HIF1A and NFAT5 coordinate Na+-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting.
Identifieur interne : 000336 ( Main/Exploration ); précédent : 000335; suivant : 000337HIF1A and NFAT5 coordinate Na+-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting.
Auteurs : Patrick Neubert [Allemagne] ; Andrea Weichselbaum [Allemagne] ; Carmen Reitinger [Allemagne] ; Valentin Schatz [Allemagne] ; Agnes Schröder [Allemagne] ; John R. Ferdinand [Royaume-Uni] ; Michaela Simon [Allemagne] ; Anna-Lorena B R [Allemagne] ; Christoph Brochhausen [Allemagne] ; Roman G. Gerlach [Allemagne] ; Stefan Tomiuk [Allemagne] ; Karin Hammer [Allemagne] ; Stefan Wagner [Allemagne] ; Ger Van Zandbergen [Allemagne] ; Katrina J. Binger [Australie] ; Dominik N. Müller [Allemagne] ; Kento Kitada [Singapour] ; Menna R. Clatworthy [Royaume-Uni] ; Christian Kurts [Allemagne] ; Jens Titze [Singapour] ; Zeinab Abdullah [Allemagne] ; Jonathan Jantsch [Allemagne]Source :
- Autophagy [ 1554-8635 ] ; 2019.
Descripteurs français
- KwdFr :
- Animaux (MeSH), Autophagie (génétique), Autophagie (immunologie), Autophagosomes (microbiologie), Autophagosomes (métabolisme), Concentration en ions d'hydrogène (MeSH), Escherichia coli (métabolisme), Escherichia coli (pathogénicité), Espèces réactives de l'oxygène (métabolisme), Facteurs de transcription (génétique), Facteurs de transcription (métabolisme), Inflammation (métabolisme), Lysosomes (génétique), Lysosomes (immunologie), Lysosomes (microbiologie), Lysosomes (métabolisme), Macrophages (effets des médicaments et des substances chimiques), Macrophages (immunologie), Macrophages (microbiologie), Macrophages (ultrastructure), Mannitol (toxicité), Microscopie électronique à transmission (MeSH), Nitric oxide synthase type II (génétique), Nitric oxide synthase type II (métabolisme), Pression osmotique (effets des médicaments et des substances chimiques), Protéines proto-oncogènes c-akt (génétique), Protéines proto-oncogènes c-akt (métabolisme), Protéines à homéodomaine (génétique), Protéines à homéodomaine (métabolisme), Sodium (métabolisme), Sodium (pharmacologie), Souris (MeSH), Sous-unité alpha du facteur-1 induit par l'hypoxie (génétique), Sous-unité alpha du facteur-1 induit par l'hypoxie (métabolisme), Séquençage par oligonucléotides en batterie (MeSH), Sérine-thréonine kinases TOR (antagonistes et inhibiteurs), Sérine-thréonine kinases TOR (génétique), Sérine-thréonine kinases TOR (métabolisme).
- MESH :
- antagonistes et inhibiteurs : Sérine-thréonine kinases TOR.
- effets des médicaments et des substances chimiques : Macrophages, Pression osmotique.
- génétique : Autophagie, Facteurs de transcription, Lysosomes, Nitric oxide synthase type II, Protéines proto-oncogènes c-akt, Protéines à homéodomaine, Sous-unité alpha du facteur-1 induit par l'hypoxie, Sérine-thréonine kinases TOR.
- immunologie : Autophagie, Lysosomes, Macrophages.
- microbiologie : Autophagosomes, Lysosomes, Macrophages.
- métabolisme : Autophagosomes, Escherichia coli, Espèces réactives de l'oxygène, Facteurs de transcription, Inflammation, Lysosomes, Nitric oxide synthase type II, Protéines proto-oncogènes c-akt, Protéines à homéodomaine, Sodium, Sous-unité alpha du facteur-1 induit par l'hypoxie, Sérine-thréonine kinases TOR.
- pathogénicité : Escherichia coli.
- pharmacologie : Sodium.
- toxicité : Mannitol.
- ultrastructure : Animaux, Concentration en ions d'hydrogène, Macrophages, Microscopie électronique à transmission, Souris, Séquençage par oligonucléotides en batterie.
English descriptors
- KwdEn :
- Animals (MeSH), Autophagosomes (metabolism), Autophagosomes (microbiology), Autophagy (genetics), Autophagy (immunology), Escherichia coli (metabolism), Escherichia coli (pathogenicity), Homeodomain Proteins (genetics), Homeodomain Proteins (metabolism), Hydrogen-Ion Concentration (MeSH), Hypoxia-Inducible Factor 1, alpha Subunit (genetics), Hypoxia-Inducible Factor 1, alpha Subunit (metabolism), Inflammation (metabolism), Lysosomes (genetics), Lysosomes (immunology), Lysosomes (metabolism), Lysosomes (microbiology), Macrophages (drug effects), Macrophages (immunology), Macrophages (microbiology), Macrophages (ultrastructure), Mannitol (toxicity), Mice (MeSH), Microscopy, Electron, Transmission (MeSH), Nitric Oxide Synthase Type II (genetics), Nitric Oxide Synthase Type II (metabolism), Oligonucleotide Array Sequence Analysis (MeSH), Osmotic Pressure (drug effects), Proto-Oncogene Proteins c-akt (genetics), Proto-Oncogene Proteins c-akt (metabolism), Reactive Oxygen Species (metabolism), Sodium (metabolism), Sodium (pharmacology), TOR Serine-Threonine Kinases (antagonists & inhibitors), TOR Serine-Threonine Kinases (genetics), TOR Serine-Threonine Kinases (metabolism), Transcription Factors (genetics), Transcription Factors (metabolism).
- MESH :
- chemical , antagonists & inhibitors : TOR Serine-Threonine Kinases.
- chemical , genetics : Homeodomain Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Nitric Oxide Synthase Type II, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases, Transcription Factors.
- drug effects : Macrophages, Osmotic Pressure.
- genetics : Autophagy, Lysosomes.
- immunology : Autophagy, Lysosomes, Macrophages.
- metabolism : Autophagosomes, Escherichia coli, Homeodomain Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Inflammation, Lysosomes, Nitric Oxide Synthase Type II, Proto-Oncogene Proteins c-akt, Reactive Oxygen Species, Sodium, TOR Serine-Threonine Kinases, Transcription Factors.
- microbiology : Autophagosomes, Lysosomes, Macrophages.
- pathogenicity : Escherichia coli.
- chemical , pharmacology : Sodium.
- chemical , toxicity : Mannitol.
- ultrastructure : Macrophages.
- Animals, Hydrogen-Ion Concentration, Mice, Microscopy, Electron, Transmission, Oligonucleotide Array Sequence Analysis.
Abstract
Infection and inflammation are able to induce diet-independent Na+-accumulation without commensurate water retention in afflicted tissues, which favors the pro-inflammatory activation of mouse macrophages and augments their antibacterial and antiparasitic activity. While Na+-boosted host defense against the protozoan parasite Leishmania major is mediated by increased expression of the leishmanicidal NOS2 (nitric oxide synthase 2, inducible), the molecular mechanisms underpinning this enhanced antibacterial defense of mouse macrophages with high Na+ (HS) exposure are unknown. Here, we provide evidence that HS-increased antibacterial activity against E. coli was neither dependent on NOS2 nor on the phagocyte oxidase. In contrast, HS-augmented antibacterial defense hinged on HIF1A (hypoxia inducible factor 1, alpha subunit)-dependent increased autophagy, and NFAT5 (nuclear factor of activated T cells 5)-dependent targeting of intracellular E. coli to acidic autolysosomal compartments. Overall, these findings suggest that the autolysosomal compartment is a novel target of Na+-modulated cell autonomous innate immunity. Abbreviations: ACT: actins; AKT: AKT serine/threonine kinase 1; ATG2A: autophagy related 2A; ATG4C: autophagy related 4C, cysteine peptidase; ATG7: autophagy related 7; ATG12: autophagy related 12; BECN1: beclin 1; BMDM: bone marrow-derived macrophages; BNIP3: BCL2/adenovirus E1B interacting protein 3; CFU: colony forming units; CM-H2DCFDA: 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester; CTSB: cathepsin B; CYBB: cytochrome b-245 beta chain; DAPI: 4,6-diamidino-2-phenylindole; DMOG: dimethyloxallyl glycine; DPI: diphenyleneiodonium chloride; E. coli: Escherichia coli; FDR: false discovery rate; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; GO: gene ontology; HIF1A: hypoxia inducible factor 1, alpha subunit; HUGO: human genome organization; HS: high salt (+ 40 mM of NaCl to standard cell culture conditions); HSP90: heat shock 90 kDa proteins; LDH: lactate dehydrogenase; LPS: lipopolysaccharide; Lyz2/LysM: lysozyme 2; NFAT5/TonEBP: nuclear factor of activated T cells 5; MΦ: macrophages; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFI: mean fluorescence intensity; MIC: minimum inhibitory concentration; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; NaCl: sodium chloride; NES: normalized enrichment score; n.s.: not significant; NO: nitric oxide; NOS2/iNOS: nitric oxide synthase 2, inducible; NS: normal salt; PCR: polymerase chain reaction; PGK1: phosphoglycerate kinase 1; PHOX: phagocyte oxidase; RFP: red fluorescent protein; RNA: ribonucleic acid; ROS: reactive oxygen species; sCFP3A: super cyan fluorescent protein 3A; SBFI: sodium-binding benzofuran isophthalate; SLC2A1/GLUT1: solute carrier family 2 (facilitated glucose transporter), member 1; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like kinase 1; v-ATPase: vacuolar-type H+-ATPase; WT: wild type.
DOI: 10.1080/15548627.2019.1596483
PubMed: 30982460
PubMed Central: PMC6844503
Affiliations:
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Ferdinand</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Immunity Unit, Department of Medicine, MRC-Laboratory of Molecular Biology, University of Cambridge , Cambridge , UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Molecular Immunity Unit, Department of Medicine, MRC-Laboratory of Molecular Biology, University of Cambridge , Cambridge </wicri:regionArea><wicri:noRegion>Cambridge </wicri:noRegion></affiliation></author><author><name sortKey="Simon, Michaela" sort="Simon, Michaela" uniqKey="Simon M" first="Michaela" last="Simon">Michaela Simon</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg </wicri:regionArea><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion></affiliation></author><author><name sortKey="B R, Anna Lorena" sort="B R, Anna Lorena" uniqKey="B R A" first="Anna-Lorena" last="B R">Anna-Lorena B R</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg </wicri:regionArea><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion></affiliation></author><author><name sortKey="Brochhausen, Christoph" sort="Brochhausen, Christoph" uniqKey="Brochhausen C" first="Christoph" last="Brochhausen">Christoph Brochhausen</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Pathology, University of Regensburg , Regensburg , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pathology, University of Regensburg , Regensburg </wicri:regionArea><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion></affiliation></author><author><name sortKey="Gerlach, Roman G" sort="Gerlach, Roman G" uniqKey="Gerlach R" first="Roman G" last="Gerlach">Roman G. Gerlach</name><affiliation wicri:level="1"><nlm:affiliation>Project Group 5, Robert Koch Institute , Wernigerode , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Project Group 5, Robert Koch Institute , Wernigerode </wicri:regionArea><wicri:noRegion>Wernigerode </wicri:noRegion><wicri:noRegion>Wernigerode </wicri:noRegion><wicri:noRegion>Wernigerode </wicri:noRegion></affiliation></author><author><name sortKey="Tomiuk, Stefan" sort="Tomiuk, Stefan" uniqKey="Tomiuk S" first="Stefan" last="Tomiuk">Stefan Tomiuk</name><affiliation wicri:level="1"><nlm:affiliation>Miltenyi Biotec GmbH , Bergisch Gladbach , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Miltenyi Biotec GmbH , Bergisch Gladbach </wicri:regionArea><wicri:noRegion>Bergisch Gladbach </wicri:noRegion><wicri:noRegion>Bergisch Gladbach </wicri:noRegion><wicri:noRegion>Bergisch Gladbach </wicri:noRegion></affiliation></author><author><name sortKey="Hammer, Karin" sort="Hammer, Karin" uniqKey="Hammer K" first="Karin" last="Hammer">Karin Hammer</name><affiliation wicri:level="1"><nlm:affiliation>Department of Internal Medicine II, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Internal Medicine II, University Hospital of Regensburg and University of Regensburg , Regensburg </wicri:regionArea><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion></affiliation></author><author><name sortKey="Wagner, Stefan" sort="Wagner, Stefan" uniqKey="Wagner S" first="Stefan" last="Wagner">Stefan Wagner</name><affiliation wicri:level="1"><nlm:affiliation>Department of Internal Medicine II, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Internal Medicine II, University Hospital of Regensburg and University of Regensburg , Regensburg </wicri:regionArea><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion></affiliation></author><author><name sortKey="Van Zandbergen, Ger" sort="Van Zandbergen, Ger" uniqKey="Van Zandbergen G" first="Ger" last="Van Zandbergen">Ger Van Zandbergen</name><affiliation wicri:level="1"><nlm:affiliation>Division of Immunology, Paul-Ehrlich-Institute , Langen , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Division of Immunology, Paul-Ehrlich-Institute , Langen </wicri:regionArea><wicri:noRegion>Langen </wicri:noRegion><wicri:noRegion>Langen </wicri:noRegion><wicri:noRegion>Langen </wicri:noRegion></affiliation></author><author><name sortKey="Binger, Katrina J" sort="Binger, Katrina J" uniqKey="Binger K" first="Katrina J" last="Binger">Katrina J. Binger</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne , Parkville , Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne , Parkville </wicri:regionArea><wicri:noRegion>Parkville </wicri:noRegion></affiliation></author><author><name sortKey="Muller, Dominik N" sort="Muller, Dominik N" uniqKey="Muller D" first="Dominik N" last="Müller">Dominik N. Müller</name><affiliation wicri:level="1"><nlm:affiliation>Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin , Berlin , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin , Berlin </wicri:regionArea><wicri:noRegion>Berlin </wicri:noRegion><wicri:noRegion>Berlin </wicri:noRegion><wicri:noRegion>Berlin </wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Max-Delbrück Center for Molecular Medicine in the Helmholtz Association , Berlin , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max-Delbrück Center for Molecular Medicine in the Helmholtz Association , Berlin </wicri:regionArea><wicri:noRegion>Berlin </wicri:noRegion><wicri:noRegion>Berlin </wicri:noRegion><wicri:noRegion>Berlin </wicri:noRegion></affiliation></author><author><name sortKey="Kitada, Kento" sort="Kitada, Kento" uniqKey="Kitada K" first="Kento" last="Kitada">Kento Kitada</name><affiliation wicri:level="1"><nlm:affiliation>Cardiovascular and Metabolic Disorders, Duke-NUS Medical School , Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>Cardiovascular and Metabolic Disorders, Duke-NUS Medical School </wicri:regionArea><wicri:noRegion>Duke-NUS Medical School </wicri:noRegion></affiliation></author><author><name sortKey="Clatworthy, Menna R" sort="Clatworthy, Menna R" uniqKey="Clatworthy M" first="Menna R" last="Clatworthy">Menna R. Clatworthy</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Immunity Unit, Department of Medicine, MRC-Laboratory of Molecular Biology, University of Cambridge , Cambridge , UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Molecular Immunity Unit, Department of Medicine, MRC-Laboratory of Molecular Biology, University of Cambridge , Cambridge </wicri:regionArea><wicri:noRegion>Cambridge </wicri:noRegion></affiliation></author><author><name sortKey="Kurts, Christian" sort="Kurts, Christian" uniqKey="Kurts C" first="Christian" last="Kurts">Christian Kurts</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Experimental Immunology, University of Bonn , Bonn , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Experimental Immunology, University of Bonn , Bonn </wicri:regionArea><wicri:noRegion>Bonn </wicri:noRegion><wicri:noRegion>Bonn </wicri:noRegion><wicri:noRegion>Bonn </wicri:noRegion></affiliation></author><author><name sortKey="Titze, Jens" sort="Titze, Jens" uniqKey="Titze J" first="Jens" last="Titze">Jens Titze</name><affiliation wicri:level="1"><nlm:affiliation>Cardiovascular and Metabolic Disorders, Duke-NUS Medical School , Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>Cardiovascular and Metabolic Disorders, Duke-NUS Medical School </wicri:regionArea><wicri:noRegion>Duke-NUS Medical School </wicri:noRegion></affiliation></author><author><name sortKey="Abdullah, Zeinab" sort="Abdullah, Zeinab" uniqKey="Abdullah Z" first="Zeinab" last="Abdullah">Zeinab Abdullah</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Experimental Immunology, University of Bonn , Bonn , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Experimental Immunology, University of Bonn , Bonn </wicri:regionArea><wicri:noRegion>Bonn </wicri:noRegion><wicri:noRegion>Bonn </wicri:noRegion><wicri:noRegion>Bonn </wicri:noRegion></affiliation></author><author><name sortKey="Jantsch, Jonathan" sort="Jantsch, Jonathan" uniqKey="Jantsch J" first="Jonathan" last="Jantsch">Jonathan Jantsch</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg </wicri:regionArea><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2019">2019</date><idno type="RBID">pubmed:30982460</idno><idno type="pmid">30982460</idno><idno type="doi">10.1080/15548627.2019.1596483</idno><idno type="pmc">PMC6844503</idno><idno type="wicri:Area/Main/Corpus">000296</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000296</idno><idno type="wicri:Area/Main/Curation">000296</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000296</idno><idno type="wicri:Area/Main/Exploration">000296</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">HIF1A and NFAT5 coordinate Na<sup>+</sup>-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting.</title><author><name sortKey="Neubert, Patrick" sort="Neubert, Patrick" uniqKey="Neubert P" first="Patrick" last="Neubert">Patrick Neubert</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg </wicri:regionArea><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion></affiliation></author><author><name sortKey="Weichselbaum, Andrea" sort="Weichselbaum, Andrea" uniqKey="Weichselbaum A" first="Andrea" last="Weichselbaum">Andrea Weichselbaum</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg </wicri:regionArea><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion></affiliation></author><author><name sortKey="Reitinger, Carmen" sort="Reitinger, Carmen" uniqKey="Reitinger C" first="Carmen" last="Reitinger">Carmen Reitinger</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg </wicri:regionArea><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion></affiliation></author><author><name sortKey="Schatz, Valentin" sort="Schatz, Valentin" uniqKey="Schatz V" first="Valentin" last="Schatz">Valentin Schatz</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg </wicri:regionArea><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion></affiliation></author><author><name sortKey="Schroder, Agnes" sort="Schroder, Agnes" uniqKey="Schroder A" first="Agnes" last="Schröder">Agnes Schröder</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Orthodontics, University Hospital of Regensburg , Regensburg , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Orthodontics, University Hospital of Regensburg , Regensburg </wicri:regionArea><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion></affiliation></author><author><name sortKey="Ferdinand, John R" sort="Ferdinand, John R" uniqKey="Ferdinand J" first="John R" last="Ferdinand">John R. Ferdinand</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Immunity Unit, Department of Medicine, MRC-Laboratory of Molecular Biology, University of Cambridge , Cambridge , UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Molecular Immunity Unit, Department of Medicine, MRC-Laboratory of Molecular Biology, University of Cambridge , Cambridge </wicri:regionArea><wicri:noRegion>Cambridge </wicri:noRegion></affiliation></author><author><name sortKey="Simon, Michaela" sort="Simon, Michaela" uniqKey="Simon M" first="Michaela" last="Simon">Michaela Simon</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg </wicri:regionArea><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion></affiliation></author><author><name sortKey="B R, Anna Lorena" sort="B R, Anna Lorena" uniqKey="B R A" first="Anna-Lorena" last="B R">Anna-Lorena B R</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg </wicri:regionArea><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion></affiliation></author><author><name sortKey="Brochhausen, Christoph" sort="Brochhausen, Christoph" uniqKey="Brochhausen C" first="Christoph" last="Brochhausen">Christoph Brochhausen</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Pathology, University of Regensburg , Regensburg , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Pathology, University of Regensburg , Regensburg </wicri:regionArea><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion></affiliation></author><author><name sortKey="Gerlach, Roman G" sort="Gerlach, Roman G" uniqKey="Gerlach R" first="Roman G" last="Gerlach">Roman G. Gerlach</name><affiliation wicri:level="1"><nlm:affiliation>Project Group 5, Robert Koch Institute , Wernigerode , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Project Group 5, Robert Koch Institute , Wernigerode </wicri:regionArea><wicri:noRegion>Wernigerode </wicri:noRegion><wicri:noRegion>Wernigerode </wicri:noRegion><wicri:noRegion>Wernigerode </wicri:noRegion></affiliation></author><author><name sortKey="Tomiuk, Stefan" sort="Tomiuk, Stefan" uniqKey="Tomiuk S" first="Stefan" last="Tomiuk">Stefan Tomiuk</name><affiliation wicri:level="1"><nlm:affiliation>Miltenyi Biotec GmbH , Bergisch Gladbach , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Miltenyi Biotec GmbH , Bergisch Gladbach </wicri:regionArea><wicri:noRegion>Bergisch Gladbach </wicri:noRegion><wicri:noRegion>Bergisch Gladbach </wicri:noRegion><wicri:noRegion>Bergisch Gladbach </wicri:noRegion></affiliation></author><author><name sortKey="Hammer, Karin" sort="Hammer, Karin" uniqKey="Hammer K" first="Karin" last="Hammer">Karin Hammer</name><affiliation wicri:level="1"><nlm:affiliation>Department of Internal Medicine II, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Internal Medicine II, University Hospital of Regensburg and University of Regensburg , Regensburg </wicri:regionArea><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion></affiliation></author><author><name sortKey="Wagner, Stefan" sort="Wagner, Stefan" uniqKey="Wagner S" first="Stefan" last="Wagner">Stefan Wagner</name><affiliation wicri:level="1"><nlm:affiliation>Department of Internal Medicine II, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Internal Medicine II, University Hospital of Regensburg and University of Regensburg , Regensburg </wicri:regionArea><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion></affiliation></author><author><name sortKey="Van Zandbergen, Ger" sort="Van Zandbergen, Ger" uniqKey="Van Zandbergen G" first="Ger" last="Van Zandbergen">Ger Van Zandbergen</name><affiliation wicri:level="1"><nlm:affiliation>Division of Immunology, Paul-Ehrlich-Institute , Langen , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Division of Immunology, Paul-Ehrlich-Institute , Langen </wicri:regionArea><wicri:noRegion>Langen </wicri:noRegion><wicri:noRegion>Langen </wicri:noRegion><wicri:noRegion>Langen </wicri:noRegion></affiliation></author><author><name sortKey="Binger, Katrina J" sort="Binger, Katrina J" uniqKey="Binger K" first="Katrina J" last="Binger">Katrina J. Binger</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne , Parkville , Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne , Parkville </wicri:regionArea><wicri:noRegion>Parkville </wicri:noRegion></affiliation></author><author><name sortKey="Muller, Dominik N" sort="Muller, Dominik N" uniqKey="Muller D" first="Dominik N" last="Müller">Dominik N. Müller</name><affiliation wicri:level="1"><nlm:affiliation>Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin , Berlin , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin , Berlin </wicri:regionArea><wicri:noRegion>Berlin </wicri:noRegion><wicri:noRegion>Berlin </wicri:noRegion><wicri:noRegion>Berlin </wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Max-Delbrück Center for Molecular Medicine in the Helmholtz Association , Berlin , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max-Delbrück Center for Molecular Medicine in the Helmholtz Association , Berlin </wicri:regionArea><wicri:noRegion>Berlin </wicri:noRegion><wicri:noRegion>Berlin </wicri:noRegion><wicri:noRegion>Berlin </wicri:noRegion></affiliation></author><author><name sortKey="Kitada, Kento" sort="Kitada, Kento" uniqKey="Kitada K" first="Kento" last="Kitada">Kento Kitada</name><affiliation wicri:level="1"><nlm:affiliation>Cardiovascular and Metabolic Disorders, Duke-NUS Medical School , Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>Cardiovascular and Metabolic Disorders, Duke-NUS Medical School </wicri:regionArea><wicri:noRegion>Duke-NUS Medical School </wicri:noRegion></affiliation></author><author><name sortKey="Clatworthy, Menna R" sort="Clatworthy, Menna R" uniqKey="Clatworthy M" first="Menna R" last="Clatworthy">Menna R. Clatworthy</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Immunity Unit, Department of Medicine, MRC-Laboratory of Molecular Biology, University of Cambridge , Cambridge , UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Molecular Immunity Unit, Department of Medicine, MRC-Laboratory of Molecular Biology, University of Cambridge , Cambridge </wicri:regionArea><wicri:noRegion>Cambridge </wicri:noRegion></affiliation></author><author><name sortKey="Kurts, Christian" sort="Kurts, Christian" uniqKey="Kurts C" first="Christian" last="Kurts">Christian Kurts</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Experimental Immunology, University of Bonn , Bonn , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Experimental Immunology, University of Bonn , Bonn </wicri:regionArea><wicri:noRegion>Bonn </wicri:noRegion><wicri:noRegion>Bonn </wicri:noRegion><wicri:noRegion>Bonn </wicri:noRegion></affiliation></author><author><name sortKey="Titze, Jens" sort="Titze, Jens" uniqKey="Titze J" first="Jens" last="Titze">Jens Titze</name><affiliation wicri:level="1"><nlm:affiliation>Cardiovascular and Metabolic Disorders, Duke-NUS Medical School , Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>Cardiovascular and Metabolic Disorders, Duke-NUS Medical School </wicri:regionArea><wicri:noRegion>Duke-NUS Medical School </wicri:noRegion></affiliation></author><author><name sortKey="Abdullah, Zeinab" sort="Abdullah, Zeinab" uniqKey="Abdullah Z" first="Zeinab" last="Abdullah">Zeinab Abdullah</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Experimental Immunology, University of Bonn , Bonn , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Experimental Immunology, University of Bonn , Bonn </wicri:regionArea><wicri:noRegion>Bonn </wicri:noRegion><wicri:noRegion>Bonn </wicri:noRegion><wicri:noRegion>Bonn </wicri:noRegion></affiliation></author><author><name sortKey="Jantsch, Jonathan" sort="Jantsch, Jonathan" uniqKey="Jantsch J" first="Jonathan" last="Jantsch">Jonathan Jantsch</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg </wicri:regionArea><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion><wicri:noRegion>Regensburg </wicri:noRegion></affiliation></author></analytic><series><title level="j">Autophagy</title><idno type="eISSN">1554-8635</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term><term>Autophagosomes (metabolism)</term><term>Autophagosomes (microbiology)</term><term>Autophagy (genetics)</term><term>Autophagy (immunology)</term><term>Escherichia coli (metabolism)</term><term>Escherichia coli (pathogenicity)</term><term>Homeodomain Proteins (genetics)</term><term>Homeodomain Proteins (metabolism)</term><term>Hydrogen-Ion Concentration (MeSH)</term><term>Hypoxia-Inducible Factor 1, alpha Subunit (genetics)</term><term>Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)</term><term>Inflammation (metabolism)</term><term>Lysosomes (genetics)</term><term>Lysosomes (immunology)</term><term>Lysosomes (metabolism)</term><term>Lysosomes (microbiology)</term><term>Macrophages (drug effects)</term><term>Macrophages (immunology)</term><term>Macrophages (microbiology)</term><term>Macrophages (ultrastructure)</term><term>Mannitol (toxicity)</term><term>Mice (MeSH)</term><term>Microscopy, Electron, Transmission (MeSH)</term><term>Nitric Oxide Synthase Type II (genetics)</term><term>Nitric Oxide Synthase Type II (metabolism)</term><term>Oligonucleotide Array Sequence Analysis (MeSH)</term><term>Osmotic Pressure (drug effects)</term><term>Proto-Oncogene Proteins c-akt (genetics)</term><term>Proto-Oncogene Proteins c-akt (metabolism)</term><term>Reactive Oxygen Species (metabolism)</term><term>Sodium (metabolism)</term><term>Sodium (pharmacology)</term><term>TOR Serine-Threonine Kinases (antagonists & inhibitors)</term><term>TOR Serine-Threonine Kinases (genetics)</term><term>TOR Serine-Threonine Kinases (metabolism)</term><term>Transcription Factors (genetics)</term><term>Transcription Factors (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term><term>Autophagie (génétique)</term><term>Autophagie (immunologie)</term><term>Autophagosomes (microbiologie)</term><term>Autophagosomes (métabolisme)</term><term>Concentration en ions d'hydrogène (MeSH)</term><term>Escherichia coli (métabolisme)</term><term>Escherichia coli (pathogénicité)</term><term>Espèces réactives de l'oxygène (métabolisme)</term><term>Facteurs de transcription (génétique)</term><term>Facteurs de transcription (métabolisme)</term><term>Inflammation (métabolisme)</term><term>Lysosomes (génétique)</term><term>Lysosomes (immunologie)</term><term>Lysosomes (microbiologie)</term><term>Lysosomes (métabolisme)</term><term>Macrophages (effets des médicaments et des substances chimiques)</term><term>Macrophages (immunologie)</term><term>Macrophages (microbiologie)</term><term>Macrophages (ultrastructure)</term><term>Mannitol (toxicité)</term><term>Microscopie électronique à transmission (MeSH)</term><term>Nitric oxide synthase type II (génétique)</term><term>Nitric oxide synthase type II (métabolisme)</term><term>Pression osmotique (effets des médicaments et des substances chimiques)</term><term>Protéines proto-oncogènes c-akt (génétique)</term><term>Protéines proto-oncogènes c-akt (métabolisme)</term><term>Protéines à homéodomaine (génétique)</term><term>Protéines à homéodomaine (métabolisme)</term><term>Sodium (métabolisme)</term><term>Sodium (pharmacologie)</term><term>Souris (MeSH)</term><term>Sous-unité alpha du facteur-1 induit par l'hypoxie (génétique)</term><term>Sous-unité alpha du facteur-1 induit par l'hypoxie (métabolisme)</term><term>Séquençage par oligonucléotides en batterie (MeSH)</term><term>Sérine-thréonine kinases TOR (antagonistes et inhibiteurs)</term><term>Sérine-thréonine kinases TOR (génétique)</term><term>Sérine-thréonine kinases TOR (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Homeodomain Proteins</term><term>Hypoxia-Inducible Factor 1, alpha Subunit</term><term>Nitric Oxide Synthase Type II</term><term>Proto-Oncogene Proteins c-akt</term><term>TOR Serine-Threonine Kinases</term><term>Transcription Factors</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Sérine-thréonine kinases TOR</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Macrophages</term><term>Osmotic Pressure</term></keywords><keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Macrophages</term><term>Pression osmotique</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Autophagy</term><term>Lysosomes</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Autophagie</term><term>Facteurs de transcription</term><term>Lysosomes</term><term>Nitric oxide synthase type II</term><term>Protéines proto-oncogènes c-akt</term><term>Protéines à homéodomaine</term><term>Sous-unité alpha du facteur-1 induit par l'hypoxie</term><term>Sérine-thréonine kinases TOR</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Autophagie</term><term>Lysosomes</term><term>Macrophages</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Autophagy</term><term>Lysosomes</term><term>Macrophages</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Autophagosomes</term><term>Escherichia coli</term><term>Homeodomain Proteins</term><term>Hypoxia-Inducible Factor 1, alpha Subunit</term><term>Inflammation</term><term>Lysosomes</term><term>Nitric Oxide Synthase Type II</term><term>Proto-Oncogene Proteins c-akt</term><term>Reactive Oxygen Species</term><term>Sodium</term><term>TOR Serine-Threonine Kinases</term><term>Transcription Factors</term></keywords><keywords scheme="MESH" qualifier="microbiologie" xml:lang="fr"><term>Autophagosomes</term><term>Lysosomes</term><term>Macrophages</term></keywords><keywords scheme="MESH" qualifier="microbiology" xml:lang="en"><term>Autophagosomes</term><term>Lysosomes</term><term>Macrophages</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Autophagosomes</term><term>Escherichia coli</term><term>Espèces réactives de l'oxygène</term><term>Facteurs de transcription</term><term>Inflammation</term><term>Lysosomes</term><term>Nitric oxide synthase type II</term><term>Protéines proto-oncogènes c-akt</term><term>Protéines à homéodomaine</term><term>Sodium</term><term>Sous-unité alpha du facteur-1 induit par l'hypoxie</term><term>Sérine-thréonine kinases TOR</term></keywords><keywords scheme="MESH" qualifier="pathogenicity" xml:lang="en"><term>Escherichia coli</term></keywords><keywords scheme="MESH" qualifier="pathogénicité" xml:lang="fr"><term>Escherichia coli</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Sodium</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Sodium</term></keywords><keywords scheme="MESH" type="chemical" qualifier="toxicity" xml:lang="en"><term>Mannitol</term></keywords><keywords scheme="MESH" qualifier="toxicité" xml:lang="fr"><term>Mannitol</term></keywords><keywords scheme="MESH" qualifier="ultrastructure" xml:lang="en"><term>Macrophages</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Hydrogen-Ion Concentration</term><term>Mice</term><term>Microscopy, Electron, Transmission</term><term>Oligonucleotide Array Sequence Analysis</term></keywords><keywords scheme="MESH" qualifier="ultrastructure" xml:lang="fr"><term>Animaux</term><term>Concentration en ions d'hydrogène</term><term>Macrophages</term><term>Microscopie électronique à transmission</term><term>Souris</term><term>Séquençage par oligonucléotides en batterie</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Infection and inflammation are able to induce diet-independent Na<sup>+</sup>-accumulation without commensurate water retention in afflicted tissues, which favors the pro-inflammatory activation of mouse macrophages and augments their antibacterial and antiparasitic activity. While Na<sup>+</sup>-boosted host defense against the protozoan parasite <i>Leishmania major</i> is mediated by increased expression of the leishmanicidal NOS2 (nitric oxide synthase 2, inducible), the molecular mechanisms underpinning this enhanced antibacterial defense of mouse macrophages with high Na<sup>+</sup> (HS) exposure are unknown. Here, we provide evidence that HS-increased antibacterial activity against <i>E. coli</i> was neither dependent on NOS2 nor on the phagocyte oxidase. In contrast, HS-augmented antibacterial defense hinged on HIF1A (hypoxia inducible factor 1, alpha subunit)-dependent increased autophagy, and NFAT5 (nuclear factor of activated T cells 5)-dependent targeting of intracellular <i>E. coli</i> to acidic autolysosomal compartments. Overall, these findings suggest that the autolysosomal compartment is a novel target of Na<sup>+</sup>-modulated cell autonomous innate immunity. <b>Abbreviations</b>: ACT: actins; AKT: AKT serine/threonine kinase 1; ATG2A: autophagy related 2A; ATG4C: autophagy related 4C, cysteine peptidase; ATG7: autophagy related 7; ATG12: autophagy related 12; BECN1: beclin 1; BMDM: bone marrow-derived macrophages; BNIP3: BCL2/adenovirus E1B interacting protein 3; CFU: colony forming units; CM-H<sub>2</sub>DCFDA: 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester; CTSB: cathepsin B; CYBB: cytochrome b-245 beta chain; DAPI: 4,6-diamidino-2-phenylindole; DMOG: dimethyloxallyl glycine; DPI: diphenyleneiodonium chloride; <i>E. coli: Escherichia coli</i>; FDR: false discovery rate; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; GO: gene ontology; HIF1A: hypoxia inducible factor 1, alpha subunit; HUGO: human genome organization; HS: high salt (+ 40 mM of NaCl to standard cell culture conditions); HSP90: heat shock 90 kDa proteins; LDH: lactate dehydrogenase; LPS: lipopolysaccharide; Lyz2/LysM: lysozyme 2; NFAT5/TonEBP: nuclear factor of activated T cells 5; MΦ: macrophages; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFI: mean fluorescence intensity; MIC: minimum inhibitory concentration; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; NaCl: sodium chloride; NES: normalized enrichment score; n.s.: not significant; NO: nitric oxide; NOS2/iNOS: nitric oxide synthase 2, inducible; NS: normal salt; PCR: polymerase chain reaction; PGK1: phosphoglycerate kinase 1; PHOX: phagocyte oxidase; RFP: red fluorescent protein; RNA: ribonucleic acid; ROS: reactive oxygen species; sCFP3A: super cyan fluorescent protein 3A; SBFI: sodium-binding benzofuran isophthalate; SLC2A1/GLUT1: solute carrier family 2 (facilitated glucose transporter), member 1; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like kinase 1; v-ATPase: vacuolar-type H<sup>+</sup>-ATPase; WT: wild type.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">30982460</PMID><DateCompleted><Year>2020</Year><Month>08</Month><Day>05</Day></DateCompleted><DateRevised><Year>2020</Year><Month>08</Month><Day>05</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1554-8635</ISSN><JournalIssue CitedMedium="Internet"><Volume>15</Volume><Issue>11</Issue><PubDate><Year>2019</Year><Month>11</Month></PubDate></JournalIssue><Title>Autophagy</Title><ISOAbbreviation>Autophagy</ISOAbbreviation></Journal><ArticleTitle>HIF1A and NFAT5 coordinate Na<sup>+</sup>-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting.</ArticleTitle><Pagination><MedlinePgn>1899-1916</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1080/15548627.2019.1596483</ELocationID><Abstract><AbstractText>Infection and inflammation are able to induce diet-independent Na<sup>+</sup>-accumulation without commensurate water retention in afflicted tissues, which favors the pro-inflammatory activation of mouse macrophages and augments their antibacterial and antiparasitic activity. While Na<sup>+</sup>-boosted host defense against the protozoan parasite <i>Leishmania major</i> is mediated by increased expression of the leishmanicidal NOS2 (nitric oxide synthase 2, inducible), the molecular mechanisms underpinning this enhanced antibacterial defense of mouse macrophages with high Na<sup>+</sup> (HS) exposure are unknown. Here, we provide evidence that HS-increased antibacterial activity against <i>E. coli</i> was neither dependent on NOS2 nor on the phagocyte oxidase. In contrast, HS-augmented antibacterial defense hinged on HIF1A (hypoxia inducible factor 1, alpha subunit)-dependent increased autophagy, and NFAT5 (nuclear factor of activated T cells 5)-dependent targeting of intracellular <i>E. coli</i> to acidic autolysosomal compartments. Overall, these findings suggest that the autolysosomal compartment is a novel target of Na<sup>+</sup>-modulated cell autonomous innate immunity. <b>Abbreviations</b>: ACT: actins; AKT: AKT serine/threonine kinase 1; ATG2A: autophagy related 2A; ATG4C: autophagy related 4C, cysteine peptidase; ATG7: autophagy related 7; ATG12: autophagy related 12; BECN1: beclin 1; BMDM: bone marrow-derived macrophages; BNIP3: BCL2/adenovirus E1B interacting protein 3; CFU: colony forming units; CM-H<sub>2</sub>DCFDA: 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester; CTSB: cathepsin B; CYBB: cytochrome b-245 beta chain; DAPI: 4,6-diamidino-2-phenylindole; DMOG: dimethyloxallyl glycine; DPI: diphenyleneiodonium chloride; <i>E. coli: Escherichia coli</i>; FDR: false discovery rate; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; GO: gene ontology; HIF1A: hypoxia inducible factor 1, alpha subunit; HUGO: human genome organization; HS: high salt (+ 40 mM of NaCl to standard cell culture conditions); HSP90: heat shock 90 kDa proteins; LDH: lactate dehydrogenase; LPS: lipopolysaccharide; Lyz2/LysM: lysozyme 2; NFAT5/TonEBP: nuclear factor of activated T cells 5; MΦ: macrophages; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFI: mean fluorescence intensity; MIC: minimum inhibitory concentration; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; NaCl: sodium chloride; NES: normalized enrichment score; n.s.: not significant; NO: nitric oxide; NOS2/iNOS: nitric oxide synthase 2, inducible; NS: normal salt; PCR: polymerase chain reaction; PGK1: phosphoglycerate kinase 1; PHOX: phagocyte oxidase; RFP: red fluorescent protein; RNA: ribonucleic acid; ROS: reactive oxygen species; sCFP3A: super cyan fluorescent protein 3A; SBFI: sodium-binding benzofuran isophthalate; SLC2A1/GLUT1: solute carrier family 2 (facilitated glucose transporter), member 1; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like kinase 1; v-ATPase: vacuolar-type H<sup>+</sup>-ATPase; WT: wild type.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Neubert</LastName><ForeName>Patrick</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Weichselbaum</LastName><ForeName>Andrea</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Reitinger</LastName><ForeName>Carmen</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schatz</LastName><ForeName>Valentin</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schröder</LastName><ForeName>Agnes</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Institute of Orthodontics, University Hospital of Regensburg , Regensburg , Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ferdinand</LastName><ForeName>John R</ForeName><Initials>JR</Initials><Identifier Source="ORCID">0000-0003-0936-0128</Identifier><AffiliationInfo><Affiliation>Molecular Immunity Unit, Department of Medicine, MRC-Laboratory of Molecular Biology, University of Cambridge , Cambridge , UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Simon</LastName><ForeName>Michaela</ForeName><Initials>M</Initials><Identifier Source="ORCID">0000-0002-8166-7178</Identifier><AffiliationInfo><Affiliation>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bär</LastName><ForeName>Anna-Lorena</ForeName><Initials>AL</Initials><AffiliationInfo><Affiliation>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Brochhausen</LastName><ForeName>Christoph</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Institute of Pathology, University of Regensburg , Regensburg , Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gerlach</LastName><ForeName>Roman G</ForeName><Initials>RG</Initials><Identifier Source="ORCID">0000-0002-5718-4758</Identifier><AffiliationInfo><Affiliation>Project Group 5, Robert Koch Institute , Wernigerode , Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tomiuk</LastName><ForeName>Stefan</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Miltenyi Biotec GmbH , Bergisch Gladbach , Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hammer</LastName><ForeName>Karin</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Department of Internal Medicine II, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wagner</LastName><ForeName>Stefan</ForeName><Initials>S</Initials><Identifier Source="ORCID">0000-0002-9471-1166</Identifier><AffiliationInfo><Affiliation>Department of Internal Medicine II, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>van Zandbergen</LastName><ForeName>Ger</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Division of Immunology, Paul-Ehrlich-Institute , Langen , Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Binger</LastName><ForeName>Katrina J</ForeName><Initials>KJ</Initials><Identifier Source="ORCID">0000-0003-1139-3308</Identifier><AffiliationInfo><Affiliation>Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne , Parkville , Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Müller</LastName><ForeName>Dominik N</ForeName><Initials>DN</Initials><AffiliationInfo><Affiliation>Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin , Berlin , Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Max-Delbrück Center for Molecular Medicine in the Helmholtz Association , Berlin , Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kitada</LastName><ForeName>Kento</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Cardiovascular and Metabolic Disorders, Duke-NUS Medical School , Singapore.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Clatworthy</LastName><ForeName>Menna R</ForeName><Initials>MR</Initials><Identifier Source="ORCID">0000-0002-3340-9828</Identifier><AffiliationInfo><Affiliation>Molecular Immunity Unit, Department of Medicine, MRC-Laboratory of Molecular Biology, University of Cambridge , Cambridge , UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kurts</LastName><ForeName>Christian</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Institute of Experimental Immunology, University of Bonn , Bonn , Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Titze</LastName><ForeName>Jens</ForeName><Initials>J</Initials><Identifier Source="ORCID">0000-0001-8463-8404</Identifier><AffiliationInfo><Affiliation>Cardiovascular and Metabolic Disorders, Duke-NUS Medical School , Singapore.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Abdullah</LastName><ForeName>Zeinab</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>Institute of Experimental Immunology, University of Bonn , Bonn , Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jantsch</LastName><ForeName>Jonathan</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><Acronym>DH_</Acronym><Agency>Department of Health</Agency><Country>United Kingdom</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2019</Year><Month>04</Month><Day>14</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Autophagy</MedlineTA><NlmUniqueID>101265188</NlmUniqueID><ISSNLinking>1554-8627</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C497443">Hif1a protein, mouse</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D018398">Homeodomain Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D051795">Hypoxia-Inducible Factor 1, alpha 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MajorTopicYN="N">ultrastructure</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008353" MajorTopicYN="N">Mannitol</DescriptorName><QualifierName UI="Q000633" MajorTopicYN="N">toxicity</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D046529" MajorTopicYN="N">Microscopy, Electron, Transmission</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D052247" MajorTopicYN="N">Nitric Oxide Synthase Type II</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020411" MajorTopicYN="N">Oligonucleotide Array Sequence Analysis</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009997" MajorTopicYN="N">Osmotic Pressure</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051057" MajorTopicYN="N">Proto-Oncogene Proteins c-akt</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017382" MajorTopicYN="N">Reactive Oxygen Species</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012964" MajorTopicYN="N">Sodium</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D058570" MajorTopicYN="N">TOR Serine-Threonine Kinases</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014157" MajorTopicYN="N">Transcription Factors</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y"></Keyword><Keyword MajorTopicYN="Y">Autophagy</Keyword><Keyword MajorTopicYN="Y">cell-autonomous immunity</Keyword><Keyword MajorTopicYN="Y">macrophage</Keyword><Keyword MajorTopicYN="Y">salt</Keyword><Keyword MajorTopicYN="Y">sodium</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2019</Year><Month>4</Month><Day>16</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>8</Month><Day>6</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate 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