Multinucleated Giant Cells Are Specialized for Complement-Mediated Phagocytosis and Large Target Destruction

Milde, Ronny; Ritter, Julia; Tennent, Glenys A.; Loesch, Andrzej; Martínez, Fernando O.; Gordon, Siamon; Pepys, Mark B.; Verschoor, Admar; Helming, Laura

doi:10.1016/j.celrep.2015.10.065

Cited by 128 publications

(137 citation statements)

References 45 publications

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“…Intriguingly, recent studies detected an extensive system of actin-rich Mac-1ebearing ruffles on the surface of Phorbol 12-myristate 13-acetateeactivated macrophages and MGCs, with latter cells involved in Mac1emediated phagocytosis of large targets. 39 Further studies may help to define the relation between Mac-1emediated adhesion/spreading and formation of actin-based membrane protrusions in macrophage fusion. Consistent with the role of Mac-1 in macrophage fusion, RAW264.7 cells sorted to express the increased density of integrin fused more frequently in the presence of IL-4 than unsorted cells (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

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%

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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“…37 It is possible that a strategy that allows a brief period of inflammation to occur prior to its inhibition would aid in biomaterial integration, like it aids chronic wound healing, 34,38 but this strategy has not been explored. Other drug delivery strategies that have been shown to inhibit the foreign body response to biomaterials include the delivery of a blocking antibody to interleukin-4 (IL4), a cytokine that mediates macrophage fusion into foreign body giant cells in vitro and in vivo, 39,40 although it is important to note that the role of IL4 in the foreign body response remains controversial. 41 Other drug delivery strategies include the delivery of nitric oxide, which promotes angiogenesis and inhibits collagen deposition during wound healing.…”

Section: Temporally Controlled Delivery Of Anti-inflammatory Drugsmentioning

confidence: 99%

Drug delivery strategies to control macrophages for tissue repair and regeneration

Garash

Bajpai

Marcinkiewicz

et al. 2016

Exp Biol Med (Maywood)

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Tissue repair and regeneration is a complex process. Our bodies have an excellent capacity to regenerate damaged tissues in many situations. However, tissue healing is impaired in injuries that exceed a critical size or are exacerbated by chronic inflammatory diseases like diabetes. In these instances, biomaterials and drug delivery strategies are often required to facilitate tissue regeneration by providing physical and biochemical cues. Inflammation is the body's response to injury. It is critical for wound healing and biomaterial integration and vascularization, as long as the timing is well controlled. For example, chronic inflammation is well known to impair healing in chronic wounds. In this review, we highlight the importance of a well-controlled inflammatory response, primarily mediated by macrophages in tissue repair and regeneration and discuss various strategies designed to promote regeneration by controlling macrophage behavior. These strategies include temporally controlled delivery of anti-inflammatory drugs, delivery of macrophages as cellular therapy, controlled release of cytokines that modulate macrophage phenotype, and the design of nanoparticles that exploit the inherent phagocytic behavior of macrophages. A clear outcome of this review is that a deeper understanding of the role and timing of complex macrophage phenotypes or activation states is required to fully harness their abilities with drug delivery strategies.

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“…As part of the foreign body response to an implanted biomaterial, macrophages exhibiting characteristics of both M1 and M2a phenotypes fuse together to form multinucleated giant cells that promote fibrous capsule formation around the implant. 12,13 As a result, the implant is isolated from the rest of the body, thus leading to a lack of biointegration and ultimately failure. 14 Therefore, it is essential to strategically engineer biomaterials that promote or inhibit specific phenotypes of macrophages to restore a balance in their behaviour.…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory effects of octadecylamine-functionalized nanodiamond on primary human macrophages

et al. 2017

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Chronic inflammatory disorders such as rheumatoid arthritis are characterized by excessive pro-inflammatory or “M1” activation of macrophages, the primary cells of the innate immune system. Current treatments include delivery of glucocorticoids (e.g. dexamethasone – Dex), which reduce pro-inflammatory M1 behaviour in macrophages. However, these treatments have many off-target effects on cells other than macrophages, resulting in broad immunosuppression. To limit such side effects, drug-incorporated nano- and microparticles may be used to selectively target macrophages via phagocytosis, because of their roles as highly effective phagocytes in the body. In this study, surface-modified nanodiamond (ND) was explored as a platform for the delivery of dexamethasone to macrophages because of ND’s rich surface chemistry, which contributes to ND’s high potential as a versatile drug delivery platform. After finding that octadecylamine-functionalized nanodiamond (ND-ODA) enhanced adsorption of Dex compared to carboxylated ND, the effects of Dex, ND-ODA, and Dex-adsorbed ND-ODA on primary human macrophage gene expression were characterized. Surprisingly, even in the absence of Dex, ND-ODA had strong anti-inflammatory effects, as determined by multiplex gene expression via NanoString and by protein secretion analysis via ELISA. ND-ODA also inhibited expression of M2a markers yet increased the expression of M2c markers and phagocytic receptors. Interestingly, the adsorption of Dex to ND-ODA further increased some anti-inflammatory effects, but abrogated the effect on phagocytic receptors, compared to its individual components. Overall, the ability of ND-ODA to promote anti-inflammatory and pro-phagocytic behaviour in macrophages, even in the absence of loaded drugs, suggests its potential for use as an anti-inflammatory therapeutic to directly target macrophages through phagocytosis.

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Multinucleated Giant Cells Are Specialized for Complement-Mediated Phagocytosis and Large Target Destruction

Cited by 128 publications

References 45 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

Drug delivery strategies to control macrophages for tissue repair and regeneration

Anti-inflammatory effects of octadecylamine-functionalized nanodiamond on primary human macrophages

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