**4. Release and homeostasis**

Once mature, neutrophils are released from the bone marrow. Locally, release of neutrophils into circulation is governed by cytokine signaling. Toll like receptors (TLRs) and granulo‐ cyte colony stimulating factor (G-CSF) receptors are crucial in neutrophil production, but CXCR2 and CXCR4 appear to be the primary receptors involved in neutrophil release into the circulation. [11],[12] Whereas activation of CXCR4 favors retention of mature PMNs in the bone marrow, activation of CXCR2 promotes their release into circulation. Under ho‐ meostatic conditions a normal human adult produces 1 - 2 X 10[11] neutrophils per day. The rate of neutrophil production and release is dictated largely by G-CSF in a negative feedback mechanism whereby an increasing number of apoptotic neutrophils decreases the amount of G-CSF. The apoptotic neutrophils are phagocytosed by tissue macrophages, which decrease their release of interleukin-23 (IL-23). IL-23 stimulates the release of IL-17 by helper T (TH) cells. [13] IL-17 is in turn the primary stimulus for the release of G-CSF. Thus, increased con‐ trolled destruction of neutrophils leads to decreased levels of macrophage derived IL-23 re‐ leased by macrophages, IL-17 released by TH17 cells, G-CSF released by osteoblasts, and thus a decrease in neutrophil synthesis and release. Conversely, IL-17 has been shown to act through p38 MAPK to augment IL-8 release from pulmonary epithelial cells. This mecha‐ nism, ideally, allows the body to rapidly speed neutrophil production and release during in‐ fection in a regulated fashion to minimize potential damage to the host. [10],[14]Another method by which the host regulates circulating neutrophil numbers is through the phenom‐ enon of margination and demargination. Margination occurs when resting neutrophils trav‐ el at a significantly slower pace along the endothelium of the blood vessels. The expression of previously mentioned adhesion molecules creates distinct organ-specific (marginated) pools of cells. Exercise induced stress, infection, or other sources of systemic stress leads to an increase in blood flow, a release of epinephrine and demargination of the neutrophil into the general circulation.[15]
