title: Mast cell/IL-4 control of Francisella tularensis replication and host cell death is associated with increased ATP production and phagosomal acidification.
abstract: Mast cells are now recognized as effective modulators of innate immunity. We recently reported that mast cells and secreted interleukin-4 (IL-4) effectively control intramacrophage replication of Francisella tularensis Live Vaccine Strain (LVS), and that mice deficient in mast cells or IL-4 receptor (IL-4R(-/-)) exhibit greater susceptibility to pulmonary challenge. In this study, we further evaluated the mechanism(s) by which mast cells/IL-4 control intramacrophage bacterial replication and host cell death, and found that IL-4R(-/-) mice exhibited significantly greater induction of active caspase-3 within lung macrophages than wild-type animals following intranasal challenge with either LVS or the human virulent type A strain SCHU S4. Treatment of LVS-infected bone-marrow-derived macrophages with a pancaspase inhibitor (zVAD) did not alter bacterial replication, but minimized active caspase-3 and other markers (Annexin V and propidium iodide) of cell death, whereas treatment with both rIL-4 and zVAD resulted in concomitant reduction of both parameters, suggesting that inhibition of bacterial replication by IL-4 was independent of caspase activation. Interestingly, IL-4-treated infected macrophages exhibited significantly increased ATP production and phagolysosomal acidification, as well as enhanced mannose receptor upregulation and increased internalization with acidification, which correlated with observations in mast cell-macrophage co-cultures, with resultant decreases in F. tularensis replication.
authors.affiliation: Department of Biology, South Texas Center for Emerging Infectious Diseases, University of Texas at San Antonio, San Antonio, Texas, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Rodriguez
authors.forename: J-J
authors.initials: JJ
authors.lastname: Yu
authors.forename: A K
authors.initials: AK
authors.lastname: Murthy
authors.forename: M N
authors.initials: MN
authors.lastname: Guentzel
authors.forename: K E
authors.initials: KE
authors.lastname: Klose
authors.forename: T G
authors.initials: TG
authors.lastname: Forsthuber
authors.forename: J P
authors.initials: JP
authors.lastname: Chambers
authors.forename: M T
authors.initials: MT
authors.lastname: Berton
authors.forename: B P
authors.initials: BP
authors.lastname: Arulanandam
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000276:immunology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005604:Francisella tularensis / Q000254:growth & development / Q000276:immunology; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D015847:Interleukin-4 / Q000276:immunology*; D037181:Lectins, C-Type / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009842:Oligopeptides / Q000494:pharmacology; D015388:Organelles / Q000737:chemistry / Q000382:microbiology; D010588:Phagosomes / Q000737:chemistry / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D014406:Tularemia / Q000276:immunology*
chemical_list: D004791:Enzyme Inhibitors; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D009842:Oligopeptides; D011956:Receptors, Cell Surface; D019948:Receptors, Interleukin-4; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; D015847:Interleukin-4; D000255:Adenosine Triphosphate; D053148:Caspase 3