Globular adiponectin induces leukocytosis and mobilizes hematopoietic progenitor cells in mice

Adiponectin (APN; ACRP30, AdipoQ), one of the best characterized adipokine, is a multifaceted, pleiotrophic cytokine that plays important roles in the regulation of lipid metabolism/obesity, inflammation/autoimmunity, and vascular function. APN expression is closely associated with pathology of chronic inflammatory and autoimmune diseases including rheumatoid arthritis. It exists as multiple forms including monomer, dimer, trimer, and high molecular weight oligomers. In addition, enzymatic digestion leads to the formation of smaller globular domain. While full length APN in a number of biological events has been investigated, the role of globular domain is elusive. Here, we showed that globular fragment of APN (gAPN) plays a role in murine hematopoiesis. Upon single systemic injection of 5 μg of gAPN to C57BL/6 mice, there was a marked increase in the blood leukocyte counts, mostly myeloid cells, after 3 days of gAPN treatment. While intraperitoneal injection did not affect the peripheral blood cellularity, subcutaneous gAPN injection significantly reduce the number of leukocytes in the peripheral blood. Lin-c-kit+ primitive hematopoietic progenitor cells were also mobilized into the peripheral blood of gAPN-treated mice with similar kinetics and magnitude to that of granulocytes and lymphocytes. Kinetics of plasma granulocyte colony stimulating factor (G-CSF) release by gAPN administration revealed that G-CSF is the key mediator for gAPN-induced leukocytosis and hematopoietic stem/progenitor cells mobilization. These observations suggest that leukocyte elastase or other extracellular proteases released from activated monocytes/neutrophils during immune responses generates globular APN and this cytokine serves as a potent mobilizer of hematopoietic progenitors and leukocytes into the peripheral blood.