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Tetraspanins CD9 and CD81 function to prevent the fusion of mononuclear phagocytes
Yoshito Takeda1, Isao Tachibana, Kenji Miyado
1Department of Molecular Medicine, Osaka University Graduate School of Medicine, Japan.
Insights
Tetraspanins CD9 and CD81 normally prevent mononuclear phagocyte fusion. Loss of these proteins in mice leads to increased multinucleated cell formation, suggesting a novel inhibitory role for CD9 and CD81 in phagocyte fusion.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Tetraspanins CD9 and CD81 are known to mediate fusion in various cell types, including gametes, myoblasts, and virus-infected cells.
- Their specific role in the fusion of mononuclear phagocytes, such as monocytes and macrophages, remained largely uncharacterized.
Purpose of the Study:
- To investigate the function of tetraspanins CD9 and CD81 in the fusion process of mononuclear phagocytes.
- To elucidate the regulatory mechanisms involving CD9 and CD81 in monocyte and macrophage fusion.
Main Methods:
- Analysis of CD9 and CD81 expression and their complex formation with integrins in cultured monocytes under normal and fusogenic conditions.
- Assessment of the effects of anti-CD9 and anti-CD81 antibodies on monocyte and macrophage fusion.
- In vitro and in vivo studies using CD9- and CD81-null mice to evaluate multinucleated cell formation and osteoclastogenesis.
Main Results:
- CD9 and CD81 expression and integrin complex formation were upregulated in monocytes under normal culture but downregulated under fusogenic conditions.
- Antibodies against CD9 and CD81 unexpectedly promoted monocyte and macrophage fusion, independent of adhesion, aggregation, or cytokine production.
- CD9/CD81-null mice exhibited increased multinucleated cell formation in macrophages and spontaneous development of multinucleated giant cells in the lung, alongside enhanced osteoclastogenesis.
Conclusions:
- Tetraspanins CD9 and CD81 act coordinately to inhibit the fusion of mononuclear phagocytes.
- These findings reveal a novel inhibitory role for CD9 and CD81 in regulating phagocyte fusion and multinucleated cell formation, with implications for immune responses and bone biology.
Abstract:
Tetraspanins CD9 and CD81 facilitate the fusion between gametes, myoblasts, or virus-infected cells. Here, we investigated the role of these tetraspanins in the fusion of mononuclear phagocytes. Expression of CD9 and CD81 and their complex formation with integrins were up-regulated when blood monocytes were cultured under normal conditions. Under fusogenic conditions in the presence of Con A, CD9 and CD81 up-regulation was inhibited, and their complex formation with integrins was down-regulated. Anti-CD9 and -CD81 antibodies, which were previously shown to inhibit the fusion of gametes, myoblasts, and virus-infected cells, unexpectedly promoted the fusion of monocytes and alveolar macrophages. However, these effects were not due to altered cell adhesion, aggregation, or cytokine production. When stimulated in vitro or in vivo, alveolar macrophages and bone marrow cells of CD9- and CD81-null mice formed larger numbers of multinucleated cells than those of wild-type mice. Finally, CD9/CD81 double-null mice spontaneously developed multinucleated giant cells in the lung and showed enhanced osteoclastogenesis in the bone. These results suggest that CD9 and CD81 coordinately prevent the fusion of mononuclear phagocytes.