title: SHIP-1 deficiency in the myeloid compartment is insufficient to induce myeloid expansion or chronic inflammation.
abstract: SHIP-1 has an important role in controlling immune cell function through its ability to downmodulate PI3K signaling pathways that regulate cell survival and responses to stimulation. Mice deficient in SHIP-1 display several chronic inflammatory phenotypes including antibody-mediated autoimmune disease, Crohn's disease-like ileitis and a lung disease reminiscent of chronic obstructive pulmonary disease. The ileum and lungs of SHIP-1-deficient mice are infiltrated at an early age with abundant myeloid cells and the mice have a limited lifespan primarily thought to be due to the consolidation of lungs with spontaneously activated macrophages. To determine whether the myeloid compartment is the key initiator of inflammatory disease in SHIP-1-deficient mice, we examined two independent strains of mice harboring myeloid-restricted deletion of SHIP-1. Contrary to expectations, conditional deletion of SHIP-1 in myeloid cells did not result in consolidating pneumonia or segmental ileitis typical of germline SHIP-1 deficiency. In addition, other myeloid cell abnormalities characteristic of germline loss of SHIP-1, including flagrant splenomegaly and enhanced myelopoiesis, were absent in mice lacking SHIP-1 in myeloid cells. This study indicates that the spontaneous inflammatory disease characteristic of germline SHIP-1 deficiency is not initiated solely by LysM-positive myeloid cells but requires the simultaneous loss of SHIP-1 in other hematolymphoid lineages.
authors.affiliation: Department of Immunology, Leukocyte Signalling Laboratory, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Maxwell
authors.affiliation: Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: N
authors.initials: N
authors.lastname: Srivastava
authors.affiliation: Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: M-Y
authors.initials: MY
authors.lastname: Park
authors.affiliation: Department of Immunology, Leukocyte Signalling Laboratory, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Tsantikos
authors.affiliation: Departments of Pathology and Cell Biology and Pediatrics, H. Lee Moffitt Comprehensive Cancer Center and Research Institute, University of South Florida, Tampa, FL, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Engelman
authors.affiliation: 1] Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, USA [2] Department of Pediatrics, SUNY Upstate Medical University, Syracuse, NY, USA [3] Department of Chemistry, Syracuse University, Syracuse, NY, USA.
authors.forename: W G
authors.initials: WG
authors.lastname: Kerr
authors.affiliation: Department of Immunology, Leukocyte Signalling Laboratory, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia.
authors.forename: M L
authors.initials: ML
authors.lastname: Hibbs
mesh_terms: D000818:Animals; D002908:Chronic Disease; D007082:Ileum / Q000201:enzymology / Q000276:immunology; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D000072181:Inositol Polyphosphate 5-Phosphatases; D008168:Lung / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D008262:Macrophage Activation; D008264:Macrophages / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D038042:Myelopoiesis / Q000235:genetics / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011014:Pneumonia / Q000201:enzymology / Q000235:genetics / Q000276:immunology*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases