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Abstract
BACKGROUND Beige adipose tissue is associated with improved glucose homeostasis in mice. Adipose tissue contains β3-adrenergic receptors (β3-ARs), and this study was intended to determine whether the treatment of obese, insulin-resistant humans with the β3-AR agonist mirabegron, which stimulates beige adipose formation in subcutaneous white adipose tissue (SC WAT), would induce other beneficial changes in fat and muscle and improve metabolic homeostasis.METHODS Before and after β3-AR agonist treatment, oral glucose tolerance tests and euglycemic clamps were performed, and histochemical analysis and gene expression profiling were performed on fat and muscle biopsies. PET-CT scans quantified brown adipose tissue volume and activity, and we conducted in vitro studies with primary cultures of differentiated human adipocytes and muscle.RESULTS The clinical effects of mirabegron treatment included improved oral glucose tolerance (P < 0.01), reduced hemoglobin A1c levels (P = 0.01), and improved insulin sensitivity (P = 0.03) and β cell function (P = 0.01). In SC WAT, mirabegron treatment stimulated lipolysis, reduced fibrotic gene expression, and increased alternatively activated macrophages. Subjects with the most SC WAT beiging showed the greatest improvement in β cell function. In skeletal muscle, mirabegron reduced triglycerides, increased the expression of PPARγ coactivator 1 α (PGC1A) (P < 0.05), and increased type I fibers (P < 0.01). Conditioned media from adipocytes treated with mirabegron stimulated muscle fiber PGC1A expression in vitro (P < 0.001).CONCLUSION Mirabegron treatment substantially improved multiple measures of glucose homeostasis in obese, insulin-resistant humans. Since β cells and skeletal muscle do not express β3-ARs, these data suggest that the beiging of SC WAT by mirabegron reduces adipose tissue dysfunction, which enhances muscle oxidative capacity and improves β cell function.TRIAL REGISTRATION Clinicaltrials.gov NCT02919176.FUNDING NIH: DK112282, P30GM127211, DK 71349, and Clinical and Translational science Awards (CTSA) grant UL1TR001998.
Authors
Brian S. Finlin, Hasiyet Memetimin, Beibei Zhu, Amy L. Confides, Hemendra J. Vekaria, Riham H. El Khouli, Zachary R. Johnson, Philip M. Westgate, Jianzhong Chen, Andrew J. Morris, Patrick G. Sullivan, Esther E. Dupont-Versteegden, Philip A. Kern
Abstract
BACKGROUND The live attenuated BPZE1 vaccine candidate induces protection against B. pertussis and prevents nasal colonization in animal models. Here we report on the responses in humans receiving a single intranasal administration of BPZE1.METHODS We performed multiple assays to dissect the immune responses induced in humans (n = 12) receiving BPZE1, with particular emphasis on the magnitude and characteristics of the antibody responses. Such responses were benchmarked to adolescents (n = 12) receiving the complete vaccination program of the currently used acellular pertussis vaccine (aPV). Using immunoproteomics analysis, potentially novel immunogenic B. pertussis antigens were identified.RESULTS All BPZE1 vaccinees showed robust B. pertussis–specific antibody responses with regard to significant increase in 1 or more of the following parameters: IgG, IgA, and memory B cells to B. pertussis antigens. BPZE1–specific T cells showed a Th1 phenotype, and the IgG exclusively consisted of IgG1 and IgG3. In contrast, all aPV vaccines showed a Th2-biased response. Immunoproteomics profiling revealed that BPZE1 elicited broader and different antibody specificities to B. pertussis antigens as compared with the aPV that primarily induced antibodies to the vaccine antigens. Moreover, BPZE1 was superior at inducing opsonizing antibodies that stimulated ROS production in neutrophils and enhanced bactericidal function, which was in line with the finding that antibodies against adenylate cyclase toxin were only elicited by BPZE1.CONCLUSION The breadth of the antibodies, the Th1-type cellular response, and killing mechanisms elicited by BPZE1 may hold prospects of improving vaccine efficacy and protection against B. pertussis transmission.TRIAL REGISTRATION ClinicalTrials.gov NCT02453048, NCT00870350.FUNDING ILiAD Biotechnologies, Swedish Research Council (Vetenskapsrådet), Swedish Heart-Lung Foundation.
Authors
Ang Lin, Danijela Apostolovic, Maja Jahnmatz, Frank Liang, Sebastian Ols, Teghesti Tecleab, Chenyan Wu, Marianne van Hage, Ken Solovay, Keith Rubin, Camille Locht, Rigmor Thorstensson, Marcel Thalen, Karin Loré
Abstract
Increased microvascular permeability to plasma proteins and neutrophil emigration are hallmarks of innate immunity and key features of numerous inflammatory disorders. Although neutrophils can promote microvascular leakage, the impact of vascular permeability on neutrophil trafficking is unknown. Here, through the application of confocal intravital microscopy, we report that vascular permeability–enhancing stimuli caused a significant frequency of neutrophil reverse transendothelial cell migration (rTEM). Furthermore, mice with a selective defect in microvascular permeability enhancement (VEC-Y685F-ki) showed reduced incidence of neutrophil rTEM. Mechanistically, elevated vascular leakage promoted movement of interstitial chemokines into the bloodstream, a response that supported abluminal-to-luminal neutrophil TEM. Through development of an in vivo cell labeling method we provide direct evidence for the systemic dissemination of rTEM neutrophils, and showed them to exhibit an activated phenotype and be capable of trafficking to the lungs where their presence was aligned with regions of vascular injury. Collectively, we demonstrate that increased microvascular leakage reverses the localization of directional cues across venular walls, thus causing neutrophils engaged in diapedesis to reenter the systemic circulation. This cascade of events offers a mechanism to explain how local tissue inflammation and vascular permeability can induce downstream pathological effects in remote organs, most notably in the lungs.
Authors
Charlotte Owen-Woods, Régis Joulia, Anna Barkaway, Loïc Rolas, Bin Ma, Astrid Fee Nottebaum, Kenton P. Arkill, Monja Stein, Tamara Girbl, Matthew Golding, David O. Bates, Dietmar Vestweber, Mathieu-Benoit Voisin, Sussan Nourshargh
Abstract
BACKGROUND Mirabegron is a β3-adrenergic receptor (β3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that β3-AR agonists could also improve obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODS We treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m2) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by [18F]-2-fluoro-d-2-deoxy-d-glucose (18F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test.RESULTS Chronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion.CONCLUSION These findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of β3-AR agonists as a treatment for metabolic disease.TRIAL REGISTRATION Clinicaltrials.gov NCT03049462.FUNDING This work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).
Authors
Alana E. O’Mara, James W. Johnson, Joyce D. Linderman, Robert J. Brychta, Suzanne McGehee, Laura A. Fletcher, Yael A. Fink, Devika Kapuria, Thomas M. Cassimatis, Nathan Kelsey, Cheryl Cero, Zahraa Abdul Sater, Francesca Piccinini, Alison S. Baskin, Brooks P. Leitner, Hongyi Cai, Corina M. Millo, William Dieckmann, Mary Walter, Norman B. Javitt, Yaron Rotman, Peter J. Walter, Marilyn Ader, Richard N. Bergman, Peter Herscovitch, Kong Y. Chen, Aaron M. Cypess
Abstract
Hypoxia-inducible factor (HIF) is strikingly upregulated in many types of cancer, and there is great interest in applying inhibitors of HIF as anticancer therapeutics. The most advanced of these are small molecules that target the HIF-2 isoform through binding the PAS-B domain of HIF-2α. These molecules are undergoing clinical trials with promising results in renal and other cancers where HIF-2 is considered to be driving growth. Nevertheless, a central question remains as to whether such inhibitors affect physiological responses to hypoxia at relevant doses. Here, we show that pharmacological HIF-2α inhibition with PT2385, at doses similar to those reported to inhibit tumor growth, rapidly impaired ventilatory responses to hypoxia, abrogating both ventilatory acclimatization and carotid body cell proliferative responses to sustained hypoxia. Mice carrying a HIF-2α PAS-B S305M mutation that disrupts PT2385 binding, but not dimerization with HIF-1β, did not respond to PT2385, indicating that these effects are on-target. Furthermore, the finding of a hypomorphic ventilatory phenotype in untreated HIF-2α S305M mutant mice suggests a function for the HIF-2α PAS-B domain beyond heterodimerization with HIF-1β. Although PT2385 was well tolerated, the findings indicate the need for caution in patients who are dependent on hypoxic ventilatory drive.
Authors
Xiaotong Cheng, Maria Prange-Barczynska, James W. Fielding, Minghao Zhang, Alana L. Burrell, Joanna D.C.C. Lima, Luise Eckardt, Isobel L.A. Argles, Christopher W. Pugh, Keith J. Buckler, Peter A. Robbins, Emma J. Hodson, Richard K. Bruick, Lucy M. Collinson, Fraydoon Rastinejad, Tammie Bishop, Peter J. Ratcliffe
Abstract
BACKGROUND Glucose-6-phosphate dehydrogenase (G6PD) deficiency decreases the ability of red blood cells (RBCs) to withstand oxidative stress. Refrigerated storage of RBCs induces oxidative stress. We hypothesized that G6PD-deficient donor RBCs would have inferior storage quality for transfusion as compared with G6PD-normal RBCs.METHODS Male volunteers were screened for G6PD deficiency; 27 control and 10 G6PD-deficient volunteers each donated 1 RBC unit. After 42 days of refrigerated storage, autologous 51-chromium 24-hour posttransfusion RBC recovery (PTR) studies were performed. Metabolomics analyses of these RBC units were also performed.RESULTS The mean 24-hour PTR for G6PD-deficient subjects was 78.5% ± 8.4% (mean ± SD), which was significantly lower than that for G6PD-normal RBCs (85.3% ± 3.2%; P = 0.0009). None of the G6PD-normal volunteers (0/27) and 3 G6PD-deficient volunteers (3/10) had PTR results below 75%, a key FDA acceptability criterion for stored donor RBCs. As expected, fresh G6PD-deficient RBCs demonstrated defects in the oxidative phase of the pentose phosphate pathway. During refrigerated storage, G6PD-deficient RBCs demonstrated increased glycolysis, impaired glutathione homeostasis, and increased purine oxidation, as compared with G6PD-normal RBCs. In addition, there were significant correlations between PTR and specific metabolites in these pathways.CONCLUSION Based on current FDA criteria, RBCs from G6PD-deficient donors would not meet the requirements for storage quality. Metabolomics assessment identified markers of PTR and G6PD deficiency (e.g., pyruvate/lactate ratios), along with potential compensatory pathways that could be leveraged to ameliorate the metabolic needs of G6PD-deficient RBCs.TRIAL REGISTRATION ClinicalTrials.gov NCT04081272.FUNDING The Harold Amos Medical Faculty Development Program, Robert Wood Johnson Foundation grant 71590, the National Blood Foundation, NIH grant UL1 TR000040, the Webb-Waring Early Career Award 2017 by the Boettcher Foundation, and National Heart, Lung, and Blood Institute grants R01HL14644 and R01HL148151.
Authors
Richard O. Francis, Angelo D’Alessandro, Andrew Eisenberger, Mark Soffing, Randy Yeh, Esther Coronel, Arif Sheikh, Francesca Rapido, Francesca La Carpia, Julie A. Reisz, Sarah Gehrke, Travis Nemkov, Tiffany Thomas, Joseph Schwartz, Chaitanya Divgi, Debra Kessler, Beth H. Shaz, Yelena Ginzburg, James C. Zimring, Steven L. Spitalnik, Eldad A. Hod
Abstract
Brown and beige adipose tissues contain thermogenic fat cells that can be activated by β3-adrenergic receptor agonists. In rodents, such drugs both diminish obesity and improve glucose homeostasis. In this issue of the JCI, O’Mara et al. and Finlin and Memetimin et al. report that chronic administration of the approved β3 agonist mirabegron to human subjects was without effect on body weight or fat mass, but improved several measures of glucose homeostasis. Though the mechanisms mediating these metabolic effects are uncertain, the data suggest that β3 agonists could have therapeutic utility in disorders of glucose homeostasis.
Authors
Jeffrey S. Flier
Abstract
Lipid-rich myelin forms electrically insulating, axon-wrapping multilayers that are essential for neural function, and mature myelin is traditionally considered metabolically inert. Surprisingly, we discovered that mature myelin lipids undergo rapid turnover, and quaking (Qki) is a major regulator of myelin lipid homeostasis. Oligodendrocyte-specific Qki depletion, without affecting oligodendrocyte survival, resulted in rapid demyelination, within 1 week, and gradually neurological deficits in adult mice. Myelin lipids, especially the monounsaturated fatty acids and very-long-chain fatty acids, were dramatically reduced by Qki depletion, whereas the major myelin proteins remained intact, and the demyelinating phenotypes of Qki-depleted mice were alleviated by a high-fat diet. Mechanistically, Qki serves as a coactivator of the PPARβ-RXRα complex, which controls the transcription of lipid-metabolism genes, particularly those involved in fatty acid desaturation and elongation. Treatment of Qki-depleted mice with PPARβ/RXR agonists significantly alleviated neurological disability and extended survival durations. Furthermore, a subset of lesions from patients with primary progressive multiple sclerosis were characterized by preferential reductions in myelin lipid contents, activities of various lipid metabolism pathways, and expression level of QKI-5 in human oligodendrocytes. Together, our results demonstrate that continuous lipid synthesis is indispensable for mature myelin maintenance and highlight an underappreciated role of lipid metabolism in demyelinating diseases.
Authors
Xin Zhou, Chenxi He, Jiangong Ren, Congxin Dai, Sharon R. Stevens, Qianghu Wang, Daniel Zamler, Takashi Shingu, Liang Yuan, Chythra R. Chandregowda, Yunfei Wang, Visweswaran Ravikumar, Arvind U.K. Rao, Feng Zhou, Hongwu Zheng, Matthew N. Rasband, Yiwen Chen, Fei Lan, Amy B. Heimberger, Benjamin M. Segal, Jian Hu
Abstract
The editors of JCI and JCI Insight are revisiting our editorial processes in light of the strain that the COVID-19 pandemic places on the worldwide scientific community. Here, we discuss adjustments to our decision framework in light of restrictions placed on laboratory working conditions for many of our authors.
Authors
Rexford S. Ahima, Sarah Jackson, Arturo Casadevall, Gregg L. Semenza, Gordon Tomaselli, Kathleen L. Collins, Andrew P. Lieberman, Donna M. Martin, Pavan Reddy
Abstract
Prenatal alcohol exposure (PAE) affects at least 10% of newborns globally and leads to the development of fetal alcohol spectrum disorders (FASDs). Despite its high incidence, there is no consensus on the implications of PAE on metabolic disease risk in adults. Here, we describe a cohort of adults with FASDs that had an increased incidence of metabolic abnormalities, including type 2 diabetes, low HDL, high triglycerides, and female-specific overweight and obesity. Using a zebrafish model for PAE, we performed population studies to elucidate the metabolic disease seen in the clinical cohort. Embryonic alcohol exposure (EAE) in male zebrafish increased the propensity for diet-induced obesity and fasting hyperglycemia in adulthood. We identified several consequences of EAE that may contribute to these phenotypes, including a reduction in adult locomotor activity, alterations in visceral adipose tissue and hepatic development, and persistent diet-responsive transcriptional changes. Taken together, our findings define metabolic vulnerabilities due to EAE and provide evidence that behavioral changes and primary organ dysfunction contribute to resultant metabolic abnormalities.
Authors
Olivia Weeks, Gabriel D. Bossé, Isaac M. Oderberg, Sebastian Akle, Yariv Houvras, Paul J. Wrighton, Kyle LaBella, Isabelle Iversen, Sahar Tavakoli, Isaac Adatto, Arkadi Schwartz, Daan Kloosterman, Allison Tsomides, Michael E. Charness, Randall T. Peterson, Matthew L. Steinhauser, Pouneh K. Fazeli, Wolfram Goessling
Abstract
The physical integrity of endothelial cells (ECs) lining the blood vessels regulates the inflammatory response. Both innate immunity and inflammatory disorders hinge on the EC-neutrophil interaction. Neutrophil binding, rolling, and migrating along and between ECs is associated with vascular permeability. In this issue of the JCI, Owen-Woods et al. tracked neutrophils in vivo in venules of mouse striated muscle and revealed how endothelial permeability can affect neutrophil trafficking. Strikingly, many neutrophils that migrated between EC junctions were able to rejoin the blood circulation. Further, the chemokine and neutrophil chemoattractant, CXCL1, drove this reverse transendothelial migration (rTEM). This paradigm-shifting study provides a mechanism for distal organ damage as well as an explanation for sepsis-associated acute respiratory distress syndrome.
Authors
Alex Marki, Klaus Ley
Abstract
Although Western diet and dysbiosis are the most prominent environmental factors associated with inflammatory bowel diseases (IBDs), the corresponding host factors and cellular mechanisms remain poorly defined. Here we report that the TSC1/mTOR pathway in the gut epithelium represents a metabolic and innate immune checkpoint for intestinal dysfunction and inflammation. mTOR hyperactivation triggered by Western diet or Tsc1 ablation led to epithelium necroptosis, barrier disruption, and predisposition to dextran sulfate sodium–induced colitis and inflammation-associated colon cancer. Mechanistically, our results uncovered a critical role for TSC1/mTOR in restraining the expression and activation of RIPK3 in the gut epithelium through TRIM11-mediated ubiquitination and autophagy-dependent degradation. Notably, microbiota depletion by antibiotics or gnotobiotics attenuated RIPK3 expression and activation, thereby alleviating epithelial necroptosis and colitis driven by mTOR hyperactivation. mTOR primarily impinged on RIPK3 to potentiate necroptosis induced by TNF and by microbial pathogen-associated molecular patterns (PAMPs), and hyperactive mTOR and aberrant necroptosis were intertwined in human IBDs. Together, our data reveal a previously unsuspected link between the Western diet, microbiota, and necroptosis and identify the mTOR/RIPK3/necroptosis axis as a driving force for intestinal inflammation and cancer.
Authors
Yadong Xie, Yifan Zhao, Lei Shi, Wei Li, Kun Chen, Min Li, Xia Chen, Haiwei Zhang, Tiantian Li, Yu Matsuzawa-Ishimoto, Xiaomin Yao, Dianhui Shao, Zunfu Ke, Jian Li, Yan Chen, Xiaoming Zhang, Jun Cui, Shuzhong Cui, Qibin Leng, Ken Cadwell, Xiaoxia Li, Hong Wei, Haibing Zhang, Huabin Li, Hui Xiao
Abstract
Despite the effective clinical use of steroids for the treatment of Diamond Blackfan anemia (DBA), the mechanisms through which glucocorticoids regulate human erythropoiesis remain poorly understood. We report that the sensitivity of erythroid differentiation to dexamethasone is dependent on the developmental origin of human CD34+ progenitor cells, specifically increasing the expansion of CD34+ progenitors from peripheral blood (PB) but not cord blood (CB). Dexamethasone treatment of erythroid-differentiated PB, but not CB, CD34+ progenitors resulted in the expansion of a newly defined CD34+CD36+CD71hiCD105med immature colony-forming unit–erythroid (CFU-E) population. Furthermore, proteomics analyses revealed the induction of distinct proteins in dexamethasone-treated PB and CB erythroid progenitors. Dexamethasone treatment of PB progenitors resulted in the specific upregulation of p57Kip2, a Cip/Kip cyclin–dependent kinase inhibitor, and we identified this induction as critical; shRNA-mediated downregulation of p57Kip2, but not the related p27Kip1, significantly attenuated the impact of dexamethasone on erythroid differentiation and inhibited the expansion of the immature CFU-E subset. Notably, in the context of DBA, we found that steroid resistance was associated with dysregulated p57Kip2 expression. Altogether, these data identify a unique glucocorticoid-responsive human erythroid progenitor and provide new insights into glucocorticoid-based therapeutic strategies for the treatment of patients with DBA.
Authors
Ryan J. Ashley, Hongxia Yan, Nan Wang, John Hale, Brian M. Dulmovits, Julien Papoin, Meagan E. Olive, Namrata D. Udeshi, Steven A. Carr, Adrianna Vlachos, Jeffrey M. Lipton, Lydie Da Costa, Christopher Hillyer, Sandrina Kinet, Naomi Naomi Taylor, Narla Mohandas, Anupama Narla, Lionel Blanc
Abstract
Cystic fibrosis (CF) lung disease is characterized by an inflammatory response that can lead to terminal respiratory failure. The cystic fibrosis transmembrane conductance regulator (CFTR) is mutated in CF, and we hypothesized that dysfunctional CFTR in platelets, which are key participants in immune responses, is a central determinant of CF inflammation. We found that deletion of CFTR in platelets produced exaggerated acute lung inflammation and platelet activation after intratracheal LPS or Pseudomonas aeruginosa challenge. CFTR loss of function in mouse or human platelets resulted in agonist-induced hyperactivation and increased calcium entry into platelets. Inhibition of the transient receptor potential cation channel 6 (TRPC6) reduced platelet activation and calcium flux, and reduced lung injury in CF mice after intratracheal LPS or Pseudomonas aeruginosa challenge. CF subjects receiving CFTR modulator therapy showed partial restoration of CFTR function in platelets, which may be a convenient approach to monitoring biological responses to CFTR modulators. We conclude that CFTR dysfunction in platelets produces aberrant TRPC6-dependent platelet activation, which is a major driver of CF lung inflammation and impaired bacterial clearance. Platelets and TRPC6 are what we believe to be novel therapeutic targets in the treatment of CF lung disease.
Authors
Guadalupe Ortiz-Muñoz, Michelle A. Yu, Emma Lefrançais, Beñat Mallavia, Colin Valet, Jennifer J. Tian, Serena Ranucci, Kristin M. Wang, Zhe Liu, Nicholas Kwaan, Diana Dawson, Mary Ellen Kleinhenz, Fadi T. Khasawneh, Peter M. Haggie, Alan S. Verkman, Mark R. Looney
Abstract
After trauma, regeneration of adult CNS axons is abortive, causing devastating neurologic deficits. Despite progress in rehabilitative care, there is no effective treatment that stimulates axonal growth following injury. Using models with different regenerative capacities, followed by gain- and loss-of-function analysis, we identified profilin 1 (Pfn1) as a coordinator of actin and microtubules (MTs), powering axonal growth and regeneration. In growth cones, Pfn1 increased actin retrograde flow, MT growth speed, and invasion of filopodia by MTs, orchestrating cytoskeletal dynamics toward axonal growth. In vitro, active Pfn1 promoted MT growth in a formin-dependent manner, whereas localization of MTs to growth cone filopodia was facilitated by direct MT binding and interaction with formins. In vivo, Pfn1 ablation limited regeneration of growth-competent axons after sciatic nerve and spinal cord injury. Adeno-associated viral (AAV) delivery of constitutively active Pfn1 to rodents promoted axonal regeneration, neuromuscular junction maturation, and functional recovery of injured sciatic nerves, and increased the ability of regenerating axons to penetrate the inhibitory spinal cord glial scar. Thus, we identify Pfn1 as an important regulator of axonal regeneration and suggest that AAV-mediated delivery of constitutively active Pfn1, together with the identification of modulators of Pfn1 activity, should be considered to treat the injured nervous system.
Authors
Rita Pinto-Costa, Sara C. Sousa, Sérgio C. Leite, Joana Nogueira-Rodrigues, Tiago Ferreira da Silva, Diana Machado, Joana Marques, Ana Catarina Costa, Márcia A. Liz, Francesca Bartolini, Pedro Brites, Mercedes Costell, Reinhard Fässler, Mónica M. Sousa
Abstract
Macrophages have been linked to tumor initiation, progression, metastasis, and treatment resistance. However, the transcriptional regulation of macrophages driving the protumor function remains elusive. Here, we demonstrate that the transcription factor c-Maf is a critical controller for immunosuppressive macrophage polarization and function in cancer. c-Maf controls many M2-related genes and has direct binding sites within a conserved noncoding sequence of the Csf-1r gene and promotes M2-like macrophage–mediated T cell suppression and tumor progression. c-Maf also serves as a metabolic checkpoint regulating the TCA cycle and UDP-GlcNAc biosynthesis, thus promoting M2-like macrophage polarization and activation. Additionally, c-Maf is highly expressed in tumor-associated macrophages (TAMs) and regulates TAM immunosuppressive function. Deletion of c-Maf specifically in myeloid cells results in reduced tumor burden with enhanced antitumor T cell immunity. Inhibition of c-Maf partly overcomes resistance to anti–PD-1 therapy in a subcutaneous LLC tumor model. Similarly, c-Maf is expressed in human M2 and tumor-infiltrating macrophages/monocytes as well as circulating monocytes of human non–small cell lung carcinoma (NSCLC) patients and critically regulates their immunosuppressive activity. The natural compound β-glucan downregulates c-Maf expression on macrophages, leading to enhanced antitumor immunity in mice. These findings establish a paradigm for immunosuppressive macrophage polarization and transcriptional regulation by c-Maf and suggest that c-Maf is a potential target for effective tumor immunotherapy.
Authors
Min Liu, Zan Tong, Chuanlin Ding, Fengling Luo, Shouzhen Wu, Caijun Wu, Sabrin Albeituni, Liqing He, Xiaoling Hu, David Tieri, Eric C. Rouchka, Michito Hamada, Satoru Takahashi, Andrew A. Gibb, Goetz Kloecker, Huang-ge Zhang, Michael Bousamra II, Bradford G. Hill, Xiang Zhang, Jun Yan
Abstract
Severe alcoholic hepatitis (SAH) is a deadly liver disease without an effective medical therapy. Although SAH mortality is known to correlate with hepatic accumulation of immature liver cells, why this occurs and how it causes death are unclear. Here, we demonstrate that expression of epithelial splicing regulatory protein 2 (ESRP2), an RNA-splicing factor that maintains the nonproliferative, mature phenotype of adult hepatocytes, was suppressed in both human SAH and various mouse models of SAH in parallel with the severity of alcohol consumption and liver damage. Inflammatory cytokines released by excessive alcohol ingestion reprogrammed adult hepatocytes into proliferative, fetal-like cells by suppressing ESRP2. Sustained loss of ESRP2 permitted reemergence of a fetal RNA-splicing program that attenuates the Hippo signaling pathway and thus allows fetal transcriptional regulators to accumulate in adult liver. We further showed that depleting ESRP2 in mice exacerbated alcohol-induced steatohepatitis, enabling surviving hepatocytes to shed adult hepatocyte functions and become more regenerative, but threatening overall survival by populating the liver with functionally immature hepatocytes. Our findings revealed a mechanism that explains why liver failure develops in patients with the clinical syndrome of SAH, suggesting that recovery from SAH might be improved by limiting adult-to-fetal reprogramming in hepatocytes.
Authors
Jeongeun Hyun, Zhaoli Sun, Ali Reza Ahmadi, Sushant Bangru, Ullas V. Chembazhi, Kuo Du, Tianyi Chen, Hidekazu Tsukamoto, Ivan Rusyn, Auinash Kalsotra, Anna Mae Diehl
Abstract
Authors
Donald M. Marcus
Abstract
Cystic fibrosis (CF) is a multisystem disorder, but progressive inflammatory lung disease causes the greatest burden of morbidity and death. Recent translational and mechanistic studies of samples from patients, and observations in animal models, indicate that platelets may drive lung injury and contribute to dysregulated host defense in CF lung disease. In this issue of the JCI, Ortiz-Muñoz and Yu et al. explored the role that the cystic fibrosis transmembrane conductance regulator (CFTR) plays in platelet-related inflammation. The authors used mouse and human model systems to show that CFTR dysfunction in platelets increased calcium entry though the transient receptor potential cation channel 6 (TRPC6), causing hyperactivation and consequent experimental lung inflammation. The study persuasively suggests that platelets are critical thromboinflammatory effector cells in CF lung disease. In the context of platelet-related organ injury seen in a variety of other diseases and syndromes, platelets may also contribute to nonpulmonary manifestations and comorbidities of CF.
Authors
Guy A. Zimmerman
Abstract
BACKGROUND HBV-related acute-on-chronic liver failure (HBV-ACLF) is hallmarked by high short-term mortality rates, calling for accurate prognostic biomarkers for initial risk stratification.METHODS Three tandem mass tag–labeled (TMT-labeled) quantitative proteomic studies were performed on 10 patients with HBV-related acute hepatic decompensation and on 20 patients with HBV-ACLF. Candidate biomarkers were preliminarily verified in a cross-sectional cohort (n = 144) and further confirmed in 2 prospective cohorts (n = 207 and n = 148).RESULTS Plasminogen, a potential prognostic biomarker for HBV-ACLF, was identified by TMT quantitative proteomics and preliminarily verified in the cross-sectional cohort. Further validation with a prospective cohort (n = 207) showed that plasminogen levels at admission were significantly lower (P < 0.001) in HBV-ACLF nonsurvivors than in survivors. The cumulative survival duration of patients with high plasminogen levels was significantly longer (P < 0.001) than that of patients with low plasminogen levels. During hospitalization, plasminogen levels significantly decreased (P = 0.008) in the deterioration group but significantly increased (P < 0.001) in the improvement group. Additionally, plasminogen levels gradually increased in survivors but gradually decreased in nonsurvivors. The P5 score, a prognostic panel incorporating plasminogen levels, hepatic encephalopathy occurrence, age, international normalized ratio (INR), and total bilirubin, was significantly superior to the Child-Pugh, Model for End-stage Liver Disease (MELD), Chronic Liver Failure Consortium ACLF (CLIF-C ACLF), Chinese Group on the Study of Severe Hepatitis B (COSSH), and HINT (a prognostic score based on hepatic encephalopathy occurrence, INR, neutrophil count, and thyroid-stimulating hormone) scores (all P < 0.05). The performances of the plasminogen level and P5 score were validated in a second multicenter, prospective cohort (n = 148).CONCLUSIONS Plasminogen is a promising prognostic biomarker for HBV-ACLF, and sequential plasminogen measurements could profile the clinical course of HBV-ACLF. P5 is a high-performance prognostic score for HBV-ACLF.FUNDING The National Key Research and Development Program (2017YFC1200204); the National Natural Science Foundation of China (81400589, 81600497); the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (81121002); the Chinese High-Tech Research and Development Programs (2012AA020204); the National S&T Major Project (2012ZX10002004); and the Zhejiang Provincial Medicine and Health Science and Technology Project (2016147735).
Authors
Daxian Wu, Sainan Zhang, Zhongyang Xie, Ermei Chen, Qunfang Rao, Xiaoli Liu, Kaizhou Huang, Jing Yang, Lanlan Xiao, Feiyang Ji, Zhengyi Jiang, Yalei Zhao, Xiaoxi Ouyang, Danhua Zhu, Xiahong Dai, Zhouhua Hou, Bingjie Liu, Binbin Deng, Ning Zhou, Hainv Gao, Zeyu Sun, Lanjuan Li
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Abstract
This viewpoint addresses the major impact of the COVID-19 pandemic on biomedical research, the challenges created by the COVID-19 pandemic for research-intensive institutions, and what investigators can do to maintain some level of research activity while keeping their coworkers and trainees safe and engaged.
Authors
M. Bishr Omary, Jeetendra R. Eswaraka, S. David Kimball, Prabhas V. Moghe, Reynold A. Panettieri, Jr., Kathleen W. Scotto
Abstract
A common variant in the RAB27A gene in adults was recently found to be associated with the fractional exhaled nitric oxide level, a marker of eosinophilic airway inflammation. The small GTPase, Rab27, is known to regulate intracellular vesicle traffic, although its role in allergic responses is unclear. We demonstrated that exophilin-5, a Rab27 binding protein, was predominantly expressed in both the major IL-33 producers, lung epithelial cells, and the specialized IL-5 and IL-13 producers in CD44highCXCR3lowCD62Llow pathogenic T helper 2 (Th2) cell population in mice. Exophilin-5 deficiency increased stimulant-dependent damages and IL-33 secretion of lung epithelial cells. Moreover, it enhanced IL-5 and IL-13 production in response to TCR and IL-33 stimulation from a specific subset of pathogenic Th2 cells that expresses a high level of IL-33 receptor, which exacerbated allergic airway inflammation in a mouse model of asthma. Mechanistically, exophilin-5 regulates extracellular superoxide release, intracellular ROS production, and phosphoinositide 3-kinase activity by controlling intracellular traffic of Nox2-containing vesicles, which seems to prevent the overactivation of pathogenic Th2 cells mediated by IL-33. This is the first report to establish the significance of Rab27-related protein exophilin-5 in the development of allergic airway inflammation, and provides new insights into the pathophysiology of asthma.
Authors
Katsuhide Okunishi, Hao Wang, Maho Suzukawa, Ray Ishizaki, Eri Kobayashi, Miho Kihara, Takaya Abe, Jun-ichi Miyazaki, Masafumi Horie, Akira Saito, Hirohisa Saito, Susumu Nakae, Tetsuro Izumi
Abstract
Hidradenitis suppurativa (HS) is a chronic, relapsing, inflammatory skin disease. HS appears to be a primary abnormality in the pilosebaceous-apocrine unit. In this work, we characterized hair follicle stem cells isolated from HS patients and more precisely the Outer Root Sheath Cells (ORS). We show that hair follicles from HS patients have an increased number of proliferating progenitor cells and lose quiescent stem cells. Remarkably, we also show that the progression of replication forks is altered in HS-ORS and activates the ATR-CHK1 pathway. These alterations are associated with an increased number of micronuclei and with the presence of cytoplasmic ssDNA, leading to the activation of IFI16-STING pathway and the production of type I IFNs. This mechanistic analysis of the etiology of HS in the hair follicle stem cells compartment establishes a formal link between the genetic predisposition and skin inflammation observed in HS.
Authors
Cindy Orvain, Yea-Lih Lin, Francette Jean-Louis, Hakim Hocini, Barbara Hersant, Yamina Bennasser, Nicolas Ortonne, Claire Hotz, Pierre Wolkenstein, Michele Boniotto, Pascaline Tisserand, Cecile Lefebvre, Jean-Daniel Lelievre, Monsef Benkirane, Philippe Pasero, Yves Levy, Sophie Hue
Abstract
Germinal center (GC) responses require B cells to respond to a dynamic set of intercellular and microenvironmental signals that instruct B cell positioning, differentiation, and metabolic reprogramming. ROCK2, a serine-threonine kinase that can be therapeutically targeted by ROCK inhibitors or statins, is a key downstream effector of RHOA-GTPases. While RHOA-mediated pathways are emerging as critical regulators of GC responses, the role of ROCK2 in B cells is unknown. Here, we find that ROCK2 was activated in response to key T cell signals like CD40 and IL21 and that it regulated GC formation and maintenance. RNA-seq analyses revealed that ROCK2 controlled a unique transcriptional program in GC B cells that promoted optimal GC polarization and cholesterol biosynthesis. ROCK2 regulated this program by restraining AKT activation and subsequently enhancing FOXO1 activity. ATAC-seq and biochemical analyses revealed that the effects of ROCK2 on cholesterol biosynthesis were instead mediated via a novel mechanism. ROCK2 directly phosphorylated IRF8, a crucial mediator of GC responses, and promoted its interaction with SREBP2 at key regulatory regions controlling the expression of cholesterol biosynthetic enzymes, resulting in optimal recruitment of SREBP2 at these sites. These findings thus uncover ROCK2 as a multifaceted and therapeutically targetable regulator of GC responses.
Authors
Edd Ricker, Yurii Chinenov, Tania Pannellini, Danny M. Flores Castro, Chao Ye, Sanjay Gupta, Michela Manni, James K. Liao, Alessandra Pernis
Abstract
Immune microenvironment plays a critical role in lung cancer control versus progression and metastasis. In this investigation, we explored the impact of tumor-infiltrating-lymphocyte subpopulations on lung cancer biology by studying in vitro co-cultures, in vivo mouse models and human lung cancer tissue. Lymphocyte conditioned media-(CM) induced epithelial-mesenchymal-transition (EMT), and migration in both primary human lung cancer cells and cell lines. Correspondingly, major accumulation of Th9 and Th17 cells was detected in human lung cancer tissue, and correlated with poor survival. Co-culturing lung cancer cells with Th9/Th17 cells or exposing them to the respective-CM induced-EMT in cancer cells and modulated the expression profile of genes implicated in EMT and metastasis. These features were reproduced by the signatory cytokines IL–9 and IL–17, with gene regulatory profiles evoked by these cytokines partly overlapping and partly complementary. Co-injection of Th9 and/or Th17 cells with tumor cells in wildtype, Rag1-/-, Il9r-/- and Il17ra-/- mice altered tumor growth and metastasis. Accordingly, inhibition of IL–9 or IL–17 cytokines by neutralizing antibodies decreased EMT and slowed lung cancer progression and metastasis. In conclusion, Th9 and Th17 lymphocytes induce lung cancer cell EMT, thereby promoting migration, and metastatic spreading and offering for novel therapeutic strategies.
Authors
Ylia Salazar, Xiang Zheng, David Brunn, Hartmann Raifer, Felix S.R. Picard, Yajuan Zhang, Hauke Winter, Stefan Günther, Andreas Weigert, Benno Weigmann, Laure Dumoutier, Jean-Christophe Renauld, Ari Waisman, Anja Schmall, Amanda Tufman, Ludger Fink, Bernhard Brüne, Tobias Bopp, Friedrich Grimminger, Werner Seeger, Soni Savai Pullamsetti, Magdalena Huber, Rajkumar Savai
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April 2020
On the cover:
IFN-driven neuroinflammation in Alzheimer disease
April 2020 Issue
On the cover:
IFN-driven neuroinflammation in Alzheimer disease
Pathologic inflammation leading to neurodegeneration in Alzheimer disease (AD) may be driven by immunogenic responses to β-amyloid (Aβ) fibrils, aggregates of soluble proteins that form insoluble secondary structures. In this issue of the JCI, Roy et al. highlight the IFN pathway’s contribution to neuropathology in models of AD. They reveal that Aβ-driven activation of IFN signaling in microglia drives microgliosis as well as complement-mediated synapse loss in mice. Blocking IFN reduced inflammation and synapse loss in these models. Together, the observations support further examination of the IFN pathway as a target in treating AD. The accompanying image shows the accumulation of activated microglia (Iba1, green; Clec7a, yellow) associated with Aβ plaques (blue) in a mouse model of AD. Image credit: Ethan Roy.
JCI This Month
April 2020 JCI This Month
JCI This Month is a digest of the research, reviews, and other features published each month.
Review Series - More
Series edited by Leo Luznik
Immunotherapy in Hematological Cancers
Series edited by Leo Luznik
Immunotherapeutic strategies leveraging the immune system’s antitumor activity have become a mainstay of cancer treatment. Strategies including antibody-directed approaches, stem cell transplantation, immunomodulatory drugs, immune checkpoint inhibitors, CAR T cells, and vaccines have demonstrated particular success in controlling and even eradicating hematological cancers. This Review Series, developed by JCI’s associate editor Leo Luznik, discusses ongoing progress in immunotherapeutic targeting of hematological cancers. Reviews will address the state-of-the-art in immunotherapies for acute myeloid leukemia, multiple myeloma, and lymphoma and highlight recent successes and challenges in clinical trials for these diseases; take a detailed look at recent developments in CAR T therapies for B cell malignancies; and describe how personalized antigen targeting can be applied to immunotherapeutic treatment of blood malignancies.
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Copyright © 2020 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)