Acute bacterial orchitis (AO) is a prevalent cause of intra-scrotal inflammation, often resulting in sub- or infertility. A frequent cause eliciting AO is uropathogenic Escherichia coli (UPEC), a gram negative pathovar, characterized by the expression of various iron acquisition systems to survive in a low-iron environment. On the host side, iron is tightly regulated by iron regulatory proteins (IRP) 1 and 2 and these factors are reported to play a role in testicular and immune cell function, however, their precise role remains unclear. Here, we showed in a mouse model of UPEC-induced orchitis that the absence of IRP1 results in reduced immune response and testicular damage. Compared to infected wild-type (WT)-mice, testis of UPEC-infected Irp1–/– mice showed impaired ERK signaling. Conversely, IRP2 deletion led to a stronger inflammatory response. Notably, differences in immune cell infiltrations were observed among the different genotypes. In contrast to WT and Irp2–/– mice, no increase in monocytes and neutrophils was detected in testis of Irp1–/– mice upon UPEC-infection. Interestingly, in Irp1–/– UPEC-infected testis, we observed an increase in a subpopulation of macrophages (F4/80+ CD206+) associated with anti-inflammatory and wound-healing activities compared to WT. These findings suggest that IRP1 deletion may protect against UPEC-induced inflammation by modulating ERK signaling and dampening the immune response.
Niraj Ghatpande, Aileen Harrer, Bar Azoulay-Botzer, Noga Guttmann-Raviv, Sudhanshu Bhushan, Andreas Meinhardt, Esther G. Meyron-Holtz
TDP-43 is a DNA/RNA-binding protein that regulates gene expression and its malfunction in neurons has been causally associated with multiple neurodegenerative disorders. Although progress has been made in understanding the functions of TDP-43 in neurons, little is known about its role in endothelial cells (ECs), angiogenesis and vascular function. Using inducible EC-specific TDP-43 knockout mice, we showed that TDP-43 is required for sprouting angiogenesis, vascular barrier integrity and blood vessel stability. Postnatal EC-specific deletion of TDP-43 leaded to retinal hypovascularization due to defects in vessel sprouting associated with reduced EC proliferation and migration. In mature blood vessels, loss of TDP-43 disrupted the blood-brain barrier and triggered vascular degeneration. These vascular defects were associated with an inflammatory response in the central-nervous system with activation of microglia and astrocytes. Mechanistically, deletion of TDP-43 disrupted fibronectin matrix around sprouting vessels and reduced -catenin signaling in ECs. Together, our results indicate that TDP-43 is essential for the formation of a stable and mature vasculature.
Víctor Arribas, Yara Onetti, Marina Ramiro-Pareta, Pilar Villacampa, Heike Beck, Mariona Alberola, Anna Esteve-Codina, Angelika Merkel, Markus Sperandio, Ofelia M. Martínez-Estrada, Bettina Schmid, Eloi Montanez
Adoptive transfer of immune regulatory cells can prevent or ameliorate graft-versus-host disease (GVHD), which remains the main cause of non-relapse mortality after allogeneic hematopoietic stem-cell transplantation. Mucosal-associated invariant T cells (MAITs) were recently associated with tissue repair capacities and with lower rates of GVHD in humans. Here, we analyzed the immunosuppressive effect of MAITs in an in vitro model of alloreactivity and explored their adoptive transfer in a preclinical xenogeneic-GVHD model. We found that MAIT cells, whether freshly purified or shortly expanded, dose-dependently inhibited proliferation and activation of alloreactive T cells. In immunodeficient mice injected with human PBMCs, MAITs strongly delayed GVHD onset and severity when transferred early after PBMC injection, but could also control ongoing GVHD when transferred at delayed time points. This effect was associated with decreased proliferation and effector function of human T cells infiltrating tissues of diseased mice and was correlated with lower circulating IFN-γ and TNF-α levels, and increased IL-10 levels. MAITs acted partly in a contact-dependent manner, which likely required direct interaction of their TCR with MR1 induced on host-reactive T cells. These results support the setup of clinical trials using MAITs as universal therapeutic tools to control severe GVHD or mucosal inflammatory disorders.
Nana Talvard-Balland, Marion Lambert, Mathieu F. Chevalier, Norbert Minet, Marion Salou, Marie Tourret, Armelle Bohineust, Idan Milo, Véronique Parietti, Thomas Yvorra, Gérard Socié, Olivier Lantz, Sophie Caillat-Zucman
Pseudohypoparathyroidism type 1B (PHP1B) is caused by aberrant genomic imprinting at the GNAS gene. Defining the underlying genetic cause in new patients is challenging because various genetic alterations (e.g., deletions, insertions) within the GNAS genomic region, including the neighboring STX16 gene, can cause PHP1B, and the genotype-epigenotype correlation has not been clearly established. Here, by analyzing PHP1B patients with a wide variety of genotypes and epigenotypes, we identified a GNAS differentially methylated region (DMR) of distinct diagnostic value. This region, GNAS AS2, was hypomethylated in patients with genetic alterations located centromeric but not telomeric of this DMR. The AS2 methylation status was captured by a single probe of the methylation-sensitive multiplex ligation-dependent probe amplification (MS-MLPA) assay utilized to diagnose PHP1B. In human embryonic stem cells, where NESP55 transcription regulates GNAS methylation status on the maternal allele, AS2 methylation depended on two imprinting control regions (STX16-ICR and NESP-ICR) essential for NESP55 transcription. These results suggest that the AS2 methylation status in PHP1B patients reflects the position at which the genetic alteration affects NESP55 transcription during an early embryonic period. Therefore, AS2 methylation levels enable mechanistic PHP1B categorization based on genotype-epigenotype correlation and thus help identify the underlying molecular defect in patients.
Yorihiro Iwasaki, Monica Reyes, Harald Jüppner, Murat Bastepe
A robust sterile inflammation underlies myocardial ischemia and reperfusion injury (MIRI). Several subsets of B-cells possess the immune-regulatory capacity that limits tissue damage, yet the role of B-cells in MIRI remains elusive. Here, we sought to elucidate the contribution of B-cells to the MIRI by transient ligation of the left anterior descending in the B-cell depleted or deficient mice. Following ischemia and reperfusion (I/R), regulatory B-cells are rapidly recruited to the heart. B-cell-depleted or deficient mice exhibited exacerbated tissue damage, adverse cardiac remodeling, and an augmented inflammatory response after I/R. Rescue and chimeric experiments indicated that the cardioprotective effect of B-cells was not solely dependent on IL10. Coculture experiments demonstrated that B-cells induced neutrophil apoptosis through contact-dependent interaction, subsequently promoting reparative macrophage polarization by facilitating the phagocytosis of neutrophils by macrophages. The in-vivo cardioprotective effect of B-cells was absent in absence of neutrophils after I/R. Mechanistically, ligand-receptor imputation identified FCER2A as a potential mediator of interactions between B-cells and neutrophils. Blocking FCER2A on B-cells resulted in a reduction in the percentage of apoptotic neutrophils, contributing to the deterioration of cardiac remodeling. Our findings unveil a potential cardioprotective role of B-cells in myocardial I/R through mechanisms involving FCER2A, neutrophil, and macrophage.
Fangyang Huang, Jialiang Zhang, Hao Zhou, Tianyi Qu, Yan Wang, Kexin Jiang, Yutong Liu, Yuan Ning Xu, Mao Chen, Li Chen
Colon cancer affects people of all ages. However, its frequency, as well as the related morbidity and mortality, are high among older adults. The complex physiological changes in the aging gut substantially limit the development of cancer therapies. Here, we identify a unique intestinal microenvironment that is linked with an increased risk of colon cancer in older adults. Our findings show that aging markedly influences persistent fucosylation of the apical surfaces of intestinal epithelial cells, which results in a favorable environment for tumor growth. Furthermore, our findings shed light on the importance of the host-commensal interaction, which facilitates the dysregulation of fucosylation and promotes tumor growth as people get older. We analyzed colonic microbial populations at the species level to find changes associated with aging that could contribute to the development of colon cancer. Analysis of scRNAseq from previous publication datasets identifies distinct epithelial cell subtypes involved in dysregulated fucosylation in older adults. Overall, our study provides compelling evidence that excessive fucosylation is associated with the development of colon cancer, that age-related changes increase vulnerability to colon cancer, and that a dysbiosis in microbial diversity and metabolic changes in the homeostasis of older mice dysregulate fucosylation levels with age.
Zhihan Wang, Pan Gao, Kai Guo, Grace Schirrick, Jappreet Singh Gill, Jett Weis, Abby Lund Da Costa, Mansib Rahman, Het Mehta, Julia Fleecs, Shilpi Jain, Trishna Debnath, Junguk Hur, Nadeem Khan, Robert Sticca, Holly M. Brown-Borg, Donald A. Jurivich, Ramkumar Mathur
Regulatory T (Treg) cells can facilitate transplant tolerance and attenuate autoimmune- and inflammatory diseases. Therefore, it is clinically relevant to stimulate Treg cell expansion and function in vivo and to create therapeutic Treg cell products in vitro. We report that TNF receptor 2 (TNFR2) is a unique costimulus for naïve, thymus-derived (t)Treg cells from human blood that promotes their differentiation into non-lymphoid tissue (NLT)-resident effector Treg cells, without Th-like polarization. In contrast, CD28 costimulation maintains a lymphoid tissue (LT)-resident Treg cell phenotype. We base this conclusion on transcriptome and proteome analysis of TNFR2- and CD28-costimulated CD4+ tTreg cells and conventional T (Tconv) cells, followed by bioinformatic comparison with published transcriptomic Treg cell signatures from NLT and LT in health and disease, including autoimmunity and cancer. These analyses illuminated that TNFR2 costimulation promotes tTreg cell capacity for survival, migration, immunosuppression and tissue regeneration. Functional studies confirmed improved migratory ability of TNFR2-costimulated tTreg cells. Flow cytometry validated the presence of the TNFR2-driven tTreg cell signature in effector/memory Treg cells from the human placenta as opposed to blood. Thus, TNFR2 can be exploited as driver of NLT-resident tTreg cell differentiation for adoptive cell therapy or antibody-based immunomodulation in human disease.
Mark Mensink, Lotte J. Verleng, Ellen Schrama, George M.C. Janssen, Rayman T.N. Tjokrodirijo, Peter A. van Veelen, Qinyue Jiang, M. Fernanda Pascutti, Marie-Louise van der Hoorn, Michael Eikmans, Sander de Kivit, Jannie Borst
Hemorrhagic cystitis may be induced by infection, radiation therapy, medications, or may be idiopathic. Along with hemorrhagic features, symptoms include urinary urgency and frequency, dysuria (painful urination) and visceral pain. Cystitis-induced visceral pain is one of the most challenging types of pain to treat and an effective treatment would address a major unmet medical need. We assessed the efficacy of a purine nucleoside phosphorylase (PNPase) inhibitor, 8-aminoguanine (8-AG) for the treatment of hemorrhagic/ulcerative cystitis. Lower urinary tract (LUT) function and structure were assessed in adult Sprague Dawley rats, treated chronically with cyclophosphamide (CYP; sacrificed day 8) and randomized to daily oral treatment with 8-AG (begun 14 days prior to CYP induction) or its vehicle. CYP-treated rats exhibited multiple abnormalities including increased urinary frequency and neural mechanosensitivity, reduced bladder levels of inosine, urothelial inflammation/damage, and activation of spinal cord microglia, associated with pain hypersensitivity. 8-AG treatment of CYP-treated rats normalized all observed histological, structural, biochemical, and physiological abnormalities. In cystitis 8-AG improved function and reduced both pain and inflammation likely by increasing inosine, a tissue-protective purine metabolite. These findings demonstrate that 8-AG has translational potential for reducing pain and preventing bladder damage in cystitis-associated LUT dysfunctions.
Amanda Wolf-Johnston, Youko Ikeda, Irina V. Zabbarova, Anthony J. Kanai, Sheldon Bastacky, Robert Moldwin, Joel N.H. Stern, Edwin K. Jackson, Lori A. Birder
A distinct adipose tissue distribution pattern was observed in patients with methylmalonyl-CoA mutase deficiency, an inborn error of branched-chain amino acid (BCAA) metabolism, characterized by centripetal obesity with proximal upper and lower extremities fat deposition and paucity of visceral fat, that resembles familial multiple lipomatosis syndrome. To explore brown and white fat physiology in methylmalonic acidemia (MMA), body composition, adipokines and inflammatory markers were assessed in 46 MMA subjects and 99 matched controls. Fibroblast growth factor-21 (FGF21) levels were associated with acyl-coenzyme A accretion, aberrant methylmalonylation in adipose tissue, and an attenuated inflammatory cytokine profile. In parallel, brown and white fat were examined in a liver-specific transgenic MMA mouse model (Mmut-/-;TgINS-Alb-Mmut). The MMA mice exhibited abnormal non-shivering thermogenesis with whitened brown fat and had an ineffective transcriptional response to cold stress. Treatment of the MMA mice with bezafibrates led to clinical improvement with beiging of subcutaneous fat depots, which resembled the distribution seen in the patients. These studies defined what we believe to be a novel lipodystrophy phenotype in patients with defects in the terminal steps of BCAA oxidation and demonstrated that beiging of subcutaneous adipose tissue in MMA could readily be induced with small molecules.
Irini Manoli, Justin R. Sysol, PamelaSara E. Head, Madeline W. Epping, Oksana Gavrilova, Melissa K. Crocker, Jennifer L. Sloan, Stefanos A. Koutsoukos, Cindy X. Wang, Yiouli P. Ktena, Sophia Mendelson, Alexandra R. Pass, Patricia M. Zerfas, Victoria J. Hoffmann, Hilary J. Vernon, Laura A. Fletcher, James C. Reynolds, Maria G. Tsokos, Constantine A. Stratakis, Stephan D. Voss, Kong Y. Chen, Rebecca J. Brown, Ada Hamosh, Gerard T. Berry, Xiaoyuan Chen, Jack A. Yanovski, Charles P. Venditti
High grade serous carcinoma (HGSC) is the most lethal gynecological malignancy in the United States. Late diagnosis and the emergence of chemoresistance have prompted studies into how the tumor microenvironment, and more recently tumor innervation, may be leveraged for HGSC prevention and interception. In addition to biobehavioral sources, concentrations of the sympathetic neurotransmitter norepinephrine (NE) in the ovary increase during ovulation and after menopause. Importantly, NE exacerbates advanced HGSC progression. However, little is known about the role of NE in early disease pathogenesis. Here, we investigated the role of NE in instigating anchorage independence and micrometastasis of preneoplastic lesions from the fallopian tube epithelium (FTE) to the ovary, an essential step in HGSC onset. We found that in the presence of NE, FTE cell lines are able to survive in ultra-low attachment (ULA) culture in a beta-adrenergic receptor (β-AR)-dependent manner. Importantly, spheroid formation and cell viability conferred by treatment with physiological sources of NE can be abrogated using the beta-adrenergic receptor blocker propranolol. We have also identified that NE-mediated anoikis resistance may be attributable to downregulation of colony stimulating factor 2 (CSF2). These findings provide mechanistic insight and identify targets that may be regulated by ovarian-derived NE in early HGSC.
Hunter D. Reavis, Stefan M. Gysler, Grace B. McKenney, Matthew Knarr, Hannah J. Lusk, Priyanka Rawat, Hannah S. Rendulich, Marilyn A. Mitchell, Dara S. Berger, Jamie S. Moon, Suyeon Ryu, Monica Mainigi, Marcin P. Iwanicki, Dave S.B. Hoon, Laura M. Sanchez, Ronny Drapkin
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