UBC Theses and Dissertations
The role of SHIP1 in modulating disease severity in the K/BxN serum transfer model of rheumatoid arthritis Hirukawa, Alison Misa
SHIP1 (SH2 domain containing inositol-5ʼ-phosphatase) is a negative regulator of the phosphatidylinositol-3 kinase (PI3K) pathway. SHIP1 is expressed in hematopoietic cells, and mediates its effect by hydrolyzing PIP₃, an important second messenger generated by the PI3K pathway. In this way, SHIP attenuates a variety of signaling cascades including those mediating cell survival and proliferation. Due to its importance in regulating immune cell signaling, SHIP1 is an attractive therapeutic target. In this thesis, I explored the role of SHIP1 in the context of rheumatoid arthritis, an autoimmune inflammatory disease. To this end, I employed the K/BxN serum transfer model of rheumatoid arthritis. This disease model is auto-antibody driven and lymphocyte independent, and thus facilitates characterization of the effector phase of disease, a process that relies on components of the innate immune system. Arthritis was dramatically exacerbated in global SHIP1 knock-out mice, as evidenced by changes in ankle thickness, clinical scoring and histological analysis. Heterozygous SHIP1 mice also displayed increased disease severity in comparison to wild type litter mates, possibly due to an expanded population of circulating neutrophils, that increases with age. Since naive global SHIP1 knock-out mice exhibit a range of hematopoietic abnormalities, to elucidate the cell intrinsic contribution of SHIP1 ablation to the disease phenotype, I induced K/BxN mediated arthritis in mice with lineage restricted deletion of SHIP1. Mice with a neutrophil/ macrophage-restricted loss of SHIP1 (LysMcre), like global SHIP1 knock-out mice, displayed an alternatively activated ʻM2ʼ biased macrophage phenotype, and developed exacerbated disease. Neutrophil-restricted loss of SHIP1 (GEcre) was also sufficient to exacerbate disease and resulted in earlier disease onset. In order to identify how the loss of SHIP1 in neutrophils results in heightened disease severity, I performed a series of in vitro experiments utilizing polymorphonuclear leukocytes freshly isolated from bone marrow. While we cannot exclude that SHIP1 may be playing additional roles in neutrophil functions, I report that SHIP1 plays a role in attenuating responsiveness of neutrophils to GPCR and FcγR ligation, two families of receptors that are necessary for induction and amplification of rheumatoid arthritis in the K/BxN serum transfer model.
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