G-CSF-Induced Emergency Granulopoiesis Modulates Neutrophil Effector Function in Mice

Abstract

Neutrophils function as first responders of the immune system by deploying cytotoxic armaments and orchestrating local inflammation. Their functionality is programmed during daily production in the bone marrow through granulopoiesis. During severe inflammation, increased neutrophil demand is met through activation of emergency granulopoiesis. The effect of emergency granulopoiesis on neutrophil functionality remains cryptic. In the present study, we assessed neutrophil function in mice injected with G-CSF (100 µg/kg/d for 3 days) to activate emergency granulopoiesis. We found that emergency granulopoiesis neutrophils exhibit impaired ROS production (n = 6, P = 0.003) and NETosis (n = 5, P < 0.01), but increase neutrophil elastase secretion (n = 9, P < 0.0001) and LPS-induced Tnfa, Il1b, Il1a, Il12a, and Ccl2 expression (n = 13, P < 0.01). To test the impact of emergency granulopoiesis neutrophils on the inflammatory response in vivo, we pre-treated mice with G-CSF and challenged them with zymosan to induce peritonitis. At 4 h post-zymosan injection, peritoneal neutrophils from G-CSF treated mice exhibit increased expression of Ccl2 (n = 3, P < 0.05). Subsequently, we observed enhanced peritoneal macrophage accumulation at 48 h post-zymosan administration in G-CSF-treated mice (n = 5, P < 0.05). These data indicate that emergency granulopoiesis programs neutrophils to have an enhanced immunomodulatory function that orchestrates the subsequent macrophage response in local tissue inflammation.

Keywords: Cytokine; G-CSF; Granulopoiesis; Hematopoiesis; Inflammation; Neutrophil.