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Issue published August 8, 2019

  • Volume 4, Issue 15
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  • Research Articles
  • Review
  • Editorial
Intracellular retention of mutant lysyl oxidase leads to aortic dilation in response to increased hemodynamic stress

In this issue, Lee et al. generated a mouse model of a mutation in lysyl oxidase that is associated with increased risk for thoracic aortic aneurysm and dissection in humans. They report that animals only developed aneurysmal disease in conjunction with hypertension, as a result of vessel wall thickening and alterations in aortic cell populations, including a decrease of smooth muscle cells and increased immune cell infiltration. The cover image shows immune cell infiltration (CD68, green) and elastin staining (red) in a descending aorta of a WT mouse following treatment with angiotensin II. Nuclei stained blue with DAPI.

Editorial
Come sail away
Howard A. Rockman
Howard A. Rockman
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e131371. https://doi.org/10.1172/jci.insight.131371.
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Come sail away

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Abstract

Authors

Howard A. Rockman

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Review
Necroptosis: a crucial pathogenic mediator of human disease
Mary E. Choi, … , Stefan W. Ryter, Augustine M. K. Choi
Mary E. Choi, … , Stefan W. Ryter, Augustine M. K. Choi
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e128834. https://doi.org/10.1172/jci.insight.128834.
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Necroptosis: a crucial pathogenic mediator of human disease

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Abstract

Necroptosis is a genetically regulated form of necrotic cell death that has emerged as an important pathway in human disease. The necroptosis pathway is induced by a variety of signals, including death receptor ligands, and regulated by receptor-interacting protein kinases 1 and 3 (RIPK1 and RIPK3) and mixed-lineage kinase domain–like pseudokinase (MLKL), which form a regulatory necrosome complex. RIPK3-mediated phosphorylation of MLKL executes necroptosis. Recent studies, using animal models of tissue injury, have revealed that RIPK3 and MLKL are key effectors of injury propagation. This Review explores the functional roles of RIPK3 and MLKL as crucial pathogenic determinants and markers of disease progression and severity in experimental models of human disease, including acute and chronic pulmonary diseases; renal, hepatic, cardiovascular, and neurodegenerative diseases; cancer; and critical illness.

Authors

Mary E. Choi, David R. Price, Stefan W. Ryter, Augustine M. K. Choi

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Research Articles
Restoration of insulin receptor improves diabetic phenotype in T2DM mice
Yichen Wang, … , Oksana Palyha, James Mu
Yichen Wang, … , Oksana Palyha, James Mu
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e124945. https://doi.org/10.1172/jci.insight.124945.
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Restoration of insulin receptor improves diabetic phenotype in T2DM mice

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Abstract

Type 2 diabetes mellitus (T2DM), also known as adult-onset diabetes, is characterized by ineffective insulin action due to insulin resistance in key metabolic tissues. Insulin receptor (IR) plays an important role in insulin signal transduction, defect of which has been considered the fundamental cause of T2DM. IR content reduction in diabetes is one key contributor to the defective insulin signaling and diabetes progression. Rescuing IR levels by transgenic complementation has not been considered as a treatment option because it is limited by uncontrollable expression level, tissue selectivity, or developmental defects. In the current study, we demonstrated that single-dose adeno-associated virus (AAV) vector delivered expression of human IR (hIR) in the liver of inducible IR-knockout mice and significantly improved the diabetic phenotype caused by IR deletion during adulthood. Such an approach was also applied, for the first time to our knowledge, to treating ob/ob mice, a model of severe T2DM attributed to superfluous calorie intake and insulin resistance. Interestingly, similar treatment with AAV-hIR had no obvious effect in healthy animals, indicative of low hypoglycemic risk as a consequence of potential excessive insulin action. The results described here support restoration of IR expression as a safe and effective T2DM therapeutic with a long-lasting profile.

Authors

Yichen Wang, Heather Zhou, Oksana Palyha, James Mu

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Inactivation of Sox9 in fibroblasts reduces cardiac fibrosis and inflammation
Gesine M. Scharf, … , Johann Bauersachs, Joerg Heineke
Gesine M. Scharf, … , Johann Bauersachs, Joerg Heineke
Published July 16, 2019
Citation Information: JCI Insight. 2019;4(15):e126721. https://doi.org/10.1172/jci.insight.126721.
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Inactivation of Sox9 in fibroblasts reduces cardiac fibrosis and inflammation

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Abstract

Fibrotic scarring drives the progression of heart failure after myocardial infarction (MI). Therefore, the development of specific treatment regimens to counteract fibrosis is of high clinical relevance. The transcription factor sex-determining region Y box 9 (SOX9) functions as an important regulator during embryogenesis, but recent data point toward an additional causal role in organ fibrosis. We show here that SOX9 is upregulated in the scar after MI in mice. Fibroblast-specific deletion of Sox9 ameliorated MI-induced left ventricular dysfunction, dilatation, and myocardial scarring in vivo. Unexpectedly, deletion of Sox9 also potently eliminated persisting leukocyte infiltration of the scar in the chronic phase after MI. RNA-Seq from the infarct scar revealed that Sox9 deletion in fibroblasts resulted in strongly downregulated expression of genes related to extracellular matrix, proteolysis, and inflammation. Importantly, Sox9 deletion in isolated cardiac fibroblasts in vitro similarly affected gene expression as in the cardiac scar and reduced fibroblast proliferation, migration, and contraction capacity. Together, our data demonstrate that fibroblast SOX9 functions as a master regulator of cardiac fibrosis and inflammation and might constitute a novel therapeutic target during MI.

Authors

Gesine M. Scharf, Katja Kilian, Julio Cordero, Yong Wang, Andrea Grund, Melanie Hofmann, Natali Froese, Xue Wang, Andreas Kispert, Ralf Kist, Simon J. Conway, Robert Geffers, Kai C. Wollert, Gergana Dobreva, Johann Bauersachs, Joerg Heineke

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ORC-13661 protects sensory hair cells from aminoglycoside and cisplatin ototoxicity
Siân R. Kitcher, … , Guy P. Richardson, Corné J. Kros
Siân R. Kitcher, … , Guy P. Richardson, Corné J. Kros
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e126764. https://doi.org/10.1172/jci.insight.126764.
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ORC-13661 protects sensory hair cells from aminoglycoside and cisplatin ototoxicity

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Abstract

Aminoglycoside (AG) antibiotics are widely used to prevent life-threatening infections, and cisplatin is used in the treatment of various cancers, but both are ototoxic and result in loss of sensory hair cells from the inner ear. ORC-13661 is a new drug that was derived from PROTO-1, a compound first identified as protective in a large-scale screen utilizing hair cells in the lateral line organs of zebrafish larvae. Here, we demonstrate, in zebrafish larvae and in mouse cochlear cultures, that ORC-13661 provides robust protection of hair cells against both ototoxins, the AGs and cisplatin. ORC-13661 also prevents both hearing loss in a dose-dependent manner in rats treated with amikacin and the loading of neomycin-Texas Red into lateral line hair cells. In addition, patch-clamp recordings in mouse cochlear cultures reveal that ORC-13661 is a high-affinity permeant blocker of the mechanoelectrical transducer (MET) channel in outer hair cells, suggesting that it may reduce the toxicity of AGs by directly competing for entry at the level of the MET channel and of cisplatin by a MET-dependent mechanism. ORC-13661 is therefore a promising and versatile protectant that reversibly blocks the hair cell MET channel and operates across multiple species and toxins.

Authors

Siân R. Kitcher, Nerissa K. Kirkwood, Esra D. Camci, Patricia Wu, Robin M. Gibson, Van A. Redila, Roberto Ogelman, Julian A. Simon, Edwin W. Rubel, David W. Raible, Guy P. Richardson, Corné J. Kros

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Podoplanin neutralization improves cardiac remodeling and function after myocardial infarction
Maria Cimini, … , Walter J. Koch, Raj Kishore
Maria Cimini, … , Walter J. Koch, Raj Kishore
Published July 9, 2019
Citation Information: JCI Insight. 2019;4(15):e126967. https://doi.org/10.1172/jci.insight.126967.
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Podoplanin neutralization improves cardiac remodeling and function after myocardial infarction

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Abstract

Podoplanin (PDPN), a small mucin-type transmembrane glycoprotein, has been recently shown to be expressed by lymphangiogenic, fibrogenic, and mesenchymal progenitor cells in the acutely and chronically infarcted myocardium. PDPN binds to a C-type lectin–like receptor 2 highly expressed by CD11bhi cells following inflammatory stimuli. Why PDPN expression appears only after organ injury is currently unknown. Here, we characterize the role of PDPN in different stages of myocardial repair after infarction and propose a PDPN-mediated mechanism in the resolution of post–myocardial infarction (MI) inflammatory response and cardiac repair. Neutralization of PDPN led to significant improvements in the left ventricular (LV) functions and scar composition in animals treated with PDPN-neutralizing antibody. The inhibition of the interaction between PDPN and C-type lectin–like receptor 2 expressing immune cells in the heart enhances the cardiac performance, regeneration, and angiogenesis after MI. Our data indicate that modulating the interaction between PDPN-positive cells with the immune cells after MI positively affects immune cell recruitment and may represent a novel therapeutic target to augment post-MI cardiac repair, regeneration, and function.

Authors

Maria Cimini, Venkata Naga Srikanth Garikipati, Claudio de Lucia, Zhongjian Cheng, Chunlin Wang, May M. Truongcao, Anna Maria Lucchese, Rajika Roy, Cindy Benedict, David A. Goukassian, Walter J. Koch, Raj Kishore

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Prohibitin is a prognostic marker and therapeutic target to block chemotherapy resistance in Wilms’ tumor
Michael V. Ortiz, … , Hanno Steen, Alex Kentsis
Michael V. Ortiz, … , Hanno Steen, Alex Kentsis
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e127098. https://doi.org/10.1172/jci.insight.127098.
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Prohibitin is a prognostic marker and therapeutic target to block chemotherapy resistance in Wilms’ tumor

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Abstract

Wilms’ tumor is the most common type of childhood kidney cancer. To improve risk stratification and identify novel therapeutic targets for patients with Wilms’ tumor, we used high-resolution mass spectrometry proteomics to identify urine tumor markers associated with Wilms’ tumor relapse. We determined the urine proteomes at diagnosis of 49 patients with Wilms’ tumor, non–Wilms’ tumor renal tumors, and age-matched controls, leading to the quantitation of 6520 urine proteins. Supervised analysis revealed specific urine markers of renal rhabdoid tumors, kidney clear cell sarcomas, renal cell carcinomas as well as those detected in patients with cured and relapsed Wilms’ tumor. In particular, urine prohibitin was significantly elevated at diagnosis in patients with relapsed as compared with cured Wilms’ tumor. In a validation cohort of 139 patients, a specific urine prohibitin ELISA demonstrated that prohibitin concentrations greater than 998 ng/mL at diagnosis were significantly associated with ultimate Wilms’ tumor relapse. Immunohistochemical analysis revealed that prohibitin was highly expressed in primary Wilms’ tumor specimens and associated with disease stage. Using functional genetic experiments, we found that prohibitin was required for the growth and survival of Wilms’ tumor cells. Overexpression of prohibitin was sufficient to block intrinsic mitochondrial apoptosis and to cause resistance to diverse chemotherapy drugs, at least in part by dysregulating factors that control apoptotic cytochrome c release from mitochondrial cristae. Thus, urine prohibitin may improve therapy stratification, noninvasive monitoring of treatment response, and early disease detection. In addition, therapeutic targeting of chemotherapy resistance induced by prohibitin dysregulation may offer improved therapies for patients with Wilms’ and other relapsed or refractory tumors.

Authors

Michael V. Ortiz, Saima Ahmed, Melissa Burns, Anton G. Henssen, Travis J. Hollmann, Ian MacArthur, Shehana Gunasekera, Lyvia Gaewsky, Gary Bradwin, Jeremy Ryan, Anthony Letai, Ying He, Arlene Naranjo, Yueh-Yun Chi, Michael LaQuaglia, Todd Heaton, Paolo Cifani, Jeffrey S. Dome, Samantha Gadd, Elizabeth Perlman, Elizabeth Mullen, Hanno Steen, Alex Kentsis

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RasGRP1 is a potential biomarker for stratifying anti-EGFR therapy response in colorectal cancer
Oghenekevwe M. Gbenedio, … , Jeroen P. Roose, Philippe Depeille
Oghenekevwe M. Gbenedio, … , Jeroen P. Roose, Philippe Depeille
Published June 25, 2019
Citation Information: JCI Insight. 2019;4(15):e127552. https://doi.org/10.1172/jci.insight.127552.
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RasGRP1 is a potential biomarker for stratifying anti-EGFR therapy response in colorectal cancer

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Abstract

Colorectal cancer (CRC) is the third most frequent neoplastic disorder and is a main cause of tumor-related mortality, as many patients progress to stage IV metastatic CRC. Standard care consists of combination chemotherapy (FOLFIRI or FOLFOX). Patients with WT KRAS typing are eligible to receive anti-EGFR therapy combined with chemotherapy. Unfortunately, predicting efficacy of CRC anti-EGFR therapy has remained challenging. Here we uncovered that the EGFR pathway component RasGRP1 acts as a CRC tumor suppressor in the context of aberrant Wnt signaling. We found that RasGRP1 suppresses EGF-driven proliferation of colonic epithelial organoids. Having established that RasGRP1 dosage levels impact biology, we next focused on CRC patients. Mining 5 different data platforms, we establish that RasGRP1 expression levels decrease with CRC progression and predict poor clinical outcome of patients. Last, deletion of 1 or 2 Rasgrp1 alleles made CRC spheroids more susceptible to EGFR inhibition. Retrospective analysis of the CALGB 80203 clinical trial showed that addition of anti-EGFR therapy to chemotherapy significantly improved outcome for CRC patients when tumors expressed low levels of RasGRP1 suppressor. In sum, our data support RasGRP1 as a biomarker in the EGFR pathway that has potential relevance to anti-EGFR therapy for CRC patients.

Authors

Oghenekevwe M. Gbenedio, Caroline Bonnans, Delphine Grun, Chih-Yang Wang, Ace J. Hatch, Michelle R. Mahoney, David Barras, Mary Matli, Yi Miao, K. Christopher Garcia, Sabine Tejpar, Mauro Delorenzi, Alan P. Venook, Andrew B. Nixon, Robert S. Warren, Jeroen P. Roose, Philippe Depeille

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Skin-restricted commensal colonization accelerates skin graft rejection
Yuk Man Lei, … , Yasmine Belkaid, Maria-Luisa Alegre
Yuk Man Lei, … , Yasmine Belkaid, Maria-Luisa Alegre
Published July 16, 2019
Citation Information: JCI Insight. 2019;4(15):e127569. https://doi.org/10.1172/jci.insight.127569.
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Skin-restricted commensal colonization accelerates skin graft rejection

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Solid organ transplantation can treat end-stage organ failure, but the half-life of transplanted organs colonized with commensals is much shorter than that of sterile organs. Whether organ colonization plays a role in this shorter half-life is not known. We have previously shown that an intact whole-body microbiota can accelerate the kinetics of solid organ allograft rejection in untreated colonized mice, when compared with germ-free (GF) or with antibiotic-pretreated colonized mice, by enhancing the capacity of antigen-presenting cells (APCs) to activate graft-reactive T cells. However, the contribution of intestinal versus skin microbiota to these effects was unknown. Here, we demonstrate that colonizing the skin of GF mice with a single commensal, Staphylococcus epidermidis, while preventing intestinal colonization with oral vancomycin, was sufficient to accelerate skin graft rejection. Notably, unlike the mechanism by which whole-body microbiota accelerates skin graft rejection, cutaneous S. epidermidis did not enhance the priming of alloreactive T cells in the skin-draining lymph nodes. Rather, cutaneous S. epidermidis augmented the ability of skin APCs to drive the differentiation of alloreactive T cells. This study reveals that the extraintestinal donor microbiota can affect transplant outcome and may contribute to the shorter half-life of colonized organs.

Authors

Yuk Man Lei, Martin Sepulveda, Luqiu Chen, Ying Wang, Isabella Pirozzolo, Betty Theriault, Anita S. Chong, Yasmine Belkaid, Maria-Luisa Alegre

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Identification and therapeutic rescue of autophagosome and glutamate receptor defects in C9ORF72 and sporadic ALS neurons
Yingxiao Shi, … , Berislav V. Zlokovic, Justin K. Ichida
Yingxiao Shi, … , Berislav V. Zlokovic, Justin K. Ichida
Published July 16, 2019
Citation Information: JCI Insight. 2019;4(15):e127736. https://doi.org/10.1172/jci.insight.127736.
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Identification and therapeutic rescue of autophagosome and glutamate receptor defects in C9ORF72 and sporadic ALS neurons

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Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with diverse etiologies. Therefore, the identification of common disease mechanisms and therapeutics targeting these mechanisms could dramatically improve clinical outcomes. To this end, we developed induced motor neuron (iMN) models from C9ORF72 and sporadic ALS patients to identify targets that are effective against these types of cases, which together comprise approximately 90% of patients. We find that iMNs from C9ORF72 and several sporadic ALS patients share 2 common defects — impaired autophagosome formation and the aberrant accumulation of glutamate receptors. Moreover, we show that an anticoagulation-deficient form of activated protein C, 3K3A-APC, rescues these defects in both C9ORF72 and sporadic ALS iMNs. As a result, 3K3A-APC treatment lowers C9ORF72 dipeptide-repeat protein (DPR) levels, restores nuclear TDP-43 localization, and rescues the survival of both C9ORF72 and sporadic ALS iMNs. Importantly, 3K3A-APC also lowers glutamate receptor levels and rescues proteostasis in vivo in C9ORF72 gain- and loss-of-function mouse models. Thus, motor neurons from C9ORF72 and at least a subset of sporadic ALS patients share early defects in autophagosome formation and glutamate receptor homeostasis and a single therapeutic approach may be efficacious against these disease processes.

Authors

Yingxiao Shi, Shu-Ting Hung, Gabriel Rocha, Shaoyu Lin, Gabriel R. Linares, Kim A. Staats, Carina Seah, Yaoming Wang, Michael Chickering, Jesse Lai, Tohru Sugawara, Abhay P. Sagare, Berislav V. Zlokovic, Justin K. Ichida

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Intracellular retention of mutant lysyl oxidase leads to aortic dilation in response to increased hemodynamic stress
Vivian S. Lee, … , Nathan O. Stitziel, Robert P. Mecham
Vivian S. Lee, … , Nathan O. Stitziel, Robert P. Mecham
Published June 18, 2019
Citation Information: JCI Insight. 2019;4(15):e127748. https://doi.org/10.1172/jci.insight.127748.
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Intracellular retention of mutant lysyl oxidase leads to aortic dilation in response to increased hemodynamic stress

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Heterozygous missense mutations in lysyl oxidase (LOX) are associated with thoracic aortic aneurysms and dissections. To assess how LOX mutations modify protein function and lead to aortic disease, we studied the factors that influence the onset and progression of vascular aneurysms in mice bearing a Lox mutation (p.M292R) linked to aortic dilation in humans. We show that mice heterozygous for the M292R mutation did not develop aneurysmal disease unless challenged with increased hemodynamic stress. Vessel dilation was confined to the ascending aorta, although in both ascending and descending aortae, changes in vessel wall structure, smooth muscle cell number, and inflammatory cell recruitment differed between WT and mutant animals. Studies with isolated cells revealed that M292R-mutant LOX is retained in the endoplasmic reticulum and ultimately cleared through an autophagy/proteasome pathway. Because the mutant protein does not transit to the Golgi, where copper incorporation occurs, the protein is never catalytically active. These studies show that the M292R mutation results in LOX loss of function due to a secretion defect that predisposes the ascending aorta in mice (and by extension humans with similar mutations) to arterial dilation when exposed to risk factors that impart stress to the arterial wall.

Authors

Vivian S. Lee, Carmen M. Halabi, Thomas J. Broekelmann, Philip C. Trackman, Nathan O. Stitziel, Robert P. Mecham

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Fatty acid synthase downregulation contributes to acute lung injury in murine diet-induced obesity
Maria Plataki, … , Suzanne M. Cloonan, Augustine M.K. Choi
Maria Plataki, … , Suzanne M. Cloonan, Augustine M.K. Choi
Published July 9, 2019
Citation Information: JCI Insight. 2019;4(15):e127823. https://doi.org/10.1172/jci.insight.127823.
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Fatty acid synthase downregulation contributes to acute lung injury in murine diet-induced obesity

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Abstract

The prevalence of obesity is rising worldwide, and obese patients constitute a specific population in the intensive care unit. Acute respiratory distress syndrome (ARDS) incidence is increased in obese patients. Exposure of rodents to hyperoxia mimics many of the features of ARDS. In this report, we demonstrate that high-fat diet–induced obesity increases the severity of hyperoxic acute lung injury in mice in part by altering fatty acid synthase (FASN) levels in the lung. Obese mice exposed to hyperoxia had significantly reduced survival and increased lung damage. Transcriptomic analysis of lung homogenates identified Fasn as one of the most significantly altered mitochondria-associated genes in mice receiving a 60% compared with 10% fat diet. FASN protein levels in the lung of high-fat diet mice were lower by immunoblotting and immunohistochemistry. Depletion of FASN in type II alveolar epithelial cells resulted in altered mitochondrial bioenergetics and more severe lung injury with hyperoxic exposure, even upon administration of a 60% fat diet. This is the first study to our knowledge to show that a high-fat diet leads to altered FASN expression in the lung, and that both a high-fat diet and reduced FASN expression in alveolar epithelial cells promote lung injury.

Authors

Maria Plataki, LiChao Fan, Elizabeth Sanchez, Ziling Huang, Lisa K. Torres, Mitsuru Imamura, Yizhang Zhu, David E. Cohen, Suzanne M. Cloonan, Augustine M.K. Choi

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An Hb-mediated circulating macrophage contributing to pulmonary vascular remodeling in sickle cell disease
Katherine Redinus, … , Paul W. Buehler, David C. Irwin
Katherine Redinus, … , Paul W. Buehler, David C. Irwin
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e127860. https://doi.org/10.1172/jci.insight.127860.
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An Hb-mediated circulating macrophage contributing to pulmonary vascular remodeling in sickle cell disease

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Abstract

Circulating macrophages recruited to the lung contribute to pulmonary vascular remodeling in various forms of pulmonary hypertension (PH). In this study we investigated a macrophage phenotype characterized by intracellular iron accumulation and expression of antioxidant (HO-1), vasoactive (ET-1), and proinflammatory (IL-6) mediators observed in the lung tissue of deceased sickle cell disease (SCD) patients with diagnosed PH. To this end, we evaluated an established rat model of group 5 PH that is simultaneously exposed to free hemoglobin (Hb) and hypobaric hypoxia (HX). Here, we tested the hypothesis that pulmonary vascular remodeling observed in human SCD with concomitant PH could be replicated and mechanistically driven in our rat model by a similar macrophage phenotype with iron accumulation and expression of a similar mixture of antioxidant (HO-1), vasoactive (ET-1), and inflammatory (IL-6) proteins. Our data suggest phenotypic similarities between pulmonary perivascular macrophages in our rat model and human SCD with PH, indicating a potentially novel maladaptive immune response to concomitant bouts of Hb and HX exposure. Moreover, by knocking out circulating macrophages with gadolinium trichloride (GdCl3), the response to combined Hb and hypobaric HX was significantly attenuated in rats, suggesting a critical role for macrophages in the exacerbation of SCD PH.

Authors

Katherine Redinus, Jin Hyen Baek, Ayla Yalamanoglu, Hye Kyung H. Shin, Radu Moldova, Julie W. Harral, Delaney Swindle, David Pak, Scott K. Ferguson, Rachelle Nuss, Kathryn Hassell, Eva Nozik-Grayck, Andre F. Palmer, Mehdi A. Fini, Vijaya Karoor, Kurt R. Stenmark, Paul W. Buehler, David C. Irwin

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Dual inhibition of complement factor 5 and leukotriene B4 synergistically suppresses murine pemphigoid disease
Tanya Sezin, … , Miles A. Nunn, Christian D. Sadik
Tanya Sezin, … , Miles A. Nunn, Christian D. Sadik
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e128239. https://doi.org/10.1172/jci.insight.128239.
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Dual inhibition of complement factor 5 and leukotriene B4 synergistically suppresses murine pemphigoid disease

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Abstract

The treatment of most autoimmune diseases still relies on systemic immunosuppression and is associated with severe side effects. The development of drugs that more specifically abrogate pathogenic pathways is therefore most desirable. In nature, such specificity is exemplified, e.g., by the soft tick–derived biotherapeutic Coversin, which locally suppresses immune responses by inhibiting complement factor 5 (C5) and leukotriene B4 (LTB4). C5a, a proteolytic fragment of C5, and LTB4 are critical drivers of skin inflammation in pemphigoid diseases (PDs), a group of autoimmune blistering skin diseases. Here, we demonstrate that both Coversin and its mutated form L-Coversin, which inhibits LTB4 only, dose dependently attenuate disease in a model of bullous pemphigoid–like epidermolysis bullosa acquisita (BP-like EBA). Coversin, however, reduces disease more effectively than L-Coversin, indicating that inhibition of C5 and LTB4 synergize in their suppressing effects in this model. Further supporting the therapeutic potential of Coversin in humans, we found that C5a and LTB4 are both present in the blister fluid of patients with BP in quantities inducing the recruitment of granulocytes and that the number of cells expressing their receptors, C5aR1 and BLT1, respectively, is increased in perilesional skin. Collectively, our results highlight Coversin and possibly L-Coversin as potential therapeutics for PDs.

Authors

Tanya Sezin, Sripriya Murthy, Claudia Attah, Malte Seutter, Maike M. Holtsche, Christoph M. Hammers, Enno Schmidt, Fibi Meshrkey, Sadegh Mousavi, Detlef Zillikens, Miles A. Nunn, Christian D. Sadik

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Niclosamide repurposed for the treatment of inflammatory airway disease
Inês Cabrita, … , Rainer Schreiber, Karl Kunzelmann
Inês Cabrita, … , Rainer Schreiber, Karl Kunzelmann
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e128414. https://doi.org/10.1172/jci.insight.128414.
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Niclosamide repurposed for the treatment of inflammatory airway disease

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Abstract

Inflammatory airway diseases, such as asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD), are characterized by mucus hypersecretion and airway plugging. In both CF and asthma, enhanced expression of the Ca2+-activated Cl– channel TMEM16A is detected in mucus-producing club/goblet cells and airway smooth muscle. TMEM16A contributes to mucus hypersecretion and bronchoconstriction, which are both inhibited by blockers of TMEM16A, such as niflumic acid. Here we demonstrate that the FDA-approved drug niclosamide, a potent inhibitor of TMEM16A identified by high-throughput screening, is an inhibitor of both TMEM16A and TMEM16F. In asthmatic mice, niclosamide reduced mucus production and secretion, as well as bronchoconstriction, and showed additional antiinflammatory effects. Using transgenic asthmatic mice, we found evidence that TMEM16A and TMEM16F are required for normal mucus production/secretion, which may be due to their effects on intracellular Ca2+ signaling. TMEM16A and TMEM16F support exocytic release of mucus and inflammatory mediators, both of which are blocked by niclosamide. Thus, inhibition of mucus and cytokine release, bronchorelaxation, and reported antibacterial effects make niclosamide a potentially suitable drug for the treatment of inflammatory airway diseases, such as CF, asthma, and COPD.

Authors

Inês Cabrita, Roberta Benedetto, Rainer Schreiber, Karl Kunzelmann

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Activated gp130 signaling selectively targets B cell differentiation to induce mature lymphoma and plasmacytoma
Anna K. Scherger, … , Stefan Rose-John, Ulrich Keller
Anna K. Scherger, … , Stefan Rose-John, Ulrich Keller
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e128435. https://doi.org/10.1172/jci.insight.128435.
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Activated gp130 signaling selectively targets B cell differentiation to induce mature lymphoma and plasmacytoma

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Abstract

Aberrant activity of the glycoprotein 130 130/JAK/STAT3 (gp130/JAK/STAT3) signaling axis is a recurrent event in inflammation and cancer. In particular, it is associated with a wide range of hematological malignancies, including multiple myeloma and leukemia. Novel targeted therapies have only been successful for some subtypes of these malignancies, underlining the need for developing robust mouse models to better dissect the role of this pathway in specific tumorigenic processes. Here, we investigated the role of selective gp130/JAK/STAT3 activation by generating a conditional mouse model. This model targeted constitutively active, cell-autonomous gp130 activity to B cells, as well as to the entire hematopoietic system. We found that regardless of the timing of activation in B cells, constitutively active gp130 signaling resulted in the formation specifically of mature B cell lymphomas and plasma cell disorders with full penetrance, only with different latencies, where infiltrating CD138+ cells were a dominant feature in every tumor. Furthermore, constitutively active gp130 signaling in all adult hematopoietic cells also led to the development specifically of largely mature, aggressive B cell cancers, again with a high penetrance of CD138+ tumors. Importantly, gp130 activity abrogated the differentiation block induced by a B cell–targeted Myc transgene and resulted in a complete penetrance of the gp130-associated, CD138+, mature B cell lymphoma phenotype. Thus, gp130 signaling selectively provides a strong growth and differentiation advantage for mature B cells and directs lymphomagenesis specifically toward terminally differentiated B cell cancers.

Authors

Anna K. Scherger, Mona Al-Maarri, Hans Carlo Maurer, Markus Schick, Sabine Maurer, Rupert Öllinger, Irene Gonzalez-Menendez, Manuela Martella, Markus Thaler, Konstanze Pechloff, Katja Steiger, Sandrine Sander, Jürgen Ruland, Roland Rad, Leticia Quintanilla-Martinez, Frank T. Wunderlich, Stefan Rose-John, Ulrich Keller

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Mutant p53 induces a hypoxia transcriptional program in gastric and esophageal adenocarcinoma
Nilay Sethi, … , William G. Kaelin Jr., Adam J. Bass
Nilay Sethi, … , William G. Kaelin Jr., Adam J. Bass
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e128439. https://doi.org/10.1172/jci.insight.128439.
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Mutant p53 induces a hypoxia transcriptional program in gastric and esophageal adenocarcinoma

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Abstract

Despite the propensity for gastric and esophageal adenocarcinomas to select for recurrent missense mutations in TP53, the precise functional consequence of these mutations remains unclear. Here we report that endogenous mRNA and protein levels of mutant p53 were elevated in cell lines and patients with gastric and esophageal cancer. Functional studies showed that mutant p53 was sufficient, but not necessary, for enhancing primary tumor growth in vivo. Unbiased genome-wide transcriptome analysis revealed that hypoxia signaling was induced by mutant p53 in 2 gastric cancer cell lines. Using real-time in vivo imaging, we confirmed that hypoxia reporter activity was elevated during the initiation of mutant p53 gastric cancer xenografts. Further investigation revealed that, like mutant p53, the HIF1/ARNT hypoxia pathway was not required for the primary tumor functions of advanced mutant p53 gastric cancer. These findings indicate that recurrent p53 mutations in gastroesophageal adenocarcinoma are unlikely to serve as effective therapeutic targets in advanced cancer. However, in elucidating the contribution of missense mutant p53 and hypoxia signaling, the results suggest hypotheses regarding how these recurrent genomic events may contribute to gastric and esophageal adenocarcinoma formation.

Authors

Nilay Sethi, Osamu Kikuchi, James McFarland, Yanxi Zhang, Max Chung, Nicholas Kafker, Mirazul Islam, Benjamin Lampson, Abhishek Chakraborty, William G. Kaelin Jr., Adam J. Bass

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Cell-specific ablation of Hsp47 defines the collagen-producing cells in the injured heart
Hadi Khalil, … , Kazuhiro Nagata, Jeffery D. Molkentin
Hadi Khalil, … , Kazuhiro Nagata, Jeffery D. Molkentin
Published July 2, 2019
Citation Information: JCI Insight. 2019;4(15):e128722. https://doi.org/10.1172/jci.insight.128722.
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Cell-specific ablation of Hsp47 defines the collagen-producing cells in the injured heart

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Collagen production in the adult heart is thought to be regulated by the fibroblast, although cardiomyocytes and endothelial cells also express multiple collagen mRNAs. Molecular chaperones are required for procollagen biosynthesis, including heat shock protein 47 (Hsp47). To determine the cell types critically involved in cardiac injury–induced fibrosis the Hsp47 gene was deleted in cardiomyocytes, endothelial cells, or myofibroblasts. Deletion of Hsp47 from cardiomyocytes during embryonic development or adult stages, or deletion from adult endothelial cells, did not affect cardiac fibrosis after pressure overload injury. However, myofibroblast-specific ablation of Hsp47 blocked fibrosis and deposition of collagens type I, III, and V following pressure overload as well as significantly reduced cardiac hypertrophy. Fibroblast-specific Hsp47-deleted mice showed lethality after myocardial infarction injury, with ineffective scar formation and ventricular wall rupture. Similarly, only myofibroblast-specific deletion of Hsp47 reduced fibrosis and disease in skeletal muscle in a mouse model of muscular dystrophy. Mechanistically, deletion of Hsp47 from myofibroblasts reduced mRNA expression of fibrillar collagens and attenuated their proliferation in the heart without affecting paracrine secretory activity of these cells. The results show that myofibroblasts are the primary mediators of tissue fibrosis and scar formation in the injured adult heart, which unexpectedly affects cardiomyocyte hypertrophy.

Authors

Hadi Khalil, Onur Kanisicak, Ronald J. Vagnozzi, Anne Katrine Johansen, Bryan D. Maliken, Vikram Prasad, Justin G. Boyer, Matthew J. Brody, Tobias Schips, Katja K. Kilian, Robert N. Correll, Kunito Kawasaki, Kazuhiro Nagata, Jeffery D. Molkentin

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Coupling AAV-mediated promoterless gene targeting to SaCas9 nuclease to efficiently correct liver metabolic diseases
Alessia De Caneva, … , Lorena Zentilin, Andrés F. Muro
Alessia De Caneva, … , Lorena Zentilin, Andrés F. Muro
Published June 18, 2019
Citation Information: JCI Insight. 2019;4(15):e128863. https://doi.org/10.1172/jci.insight.128863.
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Coupling AAV-mediated promoterless gene targeting to SaCas9 nuclease to efficiently correct liver metabolic diseases

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Nonintegrative AAV-mediated gene therapy in the liver is effective in adult patients but faces limitations in pediatric settings because of episomal DNA loss during hepatocyte proliferation. Gene targeting is a promising approach as it results in the permanent modification of the genome. We previously rescued neonatal lethality in Crigler-Najjar mice by inserting a promoterless human uridine glucuronosyl transferase A1 (UGT1A1) cDNA in exon 14 of the albumin gene, without the use of nucleases. To increase the recombination rate and therapeutic efficacy, we used CRISPR/SaCas9. Neonatal mice were transduced with 2 AAVs: one expressing the SaCas9 and sgRNA and one containing a promoterless cDNA flanked by albumin homology regions. Targeting efficiency increased approximately 26-fold with an EGFP reporter cDNA, reaching up to 24% of EGFP-positive hepatocytes. Next, we fully corrected the diseased phenotype of Crigler-Najjar mice by targeting the hUGT1A1 cDNA. Treated mice had normal plasma bilirubin up to 10 months after administration, hUGT1A1 protein levels were approximately 6-fold higher than in WT liver, with a 90-fold increase in recombination rate. Liver histology, inflammatory markers, and plasma albumin were normal in treated mice, with no off-targets in predicted sites. Thus, the improved efficacy and reassuring safety profile support the potential application of the proposed approach to other liver diseases.

Authors

Alessia De Caneva, Fabiola Porro, Giulia Bortolussi, Riccardo Sola, Michela Lisjak, Adi Barzel, Mauro Giacca, Mark A. Kay, Kristian Vlahoviček, Lorena Zentilin, Andrés F. Muro

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MondoA drives muscle lipid accumulation and insulin resistance
Byungyong Ahn, … , Kyoung Jae Won, Daniel P. Kelly
Byungyong Ahn, … , Kyoung Jae Won, Daniel P. Kelly
Published July 9, 2019
Citation Information: JCI Insight. 2019;4(15):e129119. https://doi.org/10.1172/jci.insight.129119.
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MondoA drives muscle lipid accumulation and insulin resistance

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Abstract

Obesity-related insulin resistance is associated with intramyocellular lipid accumulation in skeletal muscle. We hypothesized that contrary to current dogma, this linkage is related to an upstream mechanism that coordinately regulates both processes. We demonstrate that the muscle-enriched transcription factor MondoA is glucose/fructose responsive in human skeletal myotubes and directs the transcription of genes in cellular metabolic pathways involved in diversion of energy substrate from a catabolic fate into nutrient storage pathways, including fatty acid desaturation and elongation, triacylglyceride (TAG) biosynthesis, glycogen storage, and hexosamine biosynthesis. MondoA also reduces myocyte glucose uptake by suppressing insulin signaling. Mice with muscle-specific MondoA deficiency were partially protected from insulin resistance and muscle TAG accumulation in the context of diet-induced obesity. These results identify MondoA as a nutrient-regulated transcription factor that under normal physiological conditions serves a dynamic checkpoint function to prevent excess energy substrate flux into muscle catabolic pathways when myocyte nutrient balance is positive. However, in conditions of chronic caloric excess, this mechanism becomes persistently activated, leading to progressive myocyte lipid storage and insulin resistance.

Authors

Byungyong Ahn, Shibiao Wan, Natasha Jaiswal, Rick B. Vega, Donald E. Ayer, Paul M. Titchenell, Xianlin Han, Kyoung Jae Won, Daniel P. Kelly

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SREBP-regulated adipocyte lipogenesis is dependent on substrate availability and redox modulation of mTORC1
Clair Crewe, … , Jay D. Horton, Philipp E. Scherer
Clair Crewe, … , Jay D. Horton, Philipp E. Scherer
Published July 16, 2019
Citation Information: JCI Insight. 2019;4(15):e129397. https://doi.org/10.1172/jci.insight.129397.
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SREBP-regulated adipocyte lipogenesis is dependent on substrate availability and redox modulation of mTORC1

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The synthesis of lipid and sterol species through de novo lipogenesis (DNL) is regulated by 2 functionally overlapping but distinct transcription factors: the SREBPs and carbohydrate response element–binding protein (ChREBP). ChREBP is considered to be the dominant regulator of DNL in adipose tissue (AT); however, the SREBPs are highly expressed and robustly regulated in adipocytes, suggesting that the model of AT DNL may be incomplete. Here, we describe what we believe to be a new mouse model of inducible, adipocyte-specific overexpression of the insulin-induced gene 1 (Insig1), a negative regulator of SREBP transcriptional activity. Contrary to convention, Insig1 overexpression did block AT lipogenic gene expression. However, this was immediately met with a compensatory mechanism triggered by redox activation of mTORC1 to restore SREBP1 DNL gene expression. Thus, we demonstrate that SREBP1 activity sustains adipocyte lipogenesis, a conclusion that has been elusive due to the constitutive nature of current mouse models.

Authors

Clair Crewe, Yi Zhu, Vivian A. Paschoal, Nolwenn Joffin, Alexandra L. Ghaben, Ruth Gordillo, Da Young Oh, Guosheng Liang, Jay D. Horton, Philipp E. Scherer

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The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasis
Mathilde Mouchiroud, … , André Marette, Mathieu Laplante
Mathilde Mouchiroud, … , André Marette, Mathieu Laplante
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e129492. https://doi.org/10.1172/jci.insight.129492.
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The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasis

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Nonalcoholic fatty liver disease (NAFLD) prevails in obesity and is linked to several health complications including dyslipidemia and atherosclerosis. How exactly NAFLD induces atherogenic dyslipidemia to promote cardiovascular diseases is still elusive. Here, we identify Tsukushi (TSK) as a hepatokine induced in response to NAFLD. We show that both endoplasmic reticulum stress and inflammation promote the expression and release of TSK in mice. In humans, hepatic TSK expression is also associated with steatosis, and its circulating levels are markedly increased in patients suffering from acetaminophen-induced acute liver failure (ALF), a condition linked to severe hepatic inflammation. In these patients, elevated blood TSK levels were associated with decreased transplant-free survival at hospital discharge, suggesting that TSK could have a prognostic significance. Gain- and loss-of-function studies in mice revealed that TSK impacts systemic cholesterol homeostasis. TSK reduces circulating HDL cholesterol, lowers cholesterol efflux capacity, and decreases cholesterol-to–bile acid conversion in the liver. Our data identify the hepatokine TSK as a blood biomarker of liver stress that could link NAFLD to the development of atherogenic dyslipidemia and atherosclerosis.

Authors

Mathilde Mouchiroud, Étienne Camiré, Manal Aldow, Alexandre Caron, Éric Jubinville, Laurie Turcotte, Inès Kaci, Marie-Josée Beaulieu, Christian Roy, Sébastien M. Labbé, Thibault V. Varin, Yves Gélinas, Jennifer Lamothe, Jocelyn Trottier, Patricia L. Mitchell, Frédéric Guénard, William T. Festuccia, Philippe Joubert, Christopher F. Rose, Constantine J. Karvellas, Olivier Barbier, Mathieu C. Morissette, André Marette, Mathieu Laplante

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High-dimensional analysis reveals a pathogenic role of inflammatory monocytes in experimental diffuse alveolar hemorrhage
Pui Y. Lee, … , Westley H. Reeves, Peter A. Nigrovic
Pui Y. Lee, … , Westley H. Reeves, Peter A. Nigrovic
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e129703. https://doi.org/10.1172/jci.insight.129703.
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High-dimensional analysis reveals a pathogenic role of inflammatory monocytes in experimental diffuse alveolar hemorrhage

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Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary complication associated with systemic lupus erythematosus, vasculitis, and stem cell transplant. Little is known about the pathophysiology of DAH, and no targeted therapy is currently available. Pristane treatment in mice induces systemic autoimmunity and lung hemorrhage that recapitulates hallmark pathologic features of human DAH. Using this experimental model, we performed high-dimensional analysis of lung immune cells in DAH by mass cytometry and single-cell RNA sequencing. We found a large influx of myeloid cells to the lungs in DAH and defined the gene expression profile of infiltrating monocytes. Bone marrow–derived inflammatory monocytes actively migrated to the lungs and homed adjacent to blood vessels. Using 3 models of monocyte deficiency and complementary transfer studies, we established a central role of inflammatory monocytes in the development of DAH. We further found that the myeloid transcription factor interferon regulatory factor 8 is essential to the development of both DAH and type I interferon–dependent autoimmunity. These findings collectively reveal monocytes as a potential treatment target in DAH.

Authors

Pui Y. Lee, Nathan Nelson-Maney, Yuelong Huang, Anaïs Levescot, Qiang Wang, Kevin Wei, Pierre Cunin, Yi Li, James A. Lederer, Haoyang Zhuang, Shuhong Han, Edy Y. Kim, Westley H. Reeves, Peter A. Nigrovic

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Augmentation of IFN-γ+ CD8+ T cell responses correlates with survival of HCC patients on sorafenib therapy
Suresh Gopi Kalathil, … , Renuka Iyer, Yasmin Thanavala
Suresh Gopi Kalathil, … , Renuka Iyer, Yasmin Thanavala
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e130116. https://doi.org/10.1172/jci.insight.130116.
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Augmentation of IFN-γ+ CD8+ T cell responses correlates with survival of HCC patients on sorafenib therapy

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BACKGROUND Sorafenib has been shown to reduce the extent of immunosuppression in patients with hepatocellular carcinoma (HCC). The rationale of this investigation was to identify biomarkers that can predict treatment efficacy of sorafenib in HCC patients and to unravel the mechanism by which sorafenib impedes immune suppression mediated by distinct immunosuppressive cell subsets.METHODS With informed consent, blood samples were collected from 30 patients with advanced HCC, at baseline and 2 time points after initiation of sorafenib treatment. The frequency of PD-1+ T cells, ERK2 phosphorylation on flt-3+ Tregs and MDSCs, and T effector cell function were quantified by using flow cytometry.RESULTS Elevated levels of CD8+Ki67+ T cells producing IFN-γ were associated with improved progression-free survival and overall survival (OS). High frequencies of these T cells were correlated with significantly reduced risk of death over time. Patients with an increased pretreatment T effector/Treg ratio showed significant improvement in OS. ERK+flt-3+ Tregs and MDSCs were significantly decreased after sorafenib therapy. Increased numbers of baseline flt-3+p-ERK+ MDSCs were associated with survival benefit of patients.CONCLUSION A high baseline CD4+ T effector/Treg ratio is a potential biomarker of prognostic significance in HCC. CD8+Ki67+ T cells producing IFN-γ are a key biomarker of response to sorafenib therapy resulting in survival benefit. The immune modulation resulted from sorafenib-mediated blockade of signaling through the VEGF/VEGFR/flt-3 pathway, affecting ERK phosphorylation. These insights may help identify patients who likely would benefit from VEGFR antagonism and inform efforts to improve the efficacy of sorafenib in combination with immunotherapy.TRIAL REGISTRATION NCT02072486.FUNDING National Comprehensive Cancer Network Oncology Research Program from general research support provided by Bayer US LLC (NCCNSORA0002), National Cancer Institute grant P30CA016056, and pilot funds from Roswell Park Alliance Foundation.

Authors

Suresh Gopi Kalathil, Alan Hutson, Joseph Barbi, Renuka Iyer, Yasmin Thanavala

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Dysregulated claudin-5 cycling in the inner retina causes retinal pigment epithelial cell atrophy
Natalie Hudson, … , Sarah L. Doyle, Matthew Campbell
Natalie Hudson, … , Sarah L. Doyle, Matthew Campbell
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e130273. https://doi.org/10.1172/jci.insight.130273.
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Dysregulated claudin-5 cycling in the inner retina causes retinal pigment epithelial cell atrophy

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Age-related macular degeneration (AMD) is the leading cause of central retinal vision loss worldwide, with an estimated 1 in 10 people over the age of 55 showing early signs of the condition. There are currently no forms of therapy available for the end stage of dry AMD, geographic atrophy (GA). Here, we show that the inner blood-retina barrier (iBRB) is highly dynamic and may play a contributory role in GA development. We have discovered that the gene CLDN5, which encodes claudin-5, a tight junction protein abundantly expressed at the iBRB, is regulated by BMAL1 and the circadian clock. Persistent suppression of claudin-5 expression in mice exposed to a cholesterol-enriched diet induced striking retinal pigment epithelium (RPE) cell atrophy, and persistent targeted suppression of claudin-5 in the macular region of nonhuman primates induced RPE cell atrophy. Moreover, fundus fluorescein angiography in human and nonhuman primate subjects showed increased retinal vascular permeability in the evening compared with the morning. These findings implicate an inner retina–derived component in the early pathophysiological changes observed in AMD, and we suggest that restoring the integrity of the iBRB may represent a novel therapeutic target for the prevention and treatment of GA secondary to dry AMD.

Authors

Natalie Hudson, Lucia Celkova, Alan Hopkins, Chris Greene, Federica Storti, Ema Ozaki, Erin Fahey, Sofia Theodoropoulou, Paul F. Kenna, Marian M. Humphries, Annie M. Curtis, Eleanor Demmons, Akeem Browne, Shervin Liddie, Matthew S. Lawrence, Christian Grimm, Mark T. Cahill, Pete Humphries, Sarah L. Doyle, Matthew Campbell

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