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.
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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

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Figure 2

Myeloid deletion of HuR augments the severity and the chronicity of inflammation in a model of inflammatory bowel disease.

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Myeloid deletion of HuR augments the severity and the chronicity of infl...
(A) Macroscopic DAI (left) and histopathological evaluation of intestinal sections (right) after 2 rounds of DSS administration (arrows) in control and MKO mice. Line graphs depict mean values ± SD. n = 18–23 mice per group. *P ≤ 0.05 for higher MKO values. **P ≤ 0.05 for lower MKO values. (B) Representative histology of colonic tissue from control and MKO mice between days 3 and 60 of the DSS protocol, indicating the rapid induction of inflammation in the acute phase and its persistence after day 50. Photomicrographs of paraffin-embedded sections stained with H&E or DAB/hematoxylin. Original magnification, ×100. (C) Left: Detection of macrophage infiltrates in acute (Days 2–10) and chronic resolving phases (Day 60) of DSS-induced colitis via the detection of CD68+ macrophage marker in sections from control and MKO mice treated with DSS. Nuclear DAPI staining indicates tissue organization. Original magnification, ×100. Right: Immunohistochemical detection of macrophage-HuR content in cryostat sections from inflamed control and MKO colons via detection of CD68 (red), HuR (green), and DAPI (blue) stainings. Original magnification, ×200 (insets ×400). (D) Detection of inflammatory molecules in inflamed colons from control and MKO mice either as secreted proteins from cultured organ cultures and ELISA or as mRNAs in extracts and qRT-PCR.