Disruption of filamentous actin inhibits human macrophage fusion

DeFife, Kristin M.; Jenney, Christopher R.; Colton, Erica; Anderson, James M.

doi:10.1096/fasebj.13.8.823

Cited by 71 publications

(52 citation statements)

References 45 publications

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“…Overall levels of F-actin were higher in M2 and micropatterned cells compared with unpatterned cells, although dramatic changes in cytoskeletal organization were not observed. Although such differences in the cytoskeleton with the macrophage polarization state have been previously reported (21), the functional role of actin in macrophages has been primarily associated with phagocytosis (22), podosome formation (23), or fusion events (24), and little is known about the role of the cytoskeleton in macrophage polarization. We found that abrogation of actin polymerization and actin/myosin contractility, as well as ROCK and MLCK activities, completely eliminated shape-induced effects on polarization, suggesting a critical role for actin in the modulation of macrophage polarization by cell shape.…”

Section: Discussionmentioning

confidence: 98%

Modulation of macrophage phenotype by cell shape

McWhorter

Wang

Nguyen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

1,155

975

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Phenotypic polarization of macrophages is regulated by a milieu of cues in the local tissue microenvironment. Although much is known about how soluble factors influence macrophage polarization, relatively little is known about how physical cues present in the extracellular environment might modulate proinflammatory (M1) vs. prohealing (M2) activation. Specifically, the role of cell shape has not been explored, even though it has been observed that macrophages adopt different geometries in vivo. We and others observed that macrophages polarized toward different phenotypes in vitro exhibit dramatic changes in cell shape: M2 cells exhibit an elongated shape compared with M1 cells. Using a micropatterning approach to control macrophage cell shape directly, we demonstrate here that elongation itself, without exogenous cytokines, leads to the expression of M2 phenotype markers and reduces the secretion of inflammatory cytokines. Moreover, elongation enhances the effects of M2-inducing cytokines IL-4 and IL-13 and protects cells from M1-inducing stimuli LPS and IFN-γ. In addition shape-but not cytokine-induced polarization is abrogated when actin and actin/myosin contractility are inhibited by pharmacological agents, suggesting a role for the cytoskeleton in the control of macrophage polarization by cell geometry. Our studies demonstrate that alterations in cell shape associated with changes in ECM architecture may provide integral cues to modulate macrophage phenotype polarization. Macrophages play an essential role in innate immunity and are involved in a variety of immune functions, including host defense and wound healing. In addition, these cells participate in the progression of many chronic inflammatory diseases. To fulfill their functionally distinct roles, macrophages are capable of polarizing toward a spectrum of phenotypes, which include classical (proinflammatory, M1) and alternative (anti-inflammatory, prohealing, M2) activation states, as well as a regulatory phenotype and subtypes of these broad classifications (1). In the presence of inflammatory stimuli and danger signals, macrophages polarize toward the M1 state and release reactive species and inflammatory cytokines to fight pathogens. In contrast, a wound healing environment promotes polarization toward an M2 phenotype and leads to cellular processes that facilitate tissue repair. Although distinct macrophage subpopulations are clearly observed at different phases of the immune response to infection and injury (2), regulation of phenotypic polarization of these remarkably plastic cells still remains poorly defined.Activated macrophages are derived from circulating monocytes or resident tissue macrophages and migrate through the extracellular space in response to chemotactic agents to reach the target wound or infection site. Although it is thought that cytokines and chemokines are the primary regulators of macrophage behavior (3), some recent studies suggest that tissue structure and physical cues in the extracellular environment also contribute to ...

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Section: Discussionmentioning

confidence: 98%

Modulation of macrophage phenotype by cell shape

McWhorter

Wang

Nguyen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

1,155

975

View full text Add to dashboard Cite

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“…The MR, expressed on some macrophages, epithelial, and endothelial cells (Takahashi et al 1998, Linehan et al 1999, is the prototype member of a family of multi-lectin receptors that recognize carbohydrates such as terminal mannose, fucose, N-acetylglucosamine, or glucose residues on the cell walls of infectious organisms (Stahl & Ezekowitz 1998). The MR is believed to mediate both endocytosis of glycoproteins and phagocytosis of micro-organisms or glucose residues (Astarie-Dequeker et al 1999, DeFife et al 1999, Lansink et al 1999. MR-mediated fusion occurs via a filamentous action-dependent pathway (DeFife et al 1999).…”

Section: Discussionmentioning

confidence: 99%

“…The MR is believed to mediate both endocytosis of glycoproteins and phagocytosis of micro-organisms or glucose residues (Astarie-Dequeker et al 1999, DeFife et al 1999, Lansink et al 1999. MR-mediated fusion occurs via a filamentous action-dependent pathway (DeFife et al 1999). The MR is expressed on cells of the macrophage lineage, is not detectable on blood monocytes, and has its expression modulated by inflammatory mediators (Stein & Ezekowitz 1992).…”

Section: Discussionmentioning

confidence: 99%

Expression and role of mannose receptor/terminal high-mannose type oligosaccharide on osteoclast precursors during osteoclast formation

Morishima

Morita

Tokushima³

et al. 2003

Journal of Endocrinology

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Osteoclasts are formed from hematopoietic precursors via cell-cell fusion. We have previously reported that mannose residues are expressed on the outer membranes of monocytes during osteoclast differentiation. In the present study, we have attempted to demonstrate the pattern of expression levels of terminal high-mannose type oligosaccharide and to show that the mannose receptor is expressed on osteoclast precursor cells. Osteoclasts were formed using three different systems, namely mouse bone marrow cell culture, co-culture of mouse spleen cells with stromal cells, and RAW264·7 cell cultures. During osteoclast differentiation, the expression of terminal highmannose type oligosaccharide gradually increased and then peaked at the stage of fusion in all three systems. Expression of the mannose receptor gradually increased during osteoclast differentiation in bone marrow cells and the co-culture system. In contrast, that in RAW264·7 cells had already been detected in the absence of the soluble receptor activator of NF-B ligand and did not change during osteoclast differentiation. To ascertain whether expression of high-mannose type oligosaccharide is involved in tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cell (MNC) formation, glycosidase inhibitors were used on RAW264·7 cell culture. Castanospermine, an inhibitor of glucosidase I, inhibited the TRAP-positive MNCs, and deoxymannojirimycin, an inhibitor of -mannosidase I, increased the TRAPpositive MNC formation. These results indicate that the binding of terminal high-mannose and mannose receptor is important for the process of cellular fusion in osteoclast formation.

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“…13,16 In addition, similar to phagocytosis, actin polymerization and reorganization are observed during macrophage fusion and, when inhibited, prevent fusion and subsequent FBGC formation. 17 In the present study, we expanded on these observations by identifying lamellipodia formation as a key feature of the IL-4-induced cytoskeletal changes in macrophages. Consistent with the role of Rac1 in this process, we detected IL-4-induced Rac1 activation before changes in cell shape.…”

mentioning

confidence: 94%

Foreign Body Giant Cell Formation Is Preceded by Lamellipodia Formation and Can Be Attenuated by Inhibition of Rac1 Activation

Jay

Skokos

Laiwalla

et al. 2007

The American Journal of Pathology

105

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Macrophages that are recruited to the site of implanted biomaterials undergo fusion to form surfacedamaging foreign body giant cells. Exposure of peripheral blood monocytes to interleukin-4 can recapitulate the fusion process in vitro. In this study, we used interleukin-4 to induce multinucleation of murine bone marrow-derived macrophages and observed changes in cell shape, including elongation and lamellipodia formation, before fusion. Because cytoskeletal rearrangements are regulated by small GTPases, we examined the effects of inhibitors of Rho kinase (Y-32885) and Rac activation (NSC23766) on fusion. Y-32885 did not prevent cytoskeletal changes or fusion but limited the extent of multinucleation. NSC23766, on the other hand, inhibited lamellipodia formation and fusion in a dose-dependent manner. In addition, we found that in control cells, these changes were preceded by Rac1 activation. However, NSC23766 did not block the uptake of polystyrene microspheres. Likewise, short interfering RNA knockdown of Rac1 limited fusion without limiting phagocytosis. Thus, phagocytosis and fusion can be partially decoupled based on their susceptibility to NSC23766. Furthermore, poly(ethylene-co-vinyl acetate) scaffolds containing NSC23766 attenuated foreign body giant cell formation in vivo. These observations suggest that targeting Rac1 activation could protect biomaterials without compromising the ability of macrophages to perform beneficial phagocytic functions at implantation sites. (Am J Pathol

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Disruption of filamentous actin inhibits human macrophage fusion

Cited by 71 publications

References 45 publications

Modulation of macrophage phenotype by cell shape

Modulation of macrophage phenotype by cell shape

Expression and role of mannose receptor/terminal high-mannose type oligosaccharide on osteoclast precursors during osteoclast formation

Foreign Body Giant Cell Formation Is Preceded by Lamellipodia Formation and Can Be Attenuated by Inhibition of Rac1 Activation

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