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Cross-talk between HIF and PD-1/PD-L1 pathways in carcinogenesis and therapy
Michael R. Shurin, Viktor Umansky
Michael R. Shurin, Viktor Umansky
Published May 2, 2022
Citation Information: J Clin Invest. 2022;132(9):e159473. https://doi.org/10.1172/JCI159473.
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Cross-talk between HIF and PD-1/PD-L1 pathways in carcinogenesis and therapy

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Abstract

Tumor-associated hypoxia plays an important role in carcinogenesis and metastasis. The expression, activation, and stabilization of hypoxia-inducible transcription factors (HIFs) support malignant cell survival, proliferation, plasticity, and motility. Hypoxia also upregulates the expression of programmed cell death ligand 1 (PD-L1) in malignant and immune regulatory cells. Therefore, the combination of HIF inhibitors and checkpoint inhibitors (CPIs) is promising for boosting antitumor immunity and diminishing malignant cell plasticity and therapy resistance. In this issue of the JCI, Salman et al. report the development of a specific agent that inhibited HIF-1/2–mediated gene expression in tumor cells and suppressed tumor growth. Bailey, Liu, et al. in this issue demonstrate that targeting HIF-1α abrogated PD-L1–mediated immune evasion by suppressing PD-L1 expression on malignant and myeloid regulatory cells, causing tumor rejection. These findings suggest that targeting the HIF/PD-L1 axis with specific HIF inhibitors should improve the safety and efficacy of CPIs for cancer therapy.

Authors

Michael R. Shurin, Viktor Umansky

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Macrophage efferocytosis with VEGFC and lymphangiogenesis: rescuing the broken heart
Patricia A. D’Amore, Pilar Alcaide
Patricia A. D’Amore, Pilar Alcaide
Published May 2, 2022
Citation Information: J Clin Invest. 2022;132(9):e158703. https://doi.org/10.1172/JCI158703.
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Macrophage efferocytosis with VEGFC and lymphangiogenesis: rescuing the broken heart

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Abstract

Cardiac repair following ischemic injury is indispensable for survival and requires a coordinated cellular response involving the mobilization of immune cells from the secondary lymphoid organs to the site of damage. Efferocytosis, the engulfment of cell debris and dying cells by innate immune cells, along with lymphangiogenesis, the formation of new lymphatic vessels, are emerging as central to the cardiac healing response. In this issue of the JCI, Glinton et al. used state-of-the-art approaches to demonstrate that efferocytosis induced vascular endothelial growth factor C (VEGFC) in myeloid cells and stimulated lymphangiogenesis and cardiac repair. These findings provide impactful mechanistic information that can be leveraged to therapeutically target pathways in cardiac repair and ischemic heart failure.

Authors

Patricia A. D’Amore, Pilar Alcaide

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Labile iron accumulation augments T follicular helper cell differentiation
Yogesh Scindia, … , Borna Mehrad, Laurence Morel
Yogesh Scindia, … , Borna Mehrad, Laurence Morel
Published May 2, 2022
Citation Information: J Clin Invest. 2022;132(9):e159472. https://doi.org/10.1172/JCI159472.
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Labile iron accumulation augments T follicular helper cell differentiation

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Abstract

T follicular helper (Tfh) cells are a subset of CD4+ T cells that are essential in the pathogenesis of systemic lupus erythematosus (SLE). Notably, iron is required for activated CD4+ T lymphocytes to sustain high proliferation and metabolism. In this issue of the JCI, Gao et al. showed that CD4+ T cells from patients with SLE accumulated iron, augmenting their differentiation into Tfh cells and correlating with disease activity. Using human cells and murine models, the authors demonstrated that miR-21 was overexpressed in lupus T cells and inhibited 3-hydroxybutyrate dehydrogenase-2 (BDH2). The subsequent loss of BDH2 drove labile iron to accumulate in the cytoplasm and promoted TET enzyme activity, BCL6 gene demethylation, and Tfh cell differentiation. This work identifies a role for iron in CD4+ T cell biology and the development of pathogenic effectors in SLE. We await future investigations that could determine whether modulating iron levels could regulate Tfh cells in human health and disease.

Authors

Yogesh Scindia, Borna Mehrad, Laurence Morel

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Is thermogenesis really needed for brown adipose tissue–mediated metabolic benefit?
Jin-Seon Yook, Shingo Kajimura
Jin-Seon Yook, Shingo Kajimura
Published May 2, 2022
Citation Information: J Clin Invest. 2022;132(9):e159296. https://doi.org/10.1172/JCI159296.
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Is thermogenesis really needed for brown adipose tissue–mediated metabolic benefit?

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Abstract

Brown adipose tissue (BAT) dissipates energy in the form of heat and functions as a metabolic sink for lipids, glucose, and branched-chain amino acids. Enhanced BAT thermogenesis is thought to tightly couple with beneficial energy metabolism. However, in this issue of the JCI, Huang et al. report a mouse model in which BAT thermogenesis was impaired, yet systemic glucose and lipid homeostasis were improved, on a high-fat diet compared with what occurred in control mice. The authors showed that BAT-specific deletion of mitochondrial thioredoxin-2 (TRX2) impaired adaptive thermogenesis through elevated mitochondrial reactive oxygen species (ROS) and cytosolic efflux of mitochondrial DNA. On the other hand, TRX2 loss enhanced lipid uptake in the BAT and protected mice from obesity, hypertriglyceridemia, and insulin resistance. This study provides a unique model in which BAT does not require thermogenesis per se to function as a lipid sink that leads to metabolic benefits in vivo.

Authors

Jin-Seon Yook, Shingo Kajimura

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Short-term senolytic treatment: a paradigm to promote fracture repair during aging
Isabel Beerman, … , Nathan Basisty, Rafael de Cabo
Isabel Beerman, … , Nathan Basisty, Rafael de Cabo
Published April 15, 2022
Citation Information: J Clin Invest. 2022;132(8):e158871. https://doi.org/10.1172/JCI158871.
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Short-term senolytic treatment: a paradigm to promote fracture repair during aging

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Abstract

Increased age is blamed for a wide range of bone physiological changes, and although the underlying mechanisms affecting the decreased capacity for fracture healing are not fully understood, they are clearly linked to changes at the cellular level. Recent evidence suggests potential roles of senescent cells in response to most tissue injuries, including bone fractures. In this issue of the JCI, Liu, Zhang, and co-authors showed that a senolytic drug cocktail cleared senescent cells from the callus and improved bone fracture repair in aged mice. Understanding how senescent cells emerge at fracture sites and how their timely removal improves fracture healing should provide insights for effective therapeutic approaches in old age.

Authors

Isabel Beerman, Nathan Basisty, Rafael de Cabo

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Tumor Treating Fields: killing two birds with one stone
Juyeun Lee, … , Matthew M. Grabowski, Justin D. Lathia
Juyeun Lee, … , Matthew M. Grabowski, Justin D. Lathia
Published April 15, 2022
Citation Information: J Clin Invest. 2022;132(8):e159073. https://doi.org/10.1172/JCI159073.
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Tumor Treating Fields: killing two birds with one stone

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Abstract

Given its aggressive natural history and immunosuppressive nature, glioblastoma (GBM) remains difficult to treat. Tumor Treating Fields (TTFields) are a promising treatment for GBM patients, yet the entirety of their antitumor action has not been fully elucidated. In a recent issue of the JCI, Chen et al. explored the effect of TTFields in reinvigorating immune responses. By elegant step-by-step approaches, the authors demonstrated that TTFields promote the production of immune-stimulating proinflammatory and interferon type 1 cytokines in tumor cells in a cGAS/STING- and AIM2 inflammasome–dependent mechanism, thereby activating the immune system. The findings show that TTFields not only directly inhibit tumor cell growth, as previously reported, but enhance antitumor immunity, suggesting TTFields can be used as an immune-modulating approach in GBM.

Authors

Juyeun Lee, Matthew M. Grabowski, Justin D. Lathia

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Mitochondria and the future of RASopathies: the emergence of bioenergetics
Maria I. Kontaridis, Saravanakkumar Chennappan
Maria I. Kontaridis, Saravanakkumar Chennappan
Published April 15, 2022
Citation Information: J Clin Invest. 2022. https://doi.org/10.1172/JCI157560.
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Mitochondria and the future of RASopathies: the emergence of bioenergetics

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Abstract

RASopathies are a family of rare autosomal dominant disorders that affect the canonical Ras/MAPK signaling pathway and manifest as neurodevelopmental systemic syndromes, including Costello syndrome (CS). In this issue of the JCI, Dard et al. describe the molecular determinants of CS using a myriad of genetically modified models, including mice expressing HRAS p.G12S, patient-derived skin fibroblasts, hiPSC-derived human cardiomyocytes, an HRAS p.G12V zebrafish model, and human lentivirally induced fibroblasts overexpressing HRAS p.G12S or HRAS p.G12A. Mitochondrial proteostasis and oxidative phosphorylation were altered in CS, and inhibition of the AMPK signaling pathway mediated bioenergetic changes. Importantly, the pharmacological induction of this pathway restored cardiac function and reduced the developmental defects associated with CS. These findings identify a role for altered bioenergetics and provide insights into more effective treatment strategies for patients with RASopathies.

Authors

Maria I. Kontaridis, Saravanakkumar Chennappan

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Bacteria may be in the liver, but the jury is still out
Nichole A. Broderick, Laszlo Nagy
Nichole A. Broderick, Laszlo Nagy
Published April 15, 2022
Citation Information: J Clin Invest. 2022;132(8):e158999. https://doi.org/10.1172/JCI158999.
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Bacteria may be in the liver, but the jury is still out

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A fundamental and highly contested issue in microbiome research is whether internal organs such as the liver, brain, placenta, pancreas, and others are sterile and privileged or harbor a detectable and functional microbial biomass. In this issue of the JCI, Leinwand, Paul, et al. addressed this question using an array of diverse techniques and reported that normal healthy liver possesses a microbiome that is selectively recruited from the gut. They further showed that liver-enriched microbes contributed to shaping the immune network of this organ. Here, we attempt to put their findings into the context of other organs, discuss the technical challenges of defining such microbial communities, and provide some perspective about the road ahead for the field.

Authors

Nichole A. Broderick, Laszlo Nagy

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The FoxOs are in the ApoM house
MacRae F. Linton, … , Zoe M. Leuthner, Jonathan D. Brown
MacRae F. Linton, … , Zoe M. Leuthner, Jonathan D. Brown
Published April 1, 2022
Citation Information: J Clin Invest. 2022;132(7):e158471. https://doi.org/10.1172/JCI158471.
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The FoxOs are in the ApoM house

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Abstract

The prevalence of metabolic syndrome continues to increase globally and heightens the risk for cardiovascular disease (CVD). Insulin resistance is a core pathophysiologic mechanism that causes abnormal carbohydrate metabolism and atherogenic changes in circulating lipoprotein quantity and function. In particular, dysfunctional HDL is postulated to contribute to CVD risk in part via loss of HDL-associated sphingosine-1-phosphate (S1P). In this issue of the JCI, Izquierdo et al. demonstrate that HDL from humans with insulin resistance contained lower levels of S1P. Apolipoprotein M (ApoM), a protein constituent of HDL that binds S1P and controls bioavailability was decreased in insulin-resistant db/db mice. Gain- and loss-of-function mouse models implicated the forkhead box O transcription factors (FoxO1,3,4) in the regulation of both ApoM and HDL-associated S1P. These data have important implications for potential FoxO-based therapies designed to treat lipid and carbohydrate abnormalities associated with human metabolic disease and CVD.

Authors

MacRae F. Linton, Patricia G. Yancey, Zoe M. Leuthner, Jonathan D. Brown

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Training can’t always lead to Olympic macrophages
Erwan Pernet, … , Renaud Prevel, Maziar Divangahi
Erwan Pernet, … , Renaud Prevel, Maziar Divangahi
Published April 1, 2022
Citation Information: J Clin Invest. 2022;132(7):e158468. https://doi.org/10.1172/JCI158468.
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Training can’t always lead to Olympic macrophages

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Abstract

Although the memory capacity of innate immune cells, termed trained immunity (TI), is a conserved evolutionary trait, the cellular and molecular mechanisms involved are incompletely understood. One fundamental question is whether the induction of TI generates a homogeneous or heterogeneous population of trained cells. In this issue of the JCI, Zhang, Moorlag, and colleagues tackle this question by combining an in vitro model system of TI with single-cell RNA sequencing. The induction of TI in human monocytes resulted in three populations with distinct transcriptomic profiles. Interestingly, the presence of lymphocytes in the microenvironment of monocytes substantially impacted TI. The authors also identified a similar population of monocytes in various human diseases or in individuals vaccinated with bacillus Calmette-Guérin. These insights warrant in-depth analysis of TI in responsive versus nonresponsive immune cells and suggest that modulating TI may provide a strategy for treating infections and inflammatory diseases.

Authors

Erwan Pernet, Renaud Prevel, Maziar Divangahi

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