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.

Identification of the initial molecular changes in response to circulating angiogenic cells-mediated therapy in critical limb ischemia

“…VCAN/CD44 interaction appears to be involved in extracellular matrix remodeling, cell adhesion, proliferation, migration, and survival, as well as angiogenesis and maintenance of tissues during vascular diseases [69,70]. In addition, upregulation of Leucine-rich alpha-2-glycoprotein 1 (LRG1) could correlate with the capability of activated neutrophils to release LRG1 from the granule compartment and thus modulate the microenvironment in a paracrine fashion [71]. Alternatively, LRG1 can also promote cell proliferation, migration, and angiogenesis, by interacting with the TGF-β accessory receptor endoglin, thus modulating endothelial TGF-β signaling pathways and collaborating in blood vessel formation [72,73].…”

A Multifunctional Role of Leucine-Rich α-2-Glycoprotein 1 in Cutaneous Wound Healing Under Normal and Diabetic Conditions

“…Considering the important role of inflammation in DFU pathophysiology, multiple anti-inflammatory drugs have been developed but have shown limited success ( 10 ). LRG1 is a multifunctional protein that was previously linked to neutrophil activation ( 35 ), EMT ( 16 ), and angiogenesis ( 11 ), all of which are essential for effective wound closure. Here, we investigated the role of LRG1 in both physiological and pathological cutaneous wound healing.…”

Clinical classifiers of COVID-19 infection from novel ultra-high-throughput proteomics

“…LRG1 is known to promote lung fibrosis (Honda et al, 2017) . Secretion of LRG1 by neutrophils upon activation has been reported (Druhan et al, 2017) . Of note, neutrophil-lymphocyte-ratio is elevated in COVID-19 (Qin et al, 2020) .…”