title: Myeloid cell-specific inositol polyphosphate-4-phosphatase type I knockout mice impair bacteria clearance in a murine peritonitis model.
abstract: Phosphatidylinositol 3-kinase (PI3K)/Akt signaling has been implicated in the anti-inflammatory response in a mouse model of endotoxemia and sepsis. The present study focused on the role of inositol polyphosphate-4-phosphatase type I (Inpp4a), which dephosphorylates PtdIns(3,4)P2 to PtdIns(3)P, in bacterial infections. We prepared myeloid cell-specific Inpp4a-conditional knockout mice. Macrophages from these mice showed increased Akt phosphorylation and reduced production of inflammatory cytokines in response to LPS or Escherichia coli in vitro The Inpp4a knockout mice survived for a shorter time than wild type mice after i.p. infection with E. coli, with less production of inflammatory cytokines. Additionally, E. coli clearance from blood and lung was significantly impaired in the knockout mice. A likely mechanism is that the Inpp4a-catalyzed dephosphorylation of PtdIns(3,4)P2 down-regulates Akt pathways, which, in turn, increases the production of inflammatory mediators. This mechanism at least fits the decreased E. coli clearance and short survival in the Inpp4a knockout mice.
authors.affiliation: Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Morioka
authors.affiliation: Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Nigorikawa
authors.affiliation: Department of Pathology and Immunology, Akita University School of Medicine, Akita 010-8543, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Sasaki
authors.affiliation: Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan khazeki@hiroshima-u.ac.jp.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Hazeki
authors.affiliation: Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kasuu
authors.affiliation: Department of Pathology and Immunology, Akita University School of Medicine, Akita 010-8543, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Hazeki
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000502:physiology*; D004927:Escherichia coli Infections / Q000276:immunology*; D006801:Humans; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D017737:Macrophages, Peritoneal / Q000382:microbiology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010538:Peritonitis / Q000235:genetics / Q000276:immunology*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D018129:Phosphatidylinositol Phosphates; C060980:phosphatidylinositol 3,4-diphosphate; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase
keywords: Akt; Inpp4a; macrophage; phosphoinositides; sepsis