F¹⁸-FDG PET imaging as a diagnostic tool for immune checkpoint inhibitor-associated acute kidney injury

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Abstract

Authors

Shruti Gupta, Olivia Green-Lingren, Sudhir Bhimaniya, Aleksandra Krokhmal, Heather Jacene, Marlies Ostermann, Sugama Chicklore, Ben Sprangers, Christophe M. Deroose, Sandra M. Herrmann, Sophia L. Wells, Sarah A. Kaunfer, Jessica L. Ortega, Clara Garcia-Carro, Michael Bold, Kevin L. Chen, Meghan E. Sise, Pedram Heidari, Wai Lun Will Pak, Meghan D. Lee, Pazit Beckerman, Yael Eshet, Raymond K. Hsu, Miguel Hernandez Pampaloni, Arash Rashidi, Norbert Avril, Vicki Donley, Zain Mithani, Russ Kuker, Muhammad O Awiwi, Mindy X. Wang, Sujal I. Shah, Michael D. Weintraub, Heiko Schoder, Raad B. Chowdhury, Harish Seethapathy, Kerry L. Reynolds, Maria Jose Soler, Ala Abudayyeh, Ilya Glezerman, David E. Leaf

Hif-2α programmes oxygen chemosensitivity in chromaffin cells

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Abstract

The study of transcription factors that determine specialised neuronal functions has provided invaluable insights into the physiology of the nervous system. Peripheral chemoreceptors are neurone-like electro-physiologically excitable cells that link the oxygen content of arterial blood to the neuronal control of breathing. In the adult, this oxygen chemosensitivity is exemplified by the Type I cells of the carotid body and recent work has revealed one isoform of the transcription factor HIF, HIF-2α, to have a non-redundant role in the development and function of that organ. Here we show that the activation of HIF-2α, including isolated overexpression alone, is sufficient to induce oxygen chemosensitivity in the otherwise unresponsive adult adrenal medulla. This phenotypic change in the adrenal medulla was associated with retention of extra-adrenal paraganglioma-like tissues that resemble the foetal organ of Zuckerkandl and also manifest oxygen chemosensitivity. Acquisition of chemosensitivity was associated with changes in the adrenal medullary expression of classes of genes that are ordinarily characteristic of the carotid body, including G-protein regulators and atypical subunits of mitochondrial cytochrome oxidase. Overall, the findings suggest that, at least in certain tissues, HIF-2α acts as a phenotypic driver for cells that display oxygen chemosensitivity, thus linking two major oxygen sensing systems.

Authors

Maria Prange-Barczynska, Holly A. Jones, Yoichiro Sugimoto, Xiaotong Cheng, Joanna D.C.C Lima, Indrika Ratnayaka, Gillian Douglas, Keith J. Buckler, Peter J. Ratcliffe, Thomas P. Keeley, Tammie Bishop

NKT cells promote Th1 immune bias to dengue virus that governs long term protective antibody dynamics

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Abstract

NKT cells are innate-like T cells, recruited to the skin during viral infection, yet their contributions to long-term immune memory to viruses are unclear. We identified granzyme K, a product made by cytotoxic cells including NKT cells, is linked to induction of Th1-associated antibodies during primary dengue virus (DENV) infection in humans. We examined the role of NKT cells in vivo using DENV-infected mice lacking CD1d-dependent (CD1ddep) NKT cells. In CD1d-KO mice, Th1-polarized immunity and infection resolution were impaired, which was dependent on intrinsic NKT cell production of IFN-γ, since it was restored by adoptive transfer of WT but not IFN-γ-KO NKT cells. Furthermore, NKT cell deficiency triggered immune bias, resulting in higher levels of Th2-associated IgG1 than Th1-associated IgG2a, which failed to protect against a homologous DENV re-challenge and promoted antibody-dependent enhanced disease during secondary heterologous infections. Similarly, Th2-immunity, typified by a higher IgG4:IgG3 ratio, was associated with worsened human disease severity during secondary infections. Thus, CD1ddep NKT cells establish Th1 polarity during the early innate response to DENV, which promotes infection resolution, memory formation and long-term protection from secondary homologous and heterologous infections. These observations illustrate how early innate immune responses during primary infections can influence secondary infection outcomes.

Authors

Youngjoo Choi, Wilfried A.A. Saron, Aled O'Neill, Manouri Senanayake, Annelies Wilder-Smith, Abhay P.S. Rathore, Ashley L. St. John

Exosomal TNF-α mediates voltage-gated Na⁺ channels 1.6 overexpression and contributes to brain-tumor induced neuronal hyperexcitability

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Abstract

Patients affected by glioma frequently suffer of epileptic discharges, however the causes of brain tumor-related epilepsy (BTRE) are still not completely understood. We investigated the mechanisms underlying BTRE by analyzing the effects of exosomes released by U87 glioma cells and by patient-derived glioma cells. Rat hippocampal neurons incubated for 24 h with these exosomes exhibited increased spontaneous firing, while their resting membrane potential shifted positively by 10-15 mV. Voltage clamp recordings demonstrated that the activation of the Na+ current shifted towards more hyperpolarized voltages by 10-15 mV. To understand the factors inducing hyperexcitability we focused on exosomal cytokines. Western Blot and ELISA assays show that TNF-α is present inside glioma-derived exosomes. Remarkably, incubation with TNF-α fully mimicked the phenotype induced by exosomes, with neurons firing continuously, while their resting membrane potential shifted positively. RT-PCR revealed that both exosomes and TNF-α induced over-expression of the voltage-gated Na channel Nav1.6, a low-threshold Na+ channel responsible for hyperexcitability. When neurons were preincubated with Infliximab, a specific TNF-α inhibitor, the hyperexcitability induced by exosomes and TNF-α were drastically reduced. We propose that Infliximab, an FDA approved drug to treat rheumatoid arthritis, could ameliorate the conditions of glioma patients suffering of BTRE.

Authors

Cesar Adolfo Sanchez Trivino, Renza Spelat, Federica Spada, Camilla D'Angelo, Ivana Manini, Irene Giulia Rolle, Tamara Ius, Pietro Parisse, Anna Menini, Daniela Cesselli, Miran Skrap, Fabrizia Cesca, Vincent Torre

Early ascertainment of genetic diagnoses clarifies impact on medium-term survival following neonatal congenital heart surgery

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Abstract

Authors

Benjamin J. Landis, Benjamin M. Helm, Matthew D. Durbin, Lindsey R. Helvaty, Jeremy L. Herrmann, Michael Johansen, Gabrielle C. Geddes, Stephanie M. Ware

Autism-associated neuroligin-3 deficiency in medial septum causes social deficits and sleep loss in mice

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Patients with autism spectrum disorder (ASD) frequently experience sleep disturbance. Genetic mutations in Neuroligin-3 (NLG3) genes are highly correlative with ASD and sleep disturbance. However, the cellular and neural circuit bases of this correlation remain elusive. Here, we find the conditional knockout of NLG3 (NLG3-CKO) in the medial septum (MS) impairs social memory and reduces sleep. NLG3 knockout in MS causes hyperactivity of MS-GABA neurons during social avoidance and wakefulness. Activation of MSGABA neurons induces social memory deficits and sleep loss in C57BL/6 mice. In contrast, inactivation of these neurons ameliorates social memory deficits and sleep loss in NLG3-CKO mice. Sleep deprivation leads to social memory deficits, while social isolation causes sleep loss, both resulting in a reduction of NLG3 expression and an increase in activity of GABAergic neurons in MS from C57BL/6 mice. Furthermore, MS-GABA-innervated CA2 neurons specifically regulate social memory without impacting sleep, whereas MSGABA-innervating neurons in the preoptic area selectively control sleep without affecting social behavior. Together, these findings demonstrate that the hyperactive MS-GABA neurons impair social memory and disrupt sleep resulting from NLG3 knockout in MS, and achieve the modality specificity through their divergent downstream targets.

Authors

Haiyan Sun, Yu Shen, Pengtao Ni, Xin Liu, Yan Li, Zhentong Qiu, Jiawen Su, Yihan Wang, Miao Wu, Xiangxi Kong, Jun-Li Cao, Wei Xie, Shuming An

Hepatic lipopolysaccharide binding protein partially uncouples inflammation from fibrosis in MAFLD

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Abstract

Authors

Dan Wang, Ania Baghoomian, Zhengyi Zhang, Ya Cui, Emily C. Whang, Xiang Li, Josue Fraga, Rachel Spellman, Tien S. Dong, We Li, Arpana Gupta, Jihane N. Benhammou, Tamer Sallam

A correctable immune niche for epithelial stem-cell reprogramming and post-viral lung diseases

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Epithelial barriers are programmed for defense and repair but are also the site of long-term structural remodeling and disease. In general, this paradigm features epithelial stem cell (ESCs) that are called on to regenerate damaged tissues but can also be reprogrammed for detrimental remodeling. Here we identified a Wfdc21-dependent monocyte-derived dendritic cell (moDC) population that functioned as an early sentinel niche for basal-ESC reprogramming in mouse models of epithelial injury after respiratory viral infection. Niche function depended on moDC delivery of ligand GPNMB to basal-ESC receptor CD44 so that properly timed antibody blockade of ligand or receptor provided long-lasting correction of reprogramming and broad disease phenotypes. These same control points worked directly in mouse and human basal-ESC organoids. Together, the findings identify a mechanism to explain and modify what is otherwise a stereotyped but sometimes detrimental response to epithelial injury.

Authors

Kangyun Wu, Yong Zhang, Huiqing Yin-DeClue, Kelly Sun, Dailing Mao, Kuangying Yang, Stephen R. Austin, Erika C. Crouch, Steven L. Brody, Derek E. Byers, Christy M. Hoffmann, Michael E. Hughes, Michael J. Holtzman

Intercellular interaction between FAP⁺ fibroblasts and CD150⁺ inflammatory monocytes mediates fibro-stenosis in Crohn’s disease

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Crohn's disease (CD) is marked by recurring intestinal inflammation and tissue injury, often resulting in fibro-stenosis and bowel obstruction, necessitating surgical intervention with high recurrence rates. To elucidate to the mechanisms underlying fibro-stenosis in CD, we analysed the transcriptome of cells isolated from the transmural ileum of CD patients, including a trio of lesions from each patient: non-affected, inflamed, and stenotic ileum samples, and compared them with samples from non-CD patients. Our computational analysis revealed that pro-fibrotic signals from a subset of monocyte-derived cells expressing CD150 induced a disease-specific fibroblast population, resulting in chronic inflammation and tissue fibrosis. The transcription factor TWIST1 was identified as a key modulator of fibroblast activation and extracellular matrix (ECM) deposition. Genetic and pharmacological inhibition of TWIST1 prevents fibroblast activation, reducing ECM production and collagen deposition. Our findings suggest that the myeloid-stromal axis may offer a promising therapeutic target to prevent fibro-stenosis in CD.

Authors

Bo-Jun Ke, Saeed Abdurahiman, Francesca Biscu, Gaia Zanella, Gabriele Dragoni, Sneha Santhosh, Veronica De Simone, Anissa Zouzaf, Lies van Baarle, Michelle Stakenborg, Veronika Bosáková, Yentl Van Rymenant, Emile Verhulst, Sare Verstockt, Elliott Klein, Gabriele Bislenghi, Albert M. Wolthuis, Jan Frič, Christine Breynaert, Andre D'Hoore, Pieter Van der Veken, Ingrid De Meester, Sara Lovisa, Lukas J.A.C. Hawinkels, Bram Verstockt, Gert De Hertogh, Séverine Vermeire, Gianluca Matteoli

Systemic and skin-limited delayed-type drug hypersensitivity reactions associate with distinct resident and recruited T cell subsets

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Abstract

Delayed-type drug hypersensitivity reactions are major causes of morbidity and mortality. The origin, phenotype and function of pathogenic T cells across the spectrum of severity requires investigation. We leveraged recent technical advancements to study skin-resident memory T cells (TRM) versus recruited T cell subsets in the pathogenesis of severe systemic forms of disease, SJS/TEN and DRESS, and skin-limited disease, morbilliform drug eruption (MDE). Microscopy, bulk transcriptional profiling and scRNAseq + CITEseq + TCRseq supported in SJS/TEN clonal expansion and recruitment of cytotoxic CD8+ T cells from circulation into skin, along with expanded and non-expanded cytotoxic CD8+ skin TRM. Comparatively, MDE displayed a cytotoxic T cell profile in skin without appreciable expansion and recruitment of cytotoxic CD8+ T cells from circulation, implicating TRM as potential protagonists in skin-limited disease. Mechanistic interrogation in patients unable to recruit T cells from circulation into skin and in a parallel mouse model supported that skin TRM were sufficient to mediate MDE. Concomitantly, SJS/TEN displayed a reduced regulatory T cell (Treg) signature compared to MDE. DRESS demonstrated recruitment of cytotoxic CD8+ T cells into skin like SJS/TEN, yet a pro-Treg signature like MDE. These findings have important implications for fundamental skin immunology and clinical care.

Authors

Pranali N. Shah, George A. Romar, Artür Manukyan, Wei-Che Ko, Pei-Chen Hsieh, Gustavo A. Velasquez, Elisa M. Schunkert, Xiaopeng Fu, Indira Guleria, Roderick T. Bronson, Kevin Wei, Abigail H. Waldman, Frank R. Vleugels, Marilyn G. Liang, Anita Giobbie-Hurder, Arash Mostaghimi, Birgitta A.R. Schmidt, Victor Barrera, Ruth K. Foreman, Manuel Garber, Sherrie J. Divito