PDLIM2 repression by ROS in alveolar macrophages promotes lung tumorigenesis
Liwen Li, … , Gutian Xiao, Zhaoxia Qu
Liwen Li, … , Gutian Xiao, Zhaoxia Qu
Published February 4, 2021
Citation Information: JCI Insight. 2021;6(5):e144394. https://doi.org/10.1172/jci.insight.144394.
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Research Article Oncology

PDLIM2 repression by ROS in alveolar macrophages promotes lung tumorigenesis

Abstract

One of the most fundamental and challenging questions in the field of cancer is how immunity is transformed from tumor immunosurveillance to tumor-promoting inflammation. Here, we identified the tumor suppressor PDZ-LIM domain–containing protein 2 (PDLIM2) as a checkpoint of alveolar macrophages (AMs) important for lung tumor suppression. During lung tumorigenesis, PDLIM2 expression in AMs is downregulated by ROS-activated transcription repressor BTB and CNC homology 1 (BACH1). PDLIM2 downregulation leads to constitutive activation of the transcription factor STAT3, driving AM protumorigenic polarization/activation and differentiation from monocytes attracted from the circulation to suppress cytotoxic T lymphocytes and promote lung cancer. PDLIM2 downregulation also decreases AM phagocytosis. These findings establish ROS/BACH1/PDLIM2/STAT3 as a signaling pathway driving AMs for lung tumor promotion.

Authors

Liwen Li, Fan Sun, Lei Han, Xujie Liu, Yadong Xiao, Alyssa D. Gregory, Steven D. Shapiro, Gutian Xiao, Zhaoxia Qu

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Figure 2

Cell-intrinsic PDLIM2 restriction of lung recruitment and differentiation of bone marrow–derived monocytes into IMs and AMs during lung tumorigenesis.

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Cell-intrinsic PDLIM2 restriction of lung recruitment and differentiatio...
(A) FACS analysis showing increased lung macrophages (Mac) in urethane-treated PDLIM2mKO mice (n = 8). Absolute numbers of lung macrophages are shown in Supplemental Figure 4A. (B) Tumor examination showing better prevention of lung tumorigenesis in urethane-treated PDLIM2mKO mice by clodronate depletion of macrophages and to a comparable level in WT mice (n ≥ 5). Ctrl, control; Clod, clodronate. The depletion efficiencies of lung macrophages are shown in Supplemental Figure 4B. (C) FACS analysis showing increased percentage of AMs but decreased percentage of IMs among total lung macrophages in urethane-treated PDLIM2mKO mice (n = 3). (D) Experimental schedule of lung tumor induction and adoptive transfer of CFSE-labeled bone marrow–derived monocytes in WT mice. (E) FACS analysis showing increased lung recruitment of the transplanted CFSE-labeled monocytes that were derived from bone marrow cells of PDLIM2mKO mice (n = 3). (F) Experimental schedule of lung tumor induction and adoptive transfer of luciferase-expressing bone marrow cells in WT mice. (G and H) FACS analysis showing increased AM and IM differentiation from the transplanted bone marrow cells of PDLIM2mKO mice expressing luciferase (n = 3). Student’s t test (2 tailed, unpaired) (A, C, E, G, and H) and ordinary 1-way ANOVA (B) were performed, and data represent mean ± SEM. *P < 0.05; **P < 0.01; ns, not statistically significant.