Histidine-Rich Glycoprotein Stimulates Human Neutrophil Phagocytosis and Prolongs Survival through CLEC1A

Abstract

Histidine-rich glycoprotein (HRG) is a multifunctional plasma protein and maintains the homeostasis of blood cells and vascular endothelial cells. In the current study, we demonstrate that HRG and recombinant HRG concentration dependently induced the phagocytic activity of isolated human neutrophils against fluorescence-labeled Escherichia coli and Staphylococcus aureus through the stimulation of CLEC1A receptors, maintaining their spherical round shape. The phagocytosis-inducing effects of HRG were inhibited by a specific anti-HRG Ab and enhanced by opsonization of bacteria with diluted serum. HRG and C5a prolonged the survival time of isolated human neutrophils, in association with a reduction in the spontaneous production of extracellular ROS. In contrast, HRG maintained the responsiveness of neutrophils to TNF-a, zymosan, and E. coli with regard to reactive oxygen species production. The blocking Ab for CLEC1A and recombinant CLEC1A-Fc fusion protein significantly inhibited the HRGinduced neutrophil rounding, phagocytic activity, and prolongation of survival time, suggesting the involvement of the CLEC1A receptor in the action of HRG on human neutrophils. These results as a whole indicated that HRG facilitated the clearance of E. coli and S. aureus by maintaining the neutrophil morphology and phagocytosis, contributing to the antiseptic effects of HRG in vivo.

The Aging Features of Thyrotoxicosis Mice: Malnutrition, Immunosenescence and Lipotoxicity

“…Antimicrobial peptides are becoming increasingly recognized as important effectors of innate immunity, for example, Hrg is implicated in the regulation of various physiological and pathological processes including angiogenesis, coagulation, fibrinolysis, the formation of immune complexes, apoptotic/necrotic and pathogen clearance, cell adhesion and antimicrobial activity ( 32 ). Hrg can fight against Candida, Staphylococcus aureus, and Escherichia coli by direct or indirect action ( 33 – 35 ). The blood Hrg level of systemic inflammatory response syndrome (SIRS) patients was about 50% lower than that of healthy controls, indicating the consumption of HRG and the resulting decline in defense, meaning the Hrg level was negatively correlated with mortality in ICU, and Hrg was used as a biomarker of SIRS treatment ( 36 , 37 ).…”

The C-type lectin receptor Clec1A plays an important role in the development of experimental autoimmune encephalomyelitis by enhancing antigen presenting ability of dendritic cells and inducing inflammatory cytokine IL-17

“…Thus, our observation suggests presence of an endogenous ligand (s). In this context, it was reported recently that histidine-rich glycoprotein (HRG), which is a multifunctional plasma protein and stimulates human neutrophil phagocytosis and prolongs neutrophil survival, is a ligand for Clec1A [ 60 ]. Interestingly, HRG suppresses high mobility group box-1-protein-induced inflammatory responses of endothelial cells through interaction with Clec1A [ 61 ].…”

Neutrophil Myeloperoxidase Derived Chlorolipid Production During Bacteria Exposure

“…Phagocytosis was also assessed using pHrodo-labeled E. coli , which was also cyD-sensitive. Although the pHrodo technique used in this study has been used by others (e.g., 48 ) to measure phagocytosis by neutrophils there is concern regarding the pHrodo assay in neutrophils based on studies focusing on the pH of the phagosome ( 49 ). Using pH-sensitive SNARF-1 labeled dead C. albicans the neutrophil phagosome was found to be alkaline for up to 30 min.…”