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

Jay, Steven M.; Skokos, Eleni A.; Laiwalla, Farah; Krady, Marie-Marthe; Kyriakides, Themis R.

doi:10.2353/ajpath.2007.061213

Cited by 88 publications

(112 citation statements)

References 34 publications

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“…We observed that bone marrow-derived macrophages (BMDMs) stimulated in culture with cytokines to induce M1 or M2 polarization displayed markedly different cell morphologies, as has also been reported by other groups (15,16). Addition of LPS and IFN-γ, which stimulate M1 polarization, caused cells to flatten into a round, pancake-like shape within 24 h of stimulation.…”

Section: Macrophage Polarization State Is Associated With Changes In supporting

confidence: 78%

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: Macrophage Polarization State Is Associated With Changes In supporting

confidence: 78%

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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“…In contrast to ThioMΦ, BMM were stimulated with IL-4 and GM-CSF to induce macrophage fusion (Jay et al, 2007). We found that fusion was severely impaired in macrophages from CD36-KO mice compared with the wild-type control ( Fig.…”

Section: Macrophage Fusion Is Impaired In Cd36-ko Macrophagesmentioning

confidence: 79%

The scavenger receptor CD36 plays a role in cytokine-induced macrophage fusion

Helming

Winter

Gordon

2009

Journal of Cell Science

131

109

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Multinucleated giant cells, characteristic of granulomatous infections, originate from the fusion of macrophages. Using an antibody screening strategy we found that the scavenger receptor CD36 participates in macrophage fusion induced by the cytokines IL-4 and GM-CSF. Our results demonstrate that exposure of phosphatidylserine on the cell surface and lipid recognition by CD36 are required for cytokine-induced fusion of macrophages. We also show that CD36 acts in a heterotypic manner during giant-cell formation and that the formation of osteoclasts is independent of CD36. The discovery of molecules involved in the formation of multinucleated giant cells will enable us to determine their functional significance. Furthermore, our results suggest that lipid capture by cell surface receptors may be a general feature of cell fusion.

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“…8 Moreover, MCP-1-null macrophages were deficient in IL-4 -induced activation of Rac1, and inhibition of Rac1 with the low-molecular-weight inhibitor NSC23766 attenuated FBGC formation in vitro and in vivo. In addition, in a separate study, lack of MMP-9 induction by MCP-1-null macrophages was observed under fusogenic conditions.…”

Section: Inhibition Of Rac-1 Leads To Reduction In Mmp-9 Expressionmentioning

confidence: 99%

“…8,12 Expanded cells (0.5 ϫ 10 6 per well) were plated on a 24-well non-tissue culture treated polystyrene plate (BD Biosciences, Franklin Lakes, NJ) in media containing 10 ng/mL rm GM-CSF and 10 ng/mL rm IL-4. To examine the role of TNF-␣ in fusion, in separate experiments, cells were incubated with increasing dosages (5, 10, or 50 ng/mL) of rm TNF-␣.…”

Section: In Vitro Fusion Assaymentioning

confidence: 99%

“…11 Subsequent fusion experiments demonstrated that MCP-1-null macrophages are compromised in fusion because of inability to undergo cytoskeletal remodeling and induce MMP-9 in response to IL-4. 8,12 The present study investigated the hypothesis that the foreign body response in MCP-1-null mice might be tissue-specific by implanting biomaterials intraperitoneally in wild-type (WT) and MCP-1-null mice and comparing the ensuing foreign body response. Histochemical and immunohistochemical analyses indicated a reduction in macrophage adhesion, FBGC formation, and encapsulation in MCP-1-null mice.…”

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confidence: 99%

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Lack of TNF-α–Induced MMP-9 Production and Abnormal E-Cadherin Redistribution Associated with Compromised Fusion in MCP-1–Null Macrophages

Skokos

Charokopos

Khan

et al. 2011

The American Journal of Pathology

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Homotypic cell fusion occurs in several cell types including macrophages in the formation of foreign body giant cells. Previously, monocyte chemoattractant protein-1 (MCP-1) was demonstrated to be required for foreign body giant cell formation in the foreign body response. The present study investigated the fusion defect in MCP-1-null macrophages by implanting biomaterials intraperitoneally in wildtype and MCP-1-null mice and monitoring the macrophage response at 12 hours to 4 weeks. MCP-1-null mice exhibited reduced accumulation and fusion of macrophages on implants, which was associated with attenuation of the foreign body response. Consistent with previous in vitro findings, the level of matrix metalloproteinase-9 (MMP-9) was reduced in MCP-1-null macrophages adherent to implants. In contrast, CCR2 expression was unaffected. In vitro studies revealed reduced tumor necrosis factor-␣ (TNF-␣) production and abnormal subcellular redistribution of E-cadherin and ␤-catenin during fusion in MCP-1-null macrophages. Exogenous TNF-␣ caused an increase in the production of MMP-9 and rescued the fusion defect. Addition of GM6001 (MMP inhibitor) or NSC23766 (Rac1 inhibitor) indicated two distinct induction pathways, one for E-cadherin/␤-catenin and one for MCP-1, TNF-␣, and MMP-9. Considered together, these observations demonstrate that induction of E-cadherin/␤-catenin is not sufficient for fusion in the absence of MCP-1 or the downstream mediators TNF-␣ and MMP-9. Moreover, attenuation of the foreign body response in intraperitoneal implants in MCP-1-null mice demonstrates that the process depends on tissue-specific factors.

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

Cited by 88 publications

References 34 publications

Modulation of macrophage phenotype by cell shape

Modulation of macrophage phenotype by cell shape

The scavenger receptor CD36 plays a role in cytokine-induced macrophage fusion

Lack of TNF-α–Induced MMP-9 Production and Abnormal E-Cadherin Redistribution Associated with Compromised Fusion in MCP-1–Null Macrophages

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