SH2-containing inositol 5'-phosphatase-1 (SHIP1) deficiency in mice results in abnormal myeloid expansion, and proinflammatory conditions in the lung. However, the mechanisms involved in SHIP1-mediated regulation of myeloid differentiation remain unclear. Here we show that SHIP1 is a key regulator of early differentiation for dendritic cells (DCs). We also provide critical evidence to modify the function of SHIP1 in in vitro development of BMDCs using the recent framework of defining DCs. We found that loss of SHIP1 suppresses GM-CSF-induced formation of bone marrow-derived DC (BMDC) colonies, leading to reduced BMDC number in BM cell culture. The number of maturated BMDCs decreased in SHIP1-KO culture, due to reduction of immature BMDCs, suggesting SHIP1 is critical for lineage commitment rather than for maturation from myeloid precursors to DCs. We further showed that F4/80+/MHCIIlow BM macrophage-like cells (BMMs) were the main population of SHIP1-KO BM culture. Treatment of wild-type BM culture with 3 α-aminocholestane (3AC), a specific inhibitor for functional activity of SHIP1, caused a similar developmental defect in BMDCs as seen in SHIP1-KO cells, resulting in the absence of BMDC colony, and increased number of BMMs in BM culture. In conclusion, our results suggest that differentiation of BMDCs are markedly impaired under SHIP1 deficient condition, which causes skewed development of myeloid lineage cells manifested as pathological conditions associated with an excess of macrophage population.
Keywords: SHIP1; bone marrow; dendritic cells; differentiation; macrophage; maturation; myeloid precursor.