IL-4 promotes the formation of multinucleated giant cells from macrophage precursors by a STAT6-dependent, homotypic mechanism: contribution of E-cadherin.
Multinucleated giant cells (MNG) are central players in the inflammatory response to foreign materials and in adverse responses to implants. IL-4 promotes the formation of MNG from bone marrow-derived precursors in vitro and participates in the development of the foreign body reaction in vivo. Therefore, we investigated the mechanism by which IL-4 promotes formation of MNG and engulfment of foreign bodies. We found that generation of MNG cells by IL-4 was dependent on cell density and expression of STAT6; macrophages derived from STAT6(-/-) mice were unable to form MNG in response to IL-4. No soluble factors including CCL2 or supernatants from IL-4-treated macrophages compensated for the lack of MNG cells in STAT6(-/-) cultures. We found that IL-4 must remain present during the full differentiation process and that STAT6(+/+) macrophage precursors retained their ability to differentiate into MNG over time. These MNG were able to internalize large particles efficiently, and the mononuclear STAT6(-/-) macrophages were unable to do so. Furthermore, we found that IL-4 induced expression of E-cadherin and dendritic cell-specific transmembrane protein in a STAT6-dependent manner. E-cadherin expression was critical for the formation of MNG cells by IL-4; an anti-E-cadherin antibody prevented the formation of large MNG. In addition, we found that STAT6(-/-) progenitors failed to fuse with STAT6(+/+), revealing the need for a homotypic interaction. Thus, IL-4 promotes the formation of MNG in a STAT6-dependent manner by regulating cell surface expression of E-cadherin, leading to homotypic cell fusion and the incorporation of large foreign bodies.
Moreno
Jose L
JL
Department of Orthopedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Mikhailenko
Irina
I
Tondravi
Mehrdad M
MM
Keegan
Achsah D
AD
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects; D015820:Cadherins / Q000378:metabolism*; D002452:Cell Count; D002459:Cell Fusion; D002478:Cells, Cultured; D005260:Female; D005547:Foreign Bodies; D015726:Giant Cells / Q000166:cytology* / Q000187:drug effects; D015847:Interleukin-4 / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects*; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D010587:Phagocytosis / Q000187:drug effects; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D013997:Time Factors
D015820:Cadherins; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4