PLEKHO2 is essential for M-CSF-dependent macrophage survival.

Macrophage-colony stimulating factor (M-CSF) is crucial for macrophage survival; however, the mechanism associated with this signaling has not been fully elucidated. Here, we identified pleckstrin homology domain-containing family O member 2 (PLEKHO2), a protein with unknown function, as a novel regulator of macrophage survival in vitro and in vivo. We found that PLEKHO2-deficient mice exhibited severe reductions in macrophage population in the peritoneal cavity, spleen, and blood, and that PLEKHO2 expression was upregulated during macrophage differentiation and maturation. Additionally, PLEKHO2-deficient bone marrow-derived macrophages displayed increased apoptotic cell death in the absence of M-CSF, although PLEKHO2 deficiency did not affect macrophage differentiation and proliferation. Furthermore, although signaling pathways downstream of M-CSF appeared unaffected, caspase activation was elevated in PLEKHO2-deficient macrophages. Our results provided genetic evidence of roles for PLEKHO2 in promoting macrophage survival.