Osteocytes regulate neutrophil development through IL-19: A potent cytokine for neutropenia treatment
Osteocytes are the most abundant (90–95%) cells in bone and have emerged as an important regulator of hematopoiesis, but their role in neutrophil development and the underlying mechanisms remain unclear. Interleukin (IL)-19 produced predominantly by osteocytes stimulated granulopoiesis and neutrophil formation, which stimulated IL-19 receptor (IL-20R)/Stat3 signaling in neutrophil progenitors to promote their expansion and neutrophil formation. Mice with constitutive activation of the mechanistic target of rapamycin complex (mTORC1) signaling in osteocytes (Dmp1-Cre) exhibited a dramatic increase in IL-19 production and promyelocytes/myelocytic expansion, while mTORC1 inactivation in osteocytes reduced IL-19 production and neutrophil number in mice. We showed that IL-19 administration stimulated neutrophil development, while neutralizing endogenous IL-19 or depletion of its receptor inhibited the process. Importantly, low dose IL-19 reversed chemotherapy, irradiation, or chloramphenicol-induced neutropenia in mice more efficiently than G-CSF. These evidence indicated that IL-19 was an essential regulator of neutrophil development and a potent cytokine for neutropenia treatment.
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