Endogenous PMN sialidase activity exposes activation epitope on CD11b/CD18 which enhances its binding interaction with ICAM-1

Abstract

Diapedesis is a dynamic, highly regulated process by which leukocytes are recruited to inflammatory sites. We reported previously that removal of sialyl residues from PMNs enables these cells to become more adherent to EC monolayers and that sialidase activity within intracellular compartments of resting PMNs translocates to the plasma membrane following activation. We did not identify which surface adhesion molecules were targeted by endogenous sialidase. Upon activation, β2 integrin (CD11b/CD18) on the PMN surface undergoes conformational change, which allows it to bind more tightly to the ICAM-1 and ICAM-2 on the EC surface. Removal of sialyl residues from CD18 and CD11b, by exogenous neuraminidase or mobilization of PMN sialidase, unmasked activation epitopes, as detected by flow cytometry and enhanced binding to ICAM-1. One sialidase isoform, Neu1, colocalized with CD18 on confocal microscopy. Using an autoperfused microflow chamber, desialylation of immobilized ICAM-1 enhanced leukocyte arrest in vivo. Further, treatment with a sialidase inhibitor in vivo reversed endotoxin-induced binding of leukocytes to ICAM-1, thereby suggesting a role for leukocyte sialidase in the cellular arrest. These data suggest that PMN sialidase could be a physiologic source of the enzymatic activity that removes sialyl residues on β2 integrin and ICAM-1, resulting in their enhanced interaction. Thus, PMN sialidase may be an important regulator of the recruitment of these cells to inflamed sites.

Neuraminidase Reprograms Lung Tissue and Potentiates Lipopolysaccharide-Induced Acute Lung Injury in Mice

“…However, the sialyl linkages from each anatomic section of the airway are species specific. Using lectin blot techniques established in our laboratory (33), we determined the sialylation status of murine lung tissues and their response to sialidase treatment. Lectins are a group of proteins that bind specifically to different glycoconjugates: SNA and MAA II recognize terminal sialic acids in α-2,6- or α-2,3-linkages, respectively, while PNA recognizes a subterminal β-galactose after terminal sialyl residues have been removed (33, 34).…”

“…In a subsequent publication, we demonstrated that removal of sialyl residues from the TLR4 receptor complex accelerated and enhanced LPS-initiated signaling (21). Further, removal of sialyl residues led to activation of PMN β2 integrins and enhanced adhesion, while desialylation of ICAM-1 promoted leukocyte arrest in an in vivo model of cell migration (33). Recently, we reported that MUC1 and the EGF receptor on airway epithelial cells were highly sialylated and that desialylation enhanced their responsiveness to their cognate ligands (52).…”

SR-BI in Bone Marrow Derived Cells Protects Mice from Diet Induced Coronary Artery Atherosclerosis and Myocardial Infarction

“…VCAM-1 and ICAM-1 binding assays were done as described in previous studies [51]-[53]. Blood was collected from SR-BI +/+ apoE-R61 h/h or SR-BI −/− apoE-R61 h/h mice fed a normal chow diet.…”

Neuraminidase-1 mediates skeletal muscle regeneration

“…Numerous studies in vitro and in mouse models have implicated NEU1 in fundamental biological processes that go beyond its canonical degradative function; these include immune response and inflammation [11, 12], cell proliferation [13, 14], and tumor cell migration and metastasis [1, 15, 16]. A primary role of NEU1 as a negative regulator of lysosomal exocytosis has been identified [17–20].…”