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 5

HuR-null macrophages exhibit increased chemotactic responses and migration profiles.

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HuR-null macrophages exhibit increased chemotactic responses and migrati...
(A) Chemotaxis of control and MKO macrophages, as untreated or treated (plus signs) with RS504393, recombinant CCL2, CXCL12, control (C-MΦ) and MKO (MKO-MΦ) macrophage supernatants or CMT93 epithelial cells (IECs) containing or lacking CCL2 (see also Supplemental Figure 6). Values reflect migrating cells per HPF of transwell membranes. Data are from at least 2 independent experiments, each with 3 replicas per genotype. (B) Numbers of monocytes/macrophages (Mo/MΦ) and PMNs in the peritoneal cavity of control (white circles) and MKO (black circles) mice during aseptic peritonitis. Values were derived from flow cytometric detection of CD11b and Ly6G/Gr1. Graphs depict mean values (±SD) from 3 experiments, each with 3 mice per time point. (C) Detection and quantitation of Mo/MΦ (CD11b+Ly6G–) versus PMNs (CD11b+Ly6G+) in peripheral blood of control and MKO mice following LPS challenge. Representative dot plots from 2 independent experiments are shown. *P < 0.05 versus control; #P < 0.05, RS504393-treated versus untreated control or MKO; †P < 0.05, control versus MKO medium, or cells containing versus lacking CCL2.