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Abstract
Chronic beryllium disease (CBD) is a metal hypersensitivity/autoimmune disease in which damage-associated molecular patterns (DAMPs) promote a break in T cell tolerance and expansion of Be2+/self-peptide reactive CD4+ T cells. In this study, we investigated the mechanism of cell death induced by beryllium particles (Be) in alveolar macrophages (AMΦs) and its impact on DAMP release. We found that phagocytosis of Be led to AM cell death independently of caspase, RIP1K, RIP3K or ROS activity. Prior to cell death, Be-exposed AMΦs secreted TNFalpha that boosted intracellular stores of IL-1alpha followed by caspase 8-dependent fragmentation of DNA. IL-1alpha and nucleosomal DNA were subsequently released from AMΦs upon loss of plasma membrane integrity. In contrast, necrotic AMs released only unfragmented DNA and necroptotic AMΦs released only IL-1alpha. In mice exposed to Be, TNFalpha promoted release of both DAMPs and was required for the mobilization of immunogenic DCs, expansion of Be-reactive CD4+ T cells and pulmonary inflammation in a mouse model of CBD. Thus, early autocrine effects of particle-induced TNFalpha on AMs led to a break in peripheral tolerance. This novel mechanism may underlie the known relationship between fine particle inhalation, TNFalpha and loss of peripheral tolerance in T cell-mediated autoimmune disease and hypersensitivities.
Authors
Morgan K. Collins, Abigail M. Shotland, Morgan F. Wade, Shaikh M. Atif, Denay J.K. Richards, Manolo Torres-Llompart, Douglas G. Mack, Allison K. Martin, Andrew P. Fontenot, Amy S. McKee
Abstract
While blockade of PD-1/PD-L1 immune checkpoint revolutionized cancer treatment, how it works on tumor-infiltrating CD8+ T cells recognizing the same antigen at various differentiation stages remains elusive. Here, we found that the chemokine receptor CX3CR1 identified three distinct differentiation states of intratumoral CD8+ T-cell subsets. Adoptively transferred antigen-specific CX3CR1neg CD8+ T cells generated phenotypically and functionally distinct CX3CR1int and CX3CR1hi subsets in the periphery. Notably, expression of co-inhibitory receptors and Tcf1 inversely correlated with the degree of T-cell differentiation defined by CX3CR1. Despite significantly lower expression of co-inhibitory receptors and potent cytolytic activity, in vivo depletion of the CX3CR1hi subset did not alter the antitumor efficacy of adoptively transferred CD8+ T cells. Furthermore, differentiated CX3CR1int and CX3CR1hi subsets were impaired in their ability to undergo proliferation upon re-stimulation, and had no impact on established tumors upon second adoptive transfer compared with the CX3CR1neg subset that remained effective. Accordingly, anti-PD-L1 therapy preferentially rescued proliferation and cytokine production of the CX3CR1neg subset, and significantly enhanced antitumor efficacy of adoptively transferred CD8+ T cells. These findings provide a better understanding of the phenotypic and functional heterogeneity of tumor-infiltrating CD8+ T cells, and can be exploited to develop more effective immunotherapy.
Authors
Takayoshi Yamauchi, Toshifumi Hoki, Takaaki Oba, Hidehito Saito, Kristopher Attwood, Michael S. Sabel, Alfred E. Chang, Kunle Odunsi, Fumito Ito
Abstract
Background: Prehospital plasma improves survival in severely injured trauma patients at risk for hemorrhagic shock and transported by air ambulance. We hypothesized that prehospital plasma would be associated with a reduction in immune imbalance and endothelial damage. Methods: We collected blood samples from 405 trauma patients enrolled in the Prehospital Air MedicalPlasma (PAMPer) trial upon hospital admission (0 hours) and 24 hours post admission across 6 U.S. sites(9 level-one trauma centers) with air medical transport services. We assayed samples for 21 inflammatory mediators and 7 markers of endothelial damage. We performed hierarchical clustering analysis (HCA) on principal components of these biomarkers of the immune response and endothelial injury. Regression analysis was used to control for known differences across study arms near the time of randomization and to assess any association with prehospital plasma administration. Results: HCA based on inflammatory mediator and endothelial damage marker concentrations distinguished two patient clusters, each with different injury patterns and outcomes. Patients in cluster A had greater injury severity and incidence of blunt trauma, traumatic brain injury, and mortality. Cluster A patients that received prehospital plasma as compared to standard care fluid resuscitation showed improved 30-day survival. Prehospital plasma did not improve survival in cluster B patients. In an adjusted analysis of themost seriously injured patients (ISS>30), plasma was associated with a an increase in circulating levels of adiponectin, IL-1β, IL-17A, IL-23, and IL-17E upon admission. One day following admission, prehospital plasmas was associated with a reduction in syndecan-1, TM, VEGF, IL-6, IP-10, MCP-1, and TNF-α, and an increase in IL-33, IL-21, IL-23, and IL-17E. Conclusion: This is the first human study to suggest that prehospital plasma may ameliorate the endotheliopathy of trauma and modulate an imbalance between pro-inflammatory (e.g. IL-6, TNF-α, and MCP-1) and protective (e.g. IL-33 and IL-17E) mediators. These effects of early plasma administration may contribute to improved survival in severely injured patients. Trial Registration: ClinicalTrials.gov NCT01818427 Funding: National Institutes of Health T32; U.S. Army Medical Research and Materiel Command W81XWH-12-2-0023; National Institutes of Health R35; National Institutes of Health 1R35GM119526-01; the Office of the Assistant Secretary of Defense for Health Affairs, through the Defense Medical Research and Development Program W81XWH-18-2-0051 and W81XWH-15-PRORP-OCRCA. Opinions, interpretations, conclusions and recommendations are those of the authors and not necessarily endorsed by the Department of Defense.
Authors
Danielle S. Gruen, Joshua B. Brown, Francis X. Guyette, Yoram Vodovotz, Par I. Johansson, Jakob Stensballe, Derek A. Barclay, Jinling Yin, Brian J. Daley, Richard S. Miller, Brian G. Harbrecht, Jeffrey A. Claridge, Herb A. Phelan, Matthew D. Neal, Brian Zuckerbraun, Timothy R. Billiar, Jason L. Sperry
Abstract
Glucokinase (GK) is highly expressed in the hypothalamic paraventricular nucleus (PVN); however its role is currently unknown. We found that glucokinase in the PVN acts as part of a glucose sensing mechanism within the PVN that regulates glucose homeostasis by controlling glucagon like peptide 1 (GLP-1) release. GLP-1 is released from enteroendocrine L-cells in response to oral glucose. Here we identify a brain mechanism critical to the release of GLP-1 in response to oral glucose. We show that increasing expression of GK or injection of glucose into the PVN increases GLP-1 release in response to oral glucose. On the contrary decreasing expression of GK or injection of non-metabolisable glucose into the PVN prevents GLP-1 release. Our results demonstrate that glucosensitive GK neurones in the PVN, are critical to the response to oral glucose and subsequent release of GLP-1.
Authors
Yue Ma, Risheka Ratnasabapathy, Ivan De Backer, Chioma Izzi-Engbeaya, Marie-Sophie Nguyen-Tu, Joyceline Cuenco, Ben Jones, Christopher D. John, Brian Y. H. Lam, Guy A. Rutter, Giles Yeo, Waljit Dhillo, James Gardiner
Abstract
Capicua (CIC), a member of the high mobility group (HMG)-box superfamily of transcriptional repressors, is frequently mutated in human oligodendrogliomas. But its function in brain development and tumorigenesis remains poorly understood. Here, we report that brain-specific deletion of Cic compromises developmental transition of neuroblast to immature neurons in mouse hippocampus and compromises normal neuronal differentiation. Combined gene expression and ChIP-seq analyses identified VGF as an important CIC-repressed transcriptional surrogate involved in neuronal lineage regulation. Aberrant VGF expression promotes neural progenitor cell proliferation by suppressing their differentiation. Mechanistically, we demonstrated that CIC represses VGF expression by tethering SIN3-HDAC to form a transcriptional corepressor complex. Mass spectrometry analysis of CIC-interacting proteins further identified BRG1 containing mSWI/SNF complex whose function is necessary for transcriptional repression by CIC. Together, this study uncovers a novel regulatory pathway of CIC-dependent neuronal differentiation and may implicate these molecular mechanisms in CIC-dependent brain tumorigenesis.
Authors
Inah Hwang, Heng Pan, Jun Yao, Olivier Elemento, Hongwu Zheng, Jihye Paik
Abstract
Hydrocephalus is characterized by abnormal accumulation of cerebrospinal fluid (CSF) in the ventricular cavity. The circulation of CSF in brain ventricles is controlled by the coordinated beating of motile cilia at the surface of ependymal cells (ECs). Here we show that MT1-MMP is highly expressed in olfactory bulb, rostral migratory stream, and ventricular system. Mice deficient for Membrane type-1-MMP (MT1-MMP) develop typical phenotypes observed in hydrocephalus such as dome-shaped skull, dilated ventricles, corpus callosum agenesis and astrocyte hypertrophy during the first two weeks of postnatal development. MT1-MMP deficient mice exhibits reduced and disorganized motile cilia with the impaired maturation of ECs, leading to abnormal CSF flow. Consistent with the defects in motile cilia morphogenesis, the expressions of pro-multiciliogenic genes are significantly decreased with a concomitant hyper-activation of Notch signaling in the wall of lateral ventricles in Mmp14-/- brains. Inhibition of Notch signaling by γ-secretase inhibitor restores ciliogenesis in Mmp14-/- ECs. Taken together, these data suggest that MT1-MMP is required for ciliogenesis and ependymal cell maturation by suppressing Notch signaling during early brain development. Our findings implicate that MT1-MMP is critical for early brain development and loss of MT1-MMP activity gives rise to hydrocephalus.
Authors
Zhixin Jiang, Jin Zhou, Xin Qin, Huiling Zheng, Bo Gao, Xin-guang Liu, Guoxiang Jin, Zhongjun Zhou
Abstract
Background: Specific features of the tumor microenvironment (TME) may provide useful prognostic information. We conducted a systematic investigation of the cellular composition and prognostic landscape of TME in gastric cancer. Methods: We evaluated the prognostic significance of major stromal and immune cells within TME. We proposed a composite TME-based risk score and tested it in six independent cohorts of 1,678 patients with gene expression or immunohistochemistry measurements. Further, we devised a new patient classification system based on TME characteristics. Results: We identified natural killer cells, fibroblasts, and endothelial cells as the most robust prognostic markers. The TME risk score combining these cell types was an independent prognostic factor when adjusted for clinicopathologic variables (gene expression: HR [95% CI]: 1.42 [1.22–1.66]; immunohistochemistry: 1.34 [1.24–1.45], P<0.0001). Higher TME risk scores consistently associated with worse survival within every pathologic stage (HR range: 2.18-3.11, P<0.02) and among patients who received surgery only. The TME risk score provided additional prognostic value beyond stage, and combination of the two improved prognostication accuracy (likelihood-ratio test χ2 = 235.4 vs. 187.6, P<0.0001; net reclassification index: 23%). The TME risk score can predict the survival benefit of adjuvant chemotherapy in non-metastatic patients (stage I-III) (interaction test P<0.02). Patients were divided into four TME subtypes that demonstrated distinct genetic and molecular patterns and complemented established genomic and molecular subtypes. Conclusion: We developed and validated a TME-based risk score as an independent prognostic and predictive factor, which has the potential to guide personalized management of gastric cancer.
Authors
Bailiang Li, Yuming Jiang, Guoxin Li, George A. Fisher, Ruijiang Li
Abstract
BACKGROUND. Lower-grade gliomas (LGGs) vary widely in terms of the patient’s overall survival (OS). There is a lack of valid method that could exactly predict the survival. The effects of intratumoral immune infiltration on clinical outcome have been widely reported. Thus, we aim to develop an immune infiltration signature to predict the survival of LGG patients. METHODS. We analyzed 1216 LGGs from 5 public datasets, including 2 RNA-Seq datasets and 3 microarray datasets. Least absolute shrinkage and selection operator (LASSO) Cox regression was used to select an immune infiltration signature and build a risk score. The performance of the risk score was assessed in the training set (329 patients), internal validation set (140 patients), and 4 external validation sets (405, 118, 88, and 136 patients). RESULTS. An immune infiltration signature consisting of 20 immune metagenes was used to generate a risk score. The performance of the risk score was thoroughly verified in the training and validation sets. Additionally, we found that the risk score was positively correlated with the expression levels of TGFβ and PD-L1, which were important targets of combination immunotherapy. Furthermore, a nomogram incorporating the risk score, patient’s age, and tumor grade was developed to predict the OS, and it performed well in all the training and validation sets (C-index: 0.873, 0.881, 0.781, 0.765, 0.721, and 0.753, respectively). CONCLUSIONS. The risk score based on the immune infiltration signature has reliable prognostic and predictive value for patients with LGGs and might be a potential biomarker for the co-targeting immunotherapy. FUNDING. The National Natural Science Foundation of China (Grant No. 81472370 and 81672506), the Natural Science Foundation of Beijing (Grant No. J180005), the National High Technology Research and Development Program of China (863 Program, Grant No. 2014AA020610) and the National Basic Research Program of China (973 Program, Grant No. 2014CB542006).
Authors
Lai-Rong Song, Jian-Cong Weng, Cheng-Bei Li, Xu-Lei Huo, Huan Li, Shu-Yu Hao, Zhen Wu, Liang Wang, Da Li, Jun-Ting Zhang
Abstract
Familial Hypocalciuric Hypercalcemia (FHH) is a genetic condition associated with hypocalciuria, hypercalcemia and in some cases inappropriately high levels of circulating parathyroid hormone (PTH). FHH is associated with inactivating mutations in CaSR encoding the Ca2+ sensing receptor (CaSR), a G protein coupled receptor (GPCR) and GNA11 encoding G protein subunit alpha 11 (Gα11), implicating defective GPCR signaling as the root pathophysiology for FHH. However, the downstream mechanism by which CaSR activation inhibits PTH production/secretion is incompletely understood. Here, we show that mice lacking the transient receptor potential canonical channel 1 (TRPC1) develop chronic hypercalcemia, hypocalciuria, and elevated PTH levels mimicking human FHH. Ex vivo and in vitro studies reveal that TRPC1 serves a necessary and sufficient mediator to suppress PTH secretion from parathyroid glands (PTG) downstream of CaSR in response to high extracellular Ca2+ concentration. Gα11 physically interacts with both the N- and C-termini of TRPC1 and enhances CaSR-induced TRPC1 activity in transfected cells. These data identify TRPC1-mediated Ca2+ signaling as an essential component of the cellular apparatus controlling PTH secretion in the PTG downstream of CaSR.
Authors
Marta Onopiuk, Bonnie Eby, Vasyl Nesin, Peter Ngo, Megan Lerner, Caroline M. Gorvin, Victoria J. Stokes, Rajesh V. Thakker, Maria Luisa Brandi, Wenhan Chang, Mary Beth Humphrey, Leonidas Tsiokas, Kai Lau
Abstract
Septic cardiomyopathy is a life-threatening organ dysfunction caused by sepsis. Ribonuclease 1 (RNase 1) belongs to a group of host-defense peptides that specifically cleave extracellular RNA (eRNA). The activity of RNase1 is inhibited by ribonuclease-inhibitor 1 (RNH1). The role of RNase 1 in septic cardiomyopathy and associated cardiac apoptosis, however, is completely unknown. Here, we showed that sepsis resulted in a significant increase in RNH1 and eRNA serum levels compared to those of healthy subjects (p < 0.05). Treatment with RNase 1 resulted in a significant decrease of apoptosis, induced by the intrinsic pathway, and TNF expression in murine cardiomyocytes exposed to either necrotic cardiomyocytes or serum of septic patients for 16 h (p < 0.05). Furthermore, treatment of septic mice with RNase 1 resulted in a reduction in cardiac apoptosis, TNF expression and septic cardiomyopathy (p < 0.05). These data demonstrate that eRNA plays a crucial role in the pathophysiology of the organ (cardiac) dysfunction in sepsis and RNase and RNH1 may be new therapeutic targets/strategies to reduce the cardiac injury and dysfunction caused by sepsis.
Authors
Elisabeth Zechendorf, Caroline E O'Riordan, Lara Stiehler, Natalie Wischmeyer, Fausto Chiazza, Debora Collotta, Bernd Denecke, Sabrina Ernst, Gerhard Müller-Newen, Sina M. Coldewey, Bianka Wissuwa, Massimo Collino, Tim-Philipp Simon, Tobias Schuerholz, Christian Stoppe, Gernot Marx, Christoph Thiemermann, Lukas Martin
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