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Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are pathologically activated neutrophils that are crucial for the regulation of immune responses in cancer. These cells contribute to the failure of cancer therapies and are associated with poor clinical outcomes. Despite recent advances in the understanding of PMN-MDSC biology, the mechanisms responsible for the pathological activation of neutrophils are not well defined, and this limits the selective targeting of these cells. Here we report that mouse and human PMN-MDSCs exclusively upregulate fatty acid transport protein 2 (FATP2). Overexpression of FATP2 in PMN-MDSCs was controlled by granulocyte-macrophage colony-stimulating factor, through the activation of the STAT5 transcription factor. Deletion of FATP2 abrogated the suppressive activity of PMN-MDSCs. The main mechanism of FATP2-mediated suppressive activity involved the uptake of arachidonic acid and the synthesis of prostaglandin E.sub.2. The selective pharmacological inhibition of FATP2 abrogated the activity of PMN-MDSCs and substantially delayed tumour progression. In combination with checkpoint inhibitors, FATP2 inhibition blocked tumour progression in mice. Thus, FATP2 mediates the acquisition of immunosuppressive activity by PMN-MDSCs and represents a target to inhibit the functions of PMN-MDSCs selectively and to improve the efficiency of cancer therapy. The lipid transporter FATP2 reprograms neutrophils to polymorphonuclear myeloid-derived suppressor cells by mediating the uptake of arachidonic acid and promoting the synthesis of prostaglandin E.sub.2., Author(s): Filippo Veglia [sup.1] , Vladimir A. Tyurin [sup.2] , Maria Blasi [sup.3] , Alessandra De Leo [sup.4] , Andrew V. Kossenkov [sup.1] , Laxminarasimha Donthireddy [sup.1] , Tsun Ki [...]

Renal phosphate handling critically determines plasma phosphate and whole body phosphate levels. Filtered phosphate is mostly reabsorbed by Na.sup.+-dependent phosphate transporters located in the brush border membrane of the proximal tubule: NaPi-IIa (SLC34A1), NaPi-IIc (SLC34A3), and Pit-2 (SLC20A2). Here we review new evidence for the role and relevance of these transporters in inherited disorders of renal phosphate handling. The importance of NaPi-IIa and NaPi-IIc for renal phosphate reabsorption and mineral homeostasis has been highlighted by the identification of mutations in these transporters in a subset of patients with infantile idiopathic hypercalcemia and patients with hereditary hypophosphatemic rickets with hypercalciuria. Both diseases are characterized by disturbed calcium homeostasis secondary to elevated 1,25-(OH).sub.2 vitamin D.sub.3 as a consequence of hypophosphatemia. In vitro analysis of mutated NaPi-IIa or NaPi-IIc transporters suggests defective trafficking underlying disease in most cases. Monoallelic pathogenic mutations in both SLC34A1 and SLC34A3 appear to be very frequent in the general population and have been associated with kidney stones. Consistent with these findings, results from genome-wide association studies indicate that variants in SLC34A1 are associated with a higher risk to develop kidney stones and chronic kidney disease, but underlying mechanisms have not been addressed to date., Author(s): Carsten A. Wagner [sup.1] [sup.2] , Isabel Rubio-Aliaga [sup.1] [sup.2] , Nati Hernando [sup.1] [sup.2] Author Affiliations: (Aff1) 0000 0004 1937 0650, grid.7400.3, Institute of Physiology, University of Zurich, [...]

Lysine-63-linked (K63-linked) polyubiquitination of TRAF3 coordinates the engagement of pattern-recognition receptors with recruited adaptor proteins and downstream activator TBK1 in pathways that induce type I IFN. Whether autoubiquitination or other E3 ligases mediate K63-linked TRAF3 polyubiquitination remains unclear. We demonstrated that mice deficient in the E3 ligase gene Hectd3 remarkably increased host defense against infection by intracellular bacteria Francisella novicida, Mycobacterium, and Listeria by limiting bacterial dissemination. In the absence of HECTD3, type I IFN response was impaired during bacterial infection both in vivo and in vitro. HECTD3 regulated type I IFN production by mediating K63-linked polyubiquitination of TRAF3 at residue K138. The catalytic domain of HECTD3 regulated TRAF3 K63 polyubiquitination, which enabled TRAF3-TBK1 complex formation. Our study offers insights into mechanisms of TRAF3 modulation and provides potential therapeutic targets against infections by intracellular bacteria and inflammatory diseases., Introduction The high prevalence of multidrug-resistant bacterial infections is a growing public health threat and can complicate further treatment, especially for infections by intracellular bacterial pathogens, which can establish an [...]

Mitochondrial dysfunction has been implicated in the development of heart failure. Oxidative metabolism in mitochondria is the main energy source of the heart, and the inability to generate and transfer energy has long been considered the primary mechanism linking mitochondrial dysfunction and contractile failure. However, the role of mitochondria in heart failure is now increasingly recognized to be beyond that of a failed power plant. In this Review, we summarize recent evidence demonstrating vicious cycles of pathophysiological mechanisms during the pathological remodeling of the heart that drive mitochondrial contributions from being compensatory to being a suicide mission. These mechanisms include bottlenecks of metabolic flux, redox imbalance, protein modification, ROS-induced ROS generation, impaired mitochondrial [Ca.sup.2+] homeostasis, and inflammation. The interpretation of these findings will lead us to novel avenues for disease mechanisms and therapy., The heart is an organ with high energy demands. The majority of the ATP consumed by the heart (~95%) is derived from oxidative metabolism in the mitochondria, organelles that occupy [...]

Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice. Inhibition of YAP decreased proliferation and colony-forming efficiency (CFE) of [Cldn18.sup.-/-] AT2 cells and prevented increased lung size, while CLDN18 overexpression decreased YAP nuclear localization, cell proliferation, CFE, and YAP transcriptional activity. CLDN18 and YAP interacted and colocalized at cell-cell contacts, while loss of CLDN18 decreased YAP interaction with Hippo kinases p-LATS1/2. Additionally, [Cldn18.sup.-/-] mice had increased propensity to develop lung adenocarcinomas (LuAd) with age, and human LuAd showed stage-dependent reduction of CLDN18.1. These results establish CLDN18 as a regulator of YAP activity that serves to restrict organ size, progenitor cell proliferation, and tumorigenesis, and suggest a mechanism whereby TJ disruption may promote progenitor proliferation to enhance repair following injury., Introduction Apical junctional complexes (AJCs) in polarized epithelia are composed of adherens junctions (AJs) and tight junctions (TJs) (1, 2) that mediate intercellular adhesion and paracellular permeability to ions and [...]

Background Urine biomarkers are commonly used in the evaluation of acute kidney injury, and are gaining attention as tools for studying urinary tract infections (UTIs). We analyzed neutrophil gelatinase-associated lipocalin (NGAL) and seven other urine biomarkers to evaluate their usefulness in the diagnosis of UTI in infants. Methods Eight urine biomarkers were analyzed in 108 infants with UTI. Controls were 64 febrile children without UTI and 13 healthy children. Logistic regression and construction of receiver operating characteristic (ROC) curves were performed for UTI patients versus febrile controls for all biomarkers. Results The best biomarkers to differentiate between UTI and febrile controls were NGAL and interleukin 8 (IL8). Urine NGAL in absolute concentration and adjusted for creatinine had a sensitivity of 93% and 96% and a specificity of 95% and 100% for diagnosing UTI, with a cut-off concentration of 38 ng/mL and 233 ng/mg respectively. Conclusions Urine biomarkers, particularly NGAL, can aid in the diagnosis of UTI among febrile infants. The results suggest that in infants with fever and high NGAL, UTI is most likely, whereas in infants with fever and low NGAL, other causes of fever should be looked for., Author(s): Sindri Valdimarsson [sup.1] [sup.2] , Ulf Jodal [sup.1] , Lars Barregård [sup.3] , Sverker Hansson [sup.1] Author Affiliations: (1) Department of Pediatrics, Sahlgrenska University Hospital, Sahlgrenska Academy, Gothenburg, Sweden [...]

Genetic variants at the solute carrier family 39 member 8 (SLC39A8) gene locus are associated with the regulation of wholeblood manganese (Mn) and multiple physiological traits. SLC39A8 encodes ZIP8, a divalent metal ion transporter best known for zinc transport. Here, we hypothesized that ZIP8 regulates Mn homeostasis and Mn-dependent enzymes to influence metabolism. We generated S/c39o8-inducible global-knockout (ZIP8-iKO) and liver -specific-knockout (ZIP8-LSKO) mice and observed markedly decreased Mn levels in multiple organs and whole blood of both mouse models. By contrast, liver -specific overexpression of human ZIP8 (adeno-associated virus-ZIP8 [AAV-ZIP8]) resulted in increased tissue and whole blood Mn levels. ZIP8 expression was localized to the hepatocyte canalicular membrane, and bile Mn levels were increased in ZIP8-LSKO and decreased in AAV-ZIP8 mice. ZIP8-LSKO mice also displayed decreased liver and kidney activity of the Mn-dependent enzyme arginase. Both ZIP8-iKO and ZIP8-LSKO mice had defective protein N -glycosylation, and humans homozygous for the minor allele at the lead SLC39A8 variant showed hypogalactosylation, consistent with decreased activity of another Mndependent enzyme, [beta]-1,4-galactosyltransferase. In summary, hepatic ZIP8 reclaims Mn from bile and regulates whole-body Mn homeostasis, thereby modulating the activity of Mn-dependent enzymes. This work provides a mechanistic basis for the association of SLC39A8 with whole-blood Mn, potentially linking SLC39A8 variants with other physiological traits., Introduction Common genetic variants at the solute carrier family 39 member 8 (SLC39A8) genomic locus are significantly associated genome wide with whole-blood manganese (Mn) (1) as well as a variety [...]

Claudin 18 (CLDN18) is a tight junction protein that is highly expressed in the lung. While mice lacking CLDN18 exhibit the expected loss of epithelial integrity in the lung, these animals also have unexpectedly large lungs. In this issue of the JCI, Zhou, Flodby, and colleagues reveal that the increased lung size of Cldn[18.sup.-/-] mice is the result of increased type 2 alveolar epithelial (AT2) cell proliferation. This increase in proliferation was shown to be driven by translocation of the transcriptional regulator Yes-associated protein (YAP) to the nucleus and subsequent induction of proliferative pathways. CLDN18-deficent mice also had increased frequency of lung adenocarcinomas. Together, the results of this study advance our understanding of the mechanisms that likely regulate homeostasis of the normal lung as well as promote the proliferative state of malignant cells found in lung adenocarcinomas thought to originate from AT2 cells., Loss of junction protein increases lung size Previous studies by Li et al. (1) and LaFemina et al. (2) have shown that mice lacking the tight junction protein claudin 18 [...]

Author(s): Yunchen Bi [1]; Evan Mann [2]; Chris Whitfield [2]; Jochen Zimmer (corresponding author) [1] O-antigens are cell surface polysaccharides of many Gram-negative pathogens that aid in escaping innate immune [...]

Byline: Gawahir. Mukhtar, Wadha. Al Otaibi, Khalid. Al-Mobaireek, Suhail. Al-Saleh Mutation in ABCA3, which is adenosine triphosphate-binding cassette member A3, a member of protein transporter family for phospholipids into the [...]