Hepatic glucose production (HGP) is a key determinant of glucose homeostasis. Glucagon binding to its cognate seven-transmembrane Gs-coupled receptor in hepatocytes stimulates cAMP production, resulting in increased HGP. In this issue of the JCI, Rossi and colleagues tested the hypothesis that activation of hepatic Gi–coupled receptors, which should inhibit cAMP production, would oppose the cAMP-inducing action of glucagon and thereby decrease HGP. Surprisingly, however, the opposite occurred: activation of Gi signaling increased HGP via a novel mechanism, while inhibition of Gi signaling reduced HGP. These results define a new physiologic role for hepatic Gi signaling and identify a potential therapeutic target for HGP regulation.
Allen M. Spiegel
Tumors frequently escape from immune surveillance by hijacking the natural control mechanisms that regulate normal immune responses. The programmed death-1 receptor (PD‑1) on T cells normally helps limit excessive immune activation, but it can also suppress beneficial antitumor immunity. In the clinic, blocking either PD‑1 or one of its principal counterligands, programmed death–ligand 1 (PD‑L1), can lead to dramatic responses in certain patients. Because PD‑L1 can be expressed by both the tumor cells themselves and also the host cells, including host immune cells, the actual mechanistic target of therapy has remained unclear. In the current issue of the JCI, two papers, one by Tang and colleagues and the other by Lin and colleagues, used a variety of mouse tumor models to demonstrate that the relevant target for therapy in each case was the PD‑L1 molecules expressed by host cells and not by tumor cells. If this finding is generalized to humans, then it would suggest that the tumor persuades the host to actively suppress its own attempted immune response against the tumor cells.
David H. Munn
Hepatitis B virus (HBV) infection can be managed clinically with nucleos(t)ide therapy, which suppresses viral replication; however, these drugs must often be used long term, as they are unable to fully eliminate the virus. For many patients, discontinuation of treatment results in viral resurgence and hepatic flare, and there is not a reliable way to identify those individuals that can be successfully taken off nucleos(t)ide therapy. In this issue of the JCI, Rivino and colleagues report on their use of a multipronged approach to investigate potential biomarkers indicative of HBV-infected patients who can safely stop nucleos(t)ide therapy. The authors identified a population of HBV-specific, PD1-positive T cells that was present in HBV-infected patients who successfully discontinued treatment without hepatic flare, but not in those that developed flare upon treatment cessation. Together, these results support the concept that PD1+ cells may play an important role in viral control, the further evaluation of this T cell subset in preventing hepatic flare, and the development of assays to better detect this PD1+ T cell population in HBV-infected patients on nucleos(t)ide therapy.
Immune checkpoint inhibitors are becoming a cornerstone of cancer immunotherapy as a result of their clinical success in relieving immune suppression and driving durable antitumor T cell responses in certain subsets of patients. Unfortunately, checkpoint inhibition is also associated with treatment-related toxicities that result in a myriad of side effects, ranging from mild and manageable to severe and debilitating. In this issue of the JCI, Das and colleagues report an association between early therapy-induced changes in circulating B cells and an increased risk of high-grade immune-related adverse events (IRAEs) in patients treated with checkpoint inhibitors that target cytotoxic T lymphocyte–associated antigen-4 (CTLA4) and programmed cell death protein 1 (PD1). These findings identify potential predictive biomarkers for high-grade IRAEs that may be leveraged to improve patient monitoring and may prompt new treatment strategies to prevent IRAEs.
Shannon M. Liudahl, Lisa M. Coussens
White matter abnormalities are prevalent in neuropsychiatric disorders such as schizophrenia, but it is unclear whether these abnormalities represent a cause or consequence of these disorders. Reduced levels of the myelin protein 2′-3′-cyclic nucleotide 3′-phosphodiesterase (CNP) are associated with the schizophrenic symptom catatonia in both humans and mouse models. In this issue of the JCI, Janova et al. show that reduced CNP levels correlate with catatonia and white matter inflammation in human subjects. Furthermore, they demonstrate that microglial ablation prevents and alleviates catatonic signs in Cnp–/– mice, indicating that microglial-mediated inflammation causes catatonia. Together, this study identifies a cellular mechanism by which subtle myelin abnormalities cause low-grade neuroinflammation and catatonic behavior.
Sarah E. Pease-Raissi, Jonah R. Chan
Most of the adult CNS lacks regenerative activity in terms of both neuron birth and neurite outgrowth. While this regeneration-unfriendly environment of the adult CNS may preserve the existing neuronal circuitry that takes years to develop in higher organisms, it also poses a major obstacle for CNS repair later in life. In this issue of the JCI, Song et al. report on their development of a strategy that uses region-specific and molecularly engineered astrocytes to turn an unfavorable brain environment into a favorable one for engrafted neural stem/progenitor cells (NSC/NPCs). In a rat model of Parkinson’s disease (PD), cografting NPCs with midbrain-derived astrocytes engineered to overexpress the transcription factors Nurr1 and Foxa2 promotes maturation and survival of the graft, resulting in therapeutic improvement. The results of this study raise the prospect of using modified astrocytes to improve the survival, maturation, and integration of engrafted NSC/NPCs as a restorative treatment for PD.
Robert Y.L. Tsai
Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common heritable peripheral neuropathy and results from a duplication on chromosome 17 that results in an extra copy and increased dosage of peripheral myelin protein 22 (PMP22). Zhao et al., in this issue of the JCI, successfully utilized antisense oligonucleotides (ASOs) to reduce PMP22 and ameliorated neuropathy in both mouse and rat models of CMT1A. These data confirm that strategies to reduce PMP22 have potential as effective therapeutic approaches for CMT1A and lay the groundwork for clinical trials in humans afflicted with this chronic, debilitating neurodegenerative disease.
Michael E. Shy
The inappropriate activation of transcription factors, including STATs, is known to promote tumor initiation and progression. The most common mechanisms of misregulation lead to constitutive activation of WT STATs. However, the recent discovery of rare STAT mutations in hematopoietic malignancies suggests that STAT mutants may be oncogenic. In this issue of the JCI, Pham et al. use a transgenic mouse model to demonstrate that STAT5BN642H is sufficient for the development of T cell neoplasia. This study, along with other studies of constitutively active STAT mutants, provides insight into the pathogenesis and treatment of STAT5-driven cancer.
Lisa N. Heppler, David A. Frank
Ubiquitylation is a tightly regulated process that is essential for appropriate cell survival and function, and the ubiquitin pathway has shown promise as a therapeutic target for several forms of cancer. In this issue of the JCI, Kedves and colleagues report the identification of a subset of gynecological cancers with repressed expression of the polyubiquitin gene UBB, which renders these cancer cells sensitive to further decreases in ubiquitin production by inhibition of the polyubiquitin gene UBC. Moreover, inducible depletion of UBC in mice harboring tumors with low UBB levels dramatically decreased tumor burden and prolonged survival. Together, the results of this study indicate that there is a synthetic lethal relationship between UBB and UBC that has potential to be exploited as a therapeutic strategy to fight these devastating cancers.
Diane L. Haakonsen, Michael Rape
The prevalence of food allergies has been increasing at an alarming rate over the last few decades. Despite the dramatic increase in disease prevalence, the development of effective therapies has not kept pace. In this issue of the JCI, Ando et al. provide a causal link between histamine-releasing factor (HRF) interactions with IgE and food allergy in a murine model. Successful oral immunotherapy of both egg-allergic human patients and food-allergic mice was associated with sustained suppression of HRF-reactive IgE levels. These results support a role for HRF-IgE interactions in the amplification of intestinal inflammation and suggest HRF as a therapeutic target in food allergy.
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