The intracellular domain of CD44 promotes the fusion of macrophages

Abstract

Macrophages seed all tissues in which they have the ability, in specific and rare instances, to fuse with themselves and to differentiate into osteoclasts in bone or into giant cells in chronic inflammatory reactions. Although these cells play a central role in osteoporosis and in foreign body rejection, respectively, the molecular mechanism used by macrophages to fuse remains poorly understood. Macrophages might also fuse with somatic and tumor cells to promote tissue repair and metastasis, respectively. We reported that CD44 expression is highly induced in macrophages at the onset of fusion in which it plays a role. We report now that the intracellular domain of CD44 (CD44ICD) is cleaved in macrophages undergoing fusion and that presenilin inhibitors prevent the release of CD44ICD and fusion. We also show that CD44ICD promotes the fusion of tissue macrophages and bone marrow-derived macrophages. IntroductionMacrophages seed all tissues and have the capacity, in specific and rare instances, to undergo homotypic fusion and to differentiate into multinucleate osteoclasts or giant cells, in bone or in chronic inflammatory reactions, respectively. Multinucleation endows macrophages with the ability to resorb components located extracellularly such as bone and foreign bodies, respectively. 1,2 In as much as osteoclasts are essential for the remodeling of bone, they are chiefly responsible for the loss of bone that leads to osteoporosis. Osteoclasts are also responsible for the local loss of bone that results from inflammation, such as in rheumatoid arthritis and in periodontal disease. Giant cells differentiate around foreign bodies such as pathogens, implants, and transplants that they resorb.Increasing evidence suggests that macrophages possess the ability to fuse also with somatic cells to repair tissues and organs and with tumor cells to trigger the metastatic process. 2 So macrophages, which are ubiquitously present in tissues where they perform a wide array of functions, might be endowed with a larger repertoire of biologic activities than originally anticipated. 3 The molecular mechanisms used by macrophages to adhere to, and to fuse with each other, and possibly with other cells, is an essential step that remains to be characterized. Indeed, cell-to-cell fusion itself, whether it concerns that of sperm cells with oocytes or myoblasts with myoblasts, leading to fertilization and muscle development, respectively, remains unclear. 4 To gain insight into the fusion mechanism of macrophages, we had subjected fusing rat alveolar macrophages to genome-wide oligonucleotide microarray, an approach that revealed the transiently induced expression of presenilin 2 (PS2), a protein associated with Alzheimer disease (for a review, see Hutton and Hardy 5 ). The fact that the deletion of the ps1 gene in mice leads to severe skeletal defects, 6 and that the deletion of the ps2 gene enhances the embryonic lethal phenotype of ps1 deletion, 7 triggered our interest in PS.Presenilins (PS1 and PS2) are transmembrane proteins ide...

Osteoclast stimulatory transmembrane protein and dendritic cell–specific transmembrane protein cooperatively modulate cell–cell fusion to form osteoclasts and foreign body giant cells

“…(13) Therefore, although the functions of osteoclasts and FBGCs differ, they express common molecules, such as DC-STAMP, that function in cell-cell fusion. (3) To date, various molecules have been identified that regulate fusion of osteoclasts or macrophages, including DC-STAMP, ATP6v0d2, CD47, CD44, CD9, CD81, MFR, E-cadherin, and meltrin-a (3,(14)(15)(16)(17)(18)(19)(20)(21) ATP6v0d2-deficient mice show significant reductions in fusion of either cell type. (21) DC-STAMP-deficient osteoclasts or FBGCs show a complete lack of cell-cell fusion, a function specific for macrophage lineage fusion, since fertilization and myotube formation is normal in DC-STAMP-deficient mice.…”

Distinct Macrophage Phenotypes Contribute to Kidney Injury and Repair

“…BMMs were isolated and cultured as per the protocol of Cui et al 29 Mouse bone marrow cells were flushed from the femurs of 8-to 12-week-old mice and passed through a 40-m cell strainer (BD Falcon), and red blood cells were lysed in ACK buffer (0.15 M NH 4 Cl, 10 mM KHCO 3 , 0.1 mM EDTA). Remaining cells were incubated in MEM␣ medium (Life Technologies) containing 10% FBS (Sigma), 10% L929 fibroblast cell supernatant (generously provided by Dr. Agnes Vignery), 1% glutamine (Life Technologies), 1% MEM vitamin (Life Technologies), and 1% penicillin/streptomycin (Life Technologies).…”

An Essential Role for STAT6-STAT1 Protein Signaling in Promoting Macrophage Cell-Cell Fusion

“…Macrophage fusion receptor (MFR; also called SHPS-1), a member of immunoglobulin (Ig) superfamily, was shown to function in macrophage cell-cell fusion based on loss-of-function assays using MFR monoclonal antibodies or the soluble form of the extracellular domain of MFR (7,8). CD47, an MFR ligand, and the intracellular domain of CD44 (CD44ICD) have also been implicated in macrophage cell-cell fusion (9,10). DAP12, an ITAM motif-containing adaptor protein, and the signaling molecule Syk were also reportedly involved in cell-cell fusion of macrophages (11).…”