Foreign body-type multinucleated giant cells induced by interleukin-4 express select lymphocyte co-stimulatory molecules and are phenotypically distinct from osteoclasts and dendritic cells

Abstract

Foreign body-type multinucleated giant cells (FBGC), formed by macrophage fusion, are a prominent cell type on implanted biomaterials, although the roles they play at these and other sites of chronic inflammation are not understood. Why lymphocytes are present in this scenario and the effects of fusing macrophages/FBGC on subsequent lymphocyte responses are also unclear. To address the physiological significance of FBGC in this regard, we employed our in vitro system of interleukin (IL)-4-induced human monocyte-derived macrophage fusion/FBGC formation. Initially, we pursued the identities of lymphocyte co-stimulatory molecules on fusing macrophages/FBGC. In addition, we further compared the FBGC phenotype to that currently associated with osteoclasts and dendritic cells using recognized markers. Immunoblotting of cell lysates and immunochemistry of macrophages/FBGC in situ, revealed that IL-4-induced macrophages/FBGC strongly express HLA-DR, CD98, B7-2 (CD86), and B7-H1 (PD-L1), but not B7-1 (CD80) or B7-H2 (B7RP-1). Furthermore, molecules currently recognized to be expressed on osteoclasts (calcitonin receptor, tartrate-resistant acid phosphatase, RANK) or dendritic cells (CD1a, CD40, CD83, CD95/fas) are undetectable. In contrast, fusing macrophages/FBGC strongly express the macrophage markers αX integrin (CD11c), CD68, and dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), whereas CD14 is completely down-modulated with IL-4-induced macrophage fusion. These novel data demonstrate that IL-4-induction of macrophage multinucleation/FBGC formation features the acquisition of a CD14-negative phenotypic profile which is distinguishable from that of dendritic cells and osteoclasts, yet potentially exhibits multiple capacities for lymphocyte interactions with resultant lymphocyte down-modulation.

Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs

“…For example, fusion of macrophages results in the formation of multinucleated giant cells (MNGs), which is a typical feature of granulomatous inflammation and foreign body reactions. [94][95][96][97][98] Moreno et al found that IL-4 induces MNG generation in a STAT6-dependent manner by regulating the expression of at least 2 fusion mediators, E-cadherin and DC-STAMP, resulting in homotypic macrophage fusion and engulfment of large foreign bodies. 99 In addition TREM-2 and its signaling association partner DAP12 are required for IL-4-induced E-cadherin and DC-STAMP expression, and giant cell formation in vitro and in vivo.…”

Orthokeratinized odontogenic cyst associated with multinucleated giant cell reaction: report of unusual findings

“…Nevertheless, some reports have shown painful symptomatology associated with secondary infection [7][8] , and extension between 1 and 3 centimeters. However, cases of large dimensions have been reported 5,7 , as in the case here reported, the size of which at the largest diameters was 10.3 centimeters, covering the region from the premolars up to the body of the mandible.…”

“…Radiographically, OOCs present as well-delimited, and predominantly unilocular radiolucent lesions 2,5,8 that may be associated with the crown of an impacted tooth. It is frequently confused with the dentigerous cyst or with KOT 2,8 .…”

“…It is frequently confused with the dentigerous cyst or with KOT 2,8 . The case reported here differed from those in the reports found in the literature, relative to its extensive size and expansive radiolucent aspect, with the presence of radiopaque regions within it, and with the aspect of possible rupture of the cortical bone, which could make a differential diagnosis with the calcifying epithelial odontogenic tumor and ameloblastic fibroma-odontoma 11 .…”

“…Their treatment consists of marsupialization or surgical enucleation 2,7 . These lesions show a low level of aggressiveness and tendency towards recurrence at a rate lower than 4% 2,8 .…”