted.
Luciana Simão do Carmo, Bradford C. Berk, David G. Harrison
Survivors of sepsis and other forms of critical illness frequently experience significant and disabling cognitive and affective disorders. Inflammation, ischemia, and glial cell dysfunction contribute to this persistent brain injury. In this issue of the JCI, Hippensteel et al. show that endothelial injury in animal models of sepsis or endotoxemia leads to shedding of heparan fragments from the endothelial glycocalyx. These fragments directly sequester brain-derived neurotrophic factor and impair hippocampal long-term potentiation, an electrophysiologic correlate of memory. The authors further explore the specific characteristics of heparan fragments that bind neurotrophins and the presence of these fragments in the circulation of patients who survive sepsis. This study highlights an important mechanism by which vascular injury can impair brain function.
Benjamin H. Singer
Motoneurons are particularly sensitive to mutations in mitofusin-2 (MFN2) that cause the neurological disorder Charcot-Marie-Tooth disease type 2A (CMT2A). MFN2 is a mitochondrial outer membrane protein that, together with its homologue MFN1, fuses mitochondria in most tissues. In this issue of the JCI, Zhou and colleagues show that increasing MFN1 expression in neurons can curtail neurological defects in a CMT2A mouse model. These results show that the ratio of MFN1 to MFN2 can explain the tissue specificity of CMT2A and indicate that augmentation of MFN1 in the nervous system has potential as a possible therapeutic strategy for CMT2A.
Keiko Iwata, Luca Scorrano
Chronic unresolved inflammation contributes to the development of nonalcoholic steatohepatitis (NASH), a disorder characterized by lipotoxicity, fibrosis, and progressive liver dysfunction. In this issue of the JCI, Han et al. report that maresin 1 (MaR1), a proresolving lipid mediator, mitigates NASH by reprograming macrophages to an antiinflammatory phenotype. Mechanistically, they identified retinoic acid–related orphan receptor α (RORα) as both a target and autocrine regulator of MaR1 production. Because NASH is associated with many widely occurring metabolic diseases, including obesity and type 2 diabetes, identification of this endogenous protective pathway could have broad therapeutic implications.
The identification of JAK2 mutations as disease-initiating in myeloproliferative neoplasms (MPNs) has led to new and effective therapies for these diseases. In a study published in this issue of the JCI, Stivala et al. explored the key observation that JAK inhibition successfully suppresses MAPK activation in MPN cell lines and primary MPN cells in vitro, and the finding that it failed to completely and effectively suppress MAPK activation in vivo in two mouse models. The authors went on to show that dual inhibition of JAK and the MAP kinase pathway provided enhanced therapeutic efficacy in the in vivo models of MPN.
David A. Williams
Genetically engineered T cells have shown promising activity in the treatment of cancer. However, these cells are also potentially susceptible to immune-suppressive pathways in the tumor microenvironment that may limit their efficacy. In this issue of the JCI, Yamamoto et al. describe a new cellular engineering approach to prevent Fas-mediated inhibition of T cell function, which may be exploited to improve cellular therapy for cancer.
Madhav V. Dhodapkar
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