Neutrophil Gelatinase B and Chemokines in Leukocytosis and Stem Cell Mobilization

Abstract

Leukocytosis is a physiopathological mechanism primarily to combat infections, whereas stem cell mobilization is induced for therapeutical purposes. Both processes are dependent on the balance between leukocyte and stem cell retention and mobilization. The retention is mediated by the specific architecture of the bone marrow, adhesion molecules and the production of chemokines in the bone marrow, which attract escaped immature cells to the marrow. Mobilization is the effect of the action of "peripheral" chemokines, such as interleukin-8 (IL-8 or CXCL8) and the remodeling of the matrix and basement membranes by matrix enzymes, such as gelatinase B (MMP-9). Recent studies lead to the conclusion that neutrophils, IL-8/CXCL8 and gelatinase B/MMP-9 play control roles in leukocytosis and stem cell mobilization. Neutrophils are the predominant circulating leukocyte type and IL-8/CXCL8 is the major neutrophil chemoattractant in humans. Gelatinase B and no gelatinase A is rapidly released from prestored granules after activation of neutrophils by IL-8/CXCL8. Moreover, neutrophils do not produce TIMP-1 and can chemically activate latent progelatinase B. Activated gelatinase B catalyses the aminoterminal truncation of IL-8/CXCL8 into a tenfold more potent chemokine. This implies that, when IL-8/CXCL8 appears in the circulation, the bone marrow is instructed to release neutrophils and concomitantly stem cells. These studies suggest that IL-8/CXCL8 and gelatinase B/MMP-9 are targets for the modulation of stem cell mobilization.

Increased expression of inflammation-related genes in cultured preadipocytes/stromal vascular cells from obese compared with non-obese Pima Indians

“…As expected, MMP9 expression was elevated in preadipocytes/SVC of obese subjects compared with those of nonobese subjects. Both MMP9 and IL-8 are involved in leucocytosis and stem cell mobilisation [13]. Thus, we hypothesise that the IL-8 and MMP9 secreted by the preadipocytes/SVC may play a role in extracellular matrix changes or adipose tissue remodelling.…”

Low CXCR4 membrane expression on CD34+ cells characterizes cells mobilized to blood

“…5,14 It was postulated that this mechanism relies on degradation of SDF-1 within the BM stroma by proteolytic enzymes released by neutrophils activated during mobilization. 5,15 However, the interaction between stromal cells and haematopoietic progenitors must be more complex as in physiological situations, with normal numbers and functions of neutrophils, a proportion of CD34 þ cells is constitutively released to replace progenitors in some freed marrow niches. 16 Therefore, in the present study, we focused on the presence of CXCR4 (SDF-1 receptor) on CD34 þ cells to verify the role of regulation of CXCR4 expression in mobilization of haematopoietic progenitors to the peripheral blood.…”

Reduced expression of inducible gelatinase B/matrix metalloproteinase-9 in monocytes from patients with myelodysplastic syndrome: correlation of inducible levels with the percentage of cytogenetically marked cells and with marrow cellularity

“…[7][8][9][10] In addition to ECM remodeling, MMPs are required for bone remodeling, wound healing, angiogenesis, and stem-cell regulation. 11,12 Leukocytes require MMP function to infiltrate or egress tissues, and tumor cells secrete MMPs to facilitate invasion and disseminate metastases. Two members of the MMPs, gelatinase A (also called MMP-2) and gelatinase B (also called MMP-9) have a gelatin-binding domain homologous to the fibronectin type II domain.…”