CD44 is a phagocytic receptor

Abstract

CD44, a transmembrane adhesion molecule involved in binding and metabolism of hyaluronan, has additional functions in inflammatory and immune responses, contributing to the ingestion and clearance of particles and apoptotic cells. Our goal was to determine the specific role of CD44 in phagocytosis and whether it functions as a primary or accessory phagocytic receptor. Using hyaluronan-coated beads and erythrocytes coated with anti-CD44 antibodies as the phagocytic prey, we determined that CD44 mediates efficient phagocytosis in primary murine peritoneal macrophages and in the murine macrophage cell line RAW 264.7. In RAW cells, the phagocytic index for anti-CD44-coated erythrocytes was 25 ؎ 3 (mean ؎ SEM) compared with less than 1 for erythrocytes coated with isotype-matched control antibodies. Uptake of anti-CD44-coated erythrocytes was abrogated by pretreatment with a blocking antibody to CD44 and was absent in primary cultures of CD44-deficient murine macrophages. Down-regulation of Fc receptors by aggregated IgG-induced internalization, which blocks uptake of IgG-coated particles, had no effect on CD44-mediated particle engulfment. Using a combination of immunoprecipitation, pharmacologic inhibition, and genetic deletion, we determined that CD44-mediated phagocytosis involves Syk, Rac1, and phosphatidylinositol 3-kinase and induced activation of the phagocyte oxidase. We conclude that CD44 is a competent phagocytic receptor that efficiently mediates internalization of large particles. IntroductionThe transmembrane adhesion molecule CD44, known to be involved in binding, endocytosis, and metabolism of hyaluronan, 1-3 also has additional functions in innate and adaptive immunity. CD44 encompasses a heterogeneous family of receptors with isoforms ranging from 80 to 200 kDa that are encoded by a single gene composed of 19 exons. 4 This extensive heterogeneity of CD44 is attributable to a combination of alternate splicing 4 and extensive N-and O-glycosylation. [5][6][7][8] Purported ligands of CD44 include growth factors such as basic fibroblast growth factor and heparin-binding epidermal growth factor, 5,6 fibronectin, 9 collagen, 10 fibrin, 11,12 the proteoglycan serglycin found in lymphocytes and mast-cell granules, 13 osteopontin, 14 and other CD44 molecules on vicinal cells. 15 Diverse functions have been attributed to CD44, including involvement in cellular adhesion and migration, lymphocyte and monocyte homing, activation and proliferation, cytocidal activity of natural killer cells, and tumor metastasis. 16 Observations also point to a role for CD44 in binding, ingestion (phagocytosis), and clearance of apoptotic cells 17 and microbial pathogens. 18 With respect to clearance of apoptotic cells, direct antibody ligation of CD44 on macrophages 19 or on airway epithelial cells 20 enhanced subsequent uptake of apoptotic neutrophils and eosinophils, respectively, suggesting a costimulatory function for the receptor. However, ensuing reports have suggested that some of these effects may be attributed to the Fc...

Renal macrophage migration and crystal phagocytosis via inflammatory-related gene expression during kidney stone formation and elimination in mice: Detection by association analysis of stone-related gene expression and microstructural observation

“…(35) On the other hand, CD44 is reported to be a phagocytic receptor that is able to trigger the ingestion of large particles by macrophages. (36,37) Mgp encodes matrix gla protein (MGP), which is a vitamin K-dependent and Ca-binding protein.…”

Hyaluronan-dependent pericellular matrix☆

“…Both CD44 and RHAMM associate with the cytoskeleton [81,82], control tumor cell invasiveness, and transduce signals involved in proliferation, locomotion, focal adhesion turnover [83,84], indicating that both receptors may be responsible for hyaluronan traction. CD44 has been demonstrated to mediate phagocytosis [85,86], bringing up the idea that hyaluronan in the pericellular matrix may by used by cells to draw in other matrix components, cellular debris or other particles, thus facilitating phagocytosis. The full role of cellular traction on hyaluronan organization is not yet clear.…”

CD44 Is Critically Involved in Infarct Healing by Regulating the Inflammatory and Fibrotic Response

“…Hyaluronan participates in induction and resolution of inflammation through interactions with the transmembrane adhesion molecule CD44 (7), a ubiquitously distributed glycoprotein that mediates a wide variety of cell-cell and cellmatrix interactions. CD44-hyaluronan interactions play an important role in regulating leukocyte extravasation into inflammatory sites (8,9) and mediate efficient phagocytosis (10). In addition, a growing body of evidence suggests that CD44 serves as a key factor in resolution of inflammation through removal of matrix breakdown products and clearance of apoptotic neutrophils (6), and mediates fibroblast migration and invasion in the wound provisional matrix (11).…”