CD157 is an important mediator of neutrophil adhesion and migration

Abstract

CD157, a glycosylphosphatidylinositol (GPI)-anchored protein encoded by a member of the CD38 NADase/ADP-ribosyl cyclase gene family, is expressed on the surface of most human circulating neutrophils. This work demonstrates that CD157 is a receptor that induces reorganization of the cytoskeleton and significant changes in cell shape, and that signals mediated by CD157 act through modulation of cytosolic Ca 2؉ concentration. These signals are independent of the products of CD157's enzymatic activities (ie, cyclic adenosine diphosphate [ADP]-ribose and ADP-ribose). Indeed, the enzymatic activities of CD157 in circulating neutrophils as well as in dimethyl sulfoxide (DMSO)-differentiated (CD157 ؉ / CD38 ؊ ) HL-60 cells, are hardly detectable. This work also shows that the receptorial activity relies on cross-talk between CD157 and ␤ 2 integrin. CD157 localizes in GM1-enriched lipid rafts and, upon activation, it migrates to the uropod, a structure specialized in motility and adhesive functions. Indeed, CD157 is involved in adhesion to extracellular matrix proteins and in chemotaxis induced in vitro by formylmethionyl-leucyl-phenylalanine (fMLP). These findings were consistent with the results obtained in neutrophils from patients with paroxysmal nocturnal hemoglobinuria (PNH), in which CD157 is deficient. These neutrophils showed constant defects in adhesion and migration. Our data attribute specific and crucial roles to CD157 in the regulation of innate immunity during inflammation. IntroductionHuman CD157 is a glycosylphosphatidylinositol (GPI)-linked glycoprotein encoded by a member of the NADase/adenosine diphosphate (ADP)-ribosyl cyclase gene family, which also includes CD38. 1 The CD157 and CD38 molecules are pleiotropic in function, acting both as ectoenzymes and receptors. [2][3][4] CD157 is abundantly expressed by myeloid lineage from precursors to differentiated stages 5 by bone marrow stromal cells, synovial cells, endothelial cells, and other cell types. 6 Functional analysis by means of agonistic monoclonal antibodies (mAbs) mimicking natural ligand(s) suggested that CD157 could act as a receptor with signal transduction capacity. However, as CD157 lacks a cytoplasmic domain, it must associate with some "conventional" receptor(s) to transduce signals; much in the same way as CD38, which has a short intracellular domain, CD157 acts as a parasite on specific receptors to compensate for its structural ineptitude to exert receptorial functions. 7,8 In concert with monocytes and tissue macrophages, neutrophils carry out many of the major functional responses of the innate immune system. They participate in inflammatory responses, such as host resistance to infection, and in detrimental host inflammatory reactions, including arthritis, septic shock, stroke, and transplantation rejection. The regulation of neutrophil recruitment into the inflammatory sites and neutrophil clearance are critical processes assuring effective host defense without tissue injury. Neutrophil extravasation is a multistep process depe...

The CD157-Integrin Partnership Controls Transendothelial Migration and Adhesion of Human Monocytes

“…These conclusions are further supported by the observation that neutrophils from patients with paroxysmal nocturnal hemoglobinuria (which express neither CD157 nor other GPI-anchored molecules as a result of an acquired genetic mutation) (51) are characterized by defective transendothelial migration and adhesion to ECM proteins (11,14).…”

“…The efficiency of these effects is proportional to the extent of cross-linking, suggesting that the aggregation of many molecules is crucial to the formation of competent signaling microdomains (11). In alignment with this observation, here we demonstrated that anti-CD157 mAb, which can cross-link two molecules, is not sufficient to drag integrins into rafts and, consequently, to transduce activation signals; hence, it blocks transmigration and adhesion, likely preventing leukocyte interaction with a so far unidentified physiological ligand(s).…”

“…CD157 is involved in neutrophil polarization, adhesion, and motility (11) and controls transendothelial migration (14). This study extends the analysis of the functional role of CD157 to human monocytes, adopted as a physiological model in which to explore the molecular mechanism underlying the role of the molecule in the control of cell motility.…”

“…CD157 is also expressed by ovarian cancer epithelium and by peritoneal mesothelial cells, where it is implicated in tumor dissemination (9). Further, it is endowed with receptor-like features observed in different cell types (10) and transduces signals by interacting with transmembrane partner molecules (11,12), a strategy shared by other GPI-anchored molecules (13).…”

Genetic reprogramming of tumor cells by zinc finger transcription factors

“…Several glycosylphosphatidylinositol-anchored proteins have been shown to promote cytoskeleton reorganization, changes in cell shape, cell attachment and extracellular matrix-specific migration in neutrophil cells (24), pre-B lymphocytes (25), and breast carcinomas (26). These effects depend on a cross-talk between the glycosylphosphatidylinositolcontaining protein and specific integrins.…”