Myeloid cell expression of the RNA-binding protein HuR protects mice from pathologic inflammation and colorectal carcinogenesis
Anthie Yiakouvaki, … , Stamatis Theocharis, Dimitris L. Kontoyiannis
Anthie Yiakouvaki, … , Stamatis Theocharis, Dimitris L. Kontoyiannis
Published December 27, 2011
Citation Information: J Clin Invest. 2012;122(1):48-61. https://doi.org/10.1172/JCI45021.
View: Text | PDF
Research Article

Myeloid cell expression of the RNA-binding protein HuR protects mice from pathologic inflammation and colorectal carcinogenesis

Abstract

The innate immune response involves a variety of inflammatory reactions that can result in inflammatory disease and cancer if they are not resolved and instead are allowed to persist. The effective activation and resolution of innate immune responses relies on the production and posttranscriptional regulation of mRNAs encoding inflammatory effector proteins. The RNA-binding protein HuR binds to and regulates such mRNAs, but its exact role in inflammation remains unclear. Here we show that HuR maintains inflammatory homeostasis by controlling macrophage plasticity and migration. Mice lacking HuR in myeloid-lineage cells, which include many of the cells of the innate immune system, displayed enhanced sensitivity to endotoxemia, rapid progression of chemical-induced colitis, and severe susceptibility to colitis-associated cancer. The myeloid cell–specific HuR-deficient mice had an exacerbated inflammatory cytokine profile and showed enhanced CCR2-mediated macrophage chemotaxis. At the molecular level, activated macrophages from these mice showed enhancements in the use of inflammatory mRNAs (including Tnf, Tgfb, Il10, Ccr2, and Ccl2) due to a lack of inhibitory effects on their inducible translation and/or stability. Conversely, myeloid overexpression of HuR induced posttranscriptional silencing, reduced inflammatory profiles, and protected mice from colitis and cancer. Our results highlight the role of HuR as a homeostatic coordinator of mRNAs that encode molecules that guide innate inflammatory effects and demonstrate the potential of harnessing the effects of HuR for clinical benefit against pathologic inflammation and cancer.

Authors

Anthie Yiakouvaki, Marios Dimitriou, Ioannis Karakasiliotis, Christina Eftychi, Stamatis Theocharis, Dimitris L. Kontoyiannis

×

Figure 7

HuR targets specific UTR domains to limit the inducible use of cytokine/chemokine mRNAs.

Options: View larger image (or click on image) Download as PowerPoint
HuR targets specific UTR domains to limit the inducible use of cytokine/...
(A) Identification of 3′UTR domains from Ccl2 and Ccr2 mRNAs binding to HuR. RNA-EMSA with 32P-labeled RNA probes containing fragments of Ccl2, Ccr2, and Tnf 3′UTRs in the presence of increasing quantities of recombinant GST-HuR. Protected fragments and free probes are indicated. (B) Representative quantitation of HuR binding to the RNA probes presented in A. Percentages of radiolabeled probe in complex with HuR was determined and expressed as a percentage of the total (shifted added to free). (C) Bone marrow cells from control, MKO, and Tg632+ mice were transduced with UTR sensor constructs. Untreated or LPS-treated BMDMs were analyzed by flow cytometry. Shown are percentages of GFP+ cells in F4/80+ macrophages (left) and mean fluorescence intensities of these cells (right). (D) Enumeration of GFP+ macrophages as percentages and fluorescence values from control (white bars), MKO (black bars), and Tg632+ (gray bars) macrophages compiled from 2–3 experiments. *P < 0.05 versus untreated; #P < 0.05 versus control; †P < 0.05 versus untreated controls. (E) Effect of transient HA-HuR expression in MEFs containing UTR sensors. Shown are cytometric histograms depicting GFP levels as mean fluorescence intensity values from control and MKO MEFs bearing pEBB-HAHuR or control plasmids.