β1 and β2 Integrins Mediate Adhesion during Macrophage Fusion and Multinucleated Foreign Body Giant Cell Formation

McNally, Amy K.; Anderson, James M.

doi:10.1016/s0002-9440(10)64882-1

Cited by 204 publications

(199 citation statements)

References 54 publications

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“…In this regard, McNally and Anderson 14 have demonstrated that anti-b2 antibodies inhibited not only adhesion but also the MGC formation, suggesting that the fusion step is also mediated by b2 integrins. However, whether Mac-1 was involved in this step has not been determined in these studies.…”

Section: Discussionmentioning

confidence: 99%

“…23 The role of b2 integrins in macrophage fusion remains controversial. Although previous studies with function-blocking antibodies implicated b2 integrins in macrophage fusion, 14 other reports concluded that b2 integrins play a minor role. 24 Thus, definitive experimental evidence for the role of b2 integrins and, in particular, of Mac-1 is lacking, and the involvement of a D b 2 in fusion is unclear.…”

mentioning

confidence: 84%

“…12 Cell adhesion is mainly mediated by integrins, and previous studies that used function-blocking antibodies reported that b2 integrins play a role in adhesion of macrophages and their subsequent fusion on some, but not all, substrates. 13,14 Monocytes and macrophages express all four members of the b2 integrin subfamily, including a M b 2 (Mac-1, CD11b/ CD18), a D b 2 (CD11d/CD18), a X b 2 (CD11c/CD18), and a L b 2 (CD11a/CD18). Among the b 2 integrins, integrin Mac-1 is the most abundant and versatile receptor.…”

mentioning

confidence: 99%

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The Role of Integrins αMβ2 (Mac-1, CD11b/CD18) and αDβ2 (CD11d/CD18) in Macrophage Fusion

Podolnikova

Kushchayeva

et al. 2016

The American Journal of Pathology

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The subfamily of b2 integrins is implicated in macrophage fusion, a hallmark of chronic inflammation. Among b2 family members, integrin Mac-1 (a M b 2 , CD11b/CD18) is abundantly expressed on monocyte/ macrophages and mediates critical adhesive reactions of these cells. However, the role of Mac-1 in macrophage fusion leading to the formation of multinucleated giant cells remains unclear. Moreover, the role of integrin a D b 2 (CD11d/CD18), a receptor with recognition specificity overlapping that of Mac-1, is unknown. We found that multinucleated giant cells are formed in the inflamed mouse peritoneum during the resolution phase of inflammation, and their numbers were approximately twofold higher in wild-type mice than in Mac-1 À/À mice. Analyses of isolated inflammatory peritoneal macrophages showed that IL-4einduced fusion of Mac-1edeficient cells was strongly reduced compared with wild-type counterparts. The examination of adhesive reactions known to be required for fusion showed that spreading, but not adhesion and migration, was reduced in Mac-1edeficient macrophages. Fusion of a D b 2 -deficient macrophages was also significantly decreased, albeit to a smaller degree. Deficiency of intercellular adhesion molecule 1, a counter-receptor for Mac-1 and a D b 2 , did not alter the fusion rate. The results indicate that both Mac-1 and a D b 2 support macrophage fusion with Mac-1 playing a dominant role and suggest that Mac-1 may mediate cell-cell interactions with a previously unrecognized counter-receptor(s). (Am J Pathol 2016, 186: 2105e2116; http:// dx

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 84%

mentioning

confidence: 99%

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The Role of Integrins αMβ2 (Mac-1, CD11b/CD18) and αDβ2 (CD11d/CD18) in Macrophage Fusion

Podolnikova

Kushchayeva

et al. 2016

The American Journal of Pathology

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“…In vitro, we have demonstrated that the lymphokines IL-4 (McNally 1995) or IL-13 (DeFife 1997) induce macrophage fusion and the formation of FBGC that are morphologically indistinguishable from the IL-4-induced FBGC that form on implanted materials in vivo (Zhao 1991, Kao 1995. IL-4-induced macrophage fusion is dependent on the activity of a classic endocytic/phagocytic receptor, the mannose receptor (McNally 1996), and exhibits multiple other features of a phagocytic process (McNally 2005) that is supported by cell/substrate adhesive interactions between select β1 and β2 integrins and vitronectin (McNally 2002, McNally 2007a, McNally 2007b. Interestingly, we found that α-tocopherol is also a potent macrophage fusion factor, and that diacylglycerol kinase activity is required for both α-tocopherol-and IL-4-induced FBGC formation .…”

Section: Introductionmentioning

confidence: 99%

Foreign body-type multinucleated giant cell formation requires protein kinase C β, δ, and ζ

McNally

MacEwan

Anderson

2008

Experimental and Molecular Pathology

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Multinucleated giant cells are a classic cellular feature of chronic inflammation, although the mechanism of macrophage fusion leading to their formation is not well understood. Here, we investigate the participation of protein kinase C (PKC) in the interleukin (IL)-4-induced fusion of human monocyte-derived macrophages and foreign body giant cell (FBGC) formation in vitro. The PKC inhibitors H-7 and calphostin C attenuated macrophage fusion, whereas H-8, which is more selective for PKA and PKG, did not. Macrophage fusion was also prevented by the phospholipase C inhibitor, Et-18-OCH 3 , the PKC isoform inhibitors GO6983 or rottlerin and by peptide inhibitors for PKC (20-28), PKCβ, or PKCζ but not by HBDDE or peptide inhibitors for PKCε or PKA. In cultures of fusing macrophages/FBGC, we detected only PKCα, β, δ, and ζ by immunoprecipitation and immunoblotting, and we also observed strong expression of these isoforms by immunocytochemistry. Our collective results suggest that the γ, ε, η, μ, θ, or ι PKC isoforms are not required in the mechanism of IL-4-induced macrophage fusion; whether PKCα is required is unclear. However, new evidence is provided that FBGC formation is supported by PKCβ, PKCδ, and PKCζ in combined diacylglycerol-dependent (PKCβ and PKCδ) and -independent (PKCζ) signaling pathways.

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“…RGD was used as a positive control surface for macrophage development and adhesion and FBGC formation, as previously reported. [37][38][39] Adsorbed RGD is widely recognized for its adhesion-promoting capabilities in that it presents multiple copies of the RGD (arginine-glycine-aspartate) cell attachment sequence to integrin receptors, thus facilitating their engagement.…”

Section: Adsorption Of Human Fg and Rgd Peptidementioning

confidence: 99%

Adsorbed Fibrinogen Enhances Production of Bone- and Angiogenic-Related Factors by Monocytes/Macrophages

Maciel

Oliveira²,

Colton

et al. 2014

Tissue Engineering Part A

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Macrophages are phagocytic cells with great importance in guiding multiple stages of inflammation and tissue repair. By producing a large number of biologically active molecules, they can affect the behavior of other cells and events, such as the foreign body response and angiogenesis. Since protein adsorption to biomaterials is crucial for the inflammatory process, we addressed the ability of the pro-inflammatory molecule fibrinogen (Fg) to modulate macrophage behavior toward tissue repair/regeneration. For this purpose, we used chitosan (Ch) as a substrate for Fg adsorption. Freshly isolated human monocytes were seeded on Ch substrates alone or previously adsorbed with Fg, and allowed to differentiate into macrophages for 10 days. Cell adhesion and morphology, formation of foreign body giant cells (FBGC), and secretion of a total of 80 cytokines and growth factors were evaluated. Both substrates showed similar numbers of adherent macrophages along differentiation as compared with RGD-coated surfaces, which were used as positive controls. Fg did not potentiate FBGC formation. In addition, actin cytoskeleton staining revealed the presence of punctuate F-actin with more elongated and interconnecting cells on Ch substrates. Antibody array screening and quantification of inflammation-and wound-healing-related factors indicated an overall reduction in Ch-based substrates versus RGD-coated surfaces. At late times, most inflammatory agents were downregulated in the presence of Fg, in contrast to growth factor production, which was stimulated by Fg. Importantly, on Ch + Fg substrates, fully differentiated macrophages produced significant amounts of macrophage inflammatory protein-1delta (MIP-1d), platelet-derived growth factor-BB, bone morphogenetic protein (BMP)-5, and BMP-7 compared with Ch alone. In addition, other important factors involved in bone homeostasis and wound healing, such as growth hormone, transforming growth factor-b3, and insulin-like growth factor-binding proteins, as well as several angiogenic mediators, including endocrine gland-derived vascular endothelial factor, fibroblast growth factor-7, and placental growth factor, were significantly promoted by Fg. This work provides a new perspective on the inflammatory response in the context of bone repair/regeneration mediated by a pro-inflammatory protein (Fg) adsorbed onto a biomaterial (Ch) that does not otherwise exhibit osteogenic properties.

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β1 and β2 Integrins Mediate Adhesion during Macrophage Fusion and Multinucleated Foreign Body Giant Cell Formation

Cited by 204 publications

References 54 publications

The Role of Integrins αMβ2 (Mac-1, CD11b/CD18) and αDβ2 (CD11d/CD18) in Macrophage Fusion

The Role of Integrins αMβ2 (Mac-1, CD11b/CD18) and αDβ2 (CD11d/CD18) in Macrophage Fusion

Foreign body-type multinucleated giant cell formation requires protein kinase C β, δ, and ζ

Adsorbed Fibrinogen Enhances Production of Bone- and Angiogenic-Related Factors by Monocytes/Macrophages

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