The homeobox transcription factor VentX controls human macrophage terminal differentiation and proinflammatory activation
Xiaoming Wu, … , Roger W. Giese, Zhenglun Zhu
Xiaoming Wu, … , Roger W. Giese, Zhenglun Zhu
Published June 13, 2011
Citation Information: J Clin Invest. 2011;121(7):2599-2613. https://doi.org/10.1172/JCI45556.
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Research Article Immunology

The homeobox transcription factor VentX controls human macrophage terminal differentiation and proinflammatory activation

Abstract

Macrophages are critical players in both innate and adaptive immunity. While the exogenous signaling events leading to the terminal differentiation of macrophages from monocytes have been studied extensively, the underlying intracellular transcriptional mechanisms remain poorly understood. Here we report that the homeobox transcription factor VentX plays a pivotal role in human macrophage terminal differentiation and proinflammatory function. Our study showed that VentX expression was upregulated upon human primary monocyte-to-macrophage differentiation induced by cytokines such as M-CSF, GM-CSF, and IL-3. Moreover, ablation of VentX expression in primary monocytes profoundly impaired their differentiation to macrophages, and ectopic expression of VentX in a myeloid progenitor cell line triggered its differentiation with prominent macrophage features. Further analysis revealed that VentX was pivotal for the proinflammatory response of terminally differentiated macrophages. Mechanistically, VentX was found to control expression of proteins key to macrophage differentiation and activation, including M-CSF receptor. Importantly, preliminary analysis of gene expression in leukocytes from patients with autoimmune diseases revealed a strong correlation between levels of VentX and those of proinflammatory cytokines. Our results provide mechanistic insight into the crucial roles of VentX in macrophage differentiation and proinflammatory activation and suggest that dysregulation of VentX may play a role in the pathogenesis of autoimmune diseases.

Authors

Xiaoming Wu, Hong Gao, Weixiong Ke, Roger W. Giese, Zhenglun Zhu

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Figure 4

VentX promotes macrophage differentiation of U937 cells.

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VentX promotes macrophage differentiation of U937 cells. U937 cell lines...
U937 cell lines conditionally expressing GFP or GFP.VentX under the control of a tetracycline-inducible promoter were treated with 1.0 μg/ml DOX for 72 hours. (A) FACS analysis of monocyte/macrophage surface markers CD14, CD11b, and CD11c. (B) Effects of VentX expression on morphogenesis and adhesion of U937 cells. Upper panel: Cells were photographed using phase contrast microscopy. The percentage of adherent cells was calculated by methods of trypsinization and counting both floating and adherent fractions of cells: GFP, <0.1%; GFP.VentX, 35.3% ± 5.0%. Cells showing pseudopodia were counted as cells with morphological change: GFP, <0.1%; GFP.VentX, 28.9% ± 3.7%. Lower panel: Wright-Giemsa staining of DOX-treated U937 cells. Original magnification, ×200.