IFN regulatory factor–8 expression in macrophages governs an antimetastatic program
Danielle Y.F. Twum, … , Michael J. Nemeth, Scott I. Abrams
Danielle Y.F. Twum, … , Michael J. Nemeth, Scott I. Abrams
Published February 7, 2019
Citation Information: JCI Insight. 2019;4(3):e124267. https://doi.org/10.1172/jci.insight.124267.
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Categories: Research Article Immunology Oncology

IFN regulatory factor–8 expression in macrophages governs an antimetastatic program

Abstract

High macrophage infiltration in cancer is associated with reduced survival in animal models and in patients. This reflects a shift in the macrophage response from a tumor-suppressive to tumor-supportive program governed by transcriptional events regulated by the inflammatory milieu. Although several transcription factors are known to drive a prometastatic program, those that govern an antimetastatic program are less understood. IFN regulatory factor-8 (IRF8) is integral for macrophage responses against infections. Using a genetic loss-of-function approach, we tested the hypothesis that IRF8 expression in macrophages governs their capacity to inhibit metastasis. We found that: (a) metastasis was significantly increased in mice with IRF8-deficient macrophages; (b) IRF8-deficient macrophages displayed a program enriched for genes associated with metastasis; and (c) lower IRF8 expression correlated with reduced survival in human breast and lung cancer, as well as melanoma, with high or low macrophage infiltration. Thus, a macrophagehiIRF8hi signature was more favorable than a macrophagehiIRF8lo signature. The same held true for a macrophageloIRF8hi vs. a macrophageloIRF8lo signature. These data suggest that incorporating IRF8 expression levels within a broader macrophage signature or profile strengthens prognostic merit. Overall, to our knowledge, our findings reveal a previously unrecognized role for IRF8 in macrophage biology to control metastasis or predict outcome.

Authors

Danielle Y.F. Twum, Sean H. Colligan, Nicholas C. Hoffend, Eriko Katsuta, Eduardo Cortes Gomez, Mary Lynn Hensen, Mukund Seshadri, Michael J. Nemeth, Scott I. Abrams

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Figure 1

Conditional deletion of IRF8 does not impair myelopoiesis.

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Conditional deletion of IRF8 does not impair myelopoiesis. (A) Flow cyto...
(A) Flow cytometry plots of cell surface CD11b and F4/80 expression by M-CSF–generated BM-derived macrophages (BMDMs) from C57BL/6-derived WT or IRF8-cKO mice. (B) Intracellular flow cytometric analysis of IRF8 expression by BMDMs from A, incubated with vehicle or IFN-γ (100 U/ml) or IL-4 (20ng/ml) for 24 hours. Data shown as mean fluorescence intensity (MFI) (n = 3 biologic replicates). (C) Flow cytometry plots of CD11c+F4/80+ macrophages from a bronchial alveolar lavage (BAL) of WT or IRF8-cKO mice, as in A. (D) Intracellular flow cytometric analysis of IRF8 expression by BAL-derived macrophages from C, incubated with vehicle or IFN-γ (100 U/ml) for 24 hours. Data shown as MFI (n = 5–6 biologic replicates). (E) iNOS or Arg1 mRNA levels by BMDMs from A incubated with vehicle or IFN-γ (100 U/ml) or IL-4 (1 ng/ml) for 24 hours. (F) Percentages of monocytes in peripheral blood from WT (IRF8fl/fl) or IRF8-cKO mice. (G) Percentages of CD11b+F4/80+ macrophages in spleens from WT (IRF8fl/fl) or IRF8-cKO mice. (H) Percentages of the indicated progenitors of WT or IRF8-cKO mice. n = 6 mice for each group pooled from 2 separate experiments for panels F–H. No significant differences were observed between WT and IRF8-cKO mice for all parameters examined in H. Data represent mean ± SEM, and statistical significance was determined by a 2-tailed Mann-Whitney U test. *P < 0.05.