title: Leucine Rich α-2 Glycoprotein: A Novel Neutrophil Granule Protein and Modulator of Myelopoiesis.
abstract: Leucine-rich α2 glycoprotein (LRG1), a serum protein produced by hepatocytes, has been implicated in angiogenesis and tumor promotion. Our laboratory previously reported the expression of LRG1 in murine myeloid cell lines undergoing neutrophilic granulocyte differentiation. However, the presence of LRG1 in primary human neutrophils and a role for LRG1 in regulation of hematopoiesis have not been previously described. Here we show that LRG1 is packaged into the granule compartment of human neutrophils and secreted upon neutrophil activation to modulate the microenvironment. Using immunofluorescence microscopy and direct biochemical measurements, we demonstrate that LRG1 is present in the peroxidase-negative granules of human neutrophils. Exocytosis assays indicate that LRG1 is differentially glycosylated in neutrophils, and co-released with the secondary granule protein lactoferrin. Like LRG1 purified from human serum, LRG1 secreted from activated neutrophils also binds cytochrome c. We also show that LRG1 antagonizes the inhibitory effects of TGFβ1 on colony growth of human CD34+ cells and myeloid progenitors. Collectively, these data invoke an additional role for neutrophils in innate immunity that has not previously been reported, and suggest a novel mechanism whereby neutrophils may modulate the microenvironment via extracellular release of LRG1.
authors.affiliation: The Department of Hematologic Oncology, The Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, United States of America.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Druhan
authors.affiliation: The Department of Hematologic Oncology, The Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, United States of America.
authors.forename: Amanda
authors.initials: A
authors.lastname: Lance
authors.affiliation: The University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.
authors.forename: Shimena
authors.initials: S
authors.lastname: Li
authors.affiliation: The Department of Hematologic Oncology, The Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, United States of America.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Price
authors.affiliation: The Department of Hematologic Oncology, The Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, United States of America.
authors.forename: Jacob T
authors.initials: JT
authors.lastname: Emerson
authors.affiliation: The Department of Hematologic Oncology, The Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, United States of America.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Baxter
authors.affiliation: The Department of Hematologic Oncology, The Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, United States of America.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Gerber
authors.affiliation: The Department of Hematologic Oncology, The Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, United States of America.
authors.forename: Belinda R
authors.initials: BR
authors.lastname: Avalos
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D045304:Cytochromes c / Q000737:chemistry / Q000378:metabolism; D005089:Exocytosis; D006023:Glycoproteins / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D006031:Glycosylation; D018922:HL-60 Cells; D006801:Humans; D007781:Lactoferrin / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D038042:Myelopoiesis / Q000502:physiology*; D018375:Neutrophil Activation; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D018952:Antigens, CD34; D006023:Glycoproteins; C015246:LRG1 protein, human; D053773:Transforming Growth Factor beta1; D014212:Tretinoin; D045304:Cytochromes c; D007781:Lactoferrin; D020780:Matrix Metalloproteinase 9