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.
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Acknowledgements
This work was supported by grants from the NH&MRC of Australia and USA NIH (RO1 HL72523, R01 HL085580, R01 HL107127) and the Paige Arnold Butterfly Run to WGK. MJM and MLH were supported by NH&MRC fellowships. WGK is the Murphy Family Professor of Children’s Oncology Research, an Empire Scholar of the State University of NY and a Senior Scholar of the Crohn’s and Colitis Foundation of America. We acknowledge Jeffrey Ravetch for SHIPFLOX mice, Cathy Quilici, Melissa Inglese and Ryan Farid for technical assistance, Monash Micro Imaging for imaging assistance, Bonnie Toms and Christy Youngs for genotyping of LysCreSHIPflox/flox mice and animal facility staff.
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WGK is an inventor of issued and pending patents pertaining to detection or modulation of SHIP-1 expression in various diseases, including inflammatory diseases. The remaining authors declare no conflict of interest.
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Maxwell, M., Srivastava, N., Park, MY. et al. SHIP-1 deficiency in the myeloid compartment is insufficient to induce myeloid expansion or chronic inflammation. Genes Immun 15, 233–240 (2014). https://doi.org/10.1038/gene.2014.9
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DOI: https://doi.org/10.1038/gene.2014.9
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