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

• Published in: The Journal of clinical investigation Vol. 122; no. 1; pp. 48 - 61
• Main Authors: Yiakouvaki, Anthie, Dimitriou, Marios, Karakasiliotis, Ioannis, Eftychi, Christina, Theocharis, Stamatis, Kontoyiannis, Dimitris L
• Format: Journal Article
• Language: English
• Published: American Society for Clinical Investigation 01-01-2012
• Subjects: Binding proteins; Colorectal cancer; Genetic aspects; Immune response; Physiological aspects; Risk factors; Greece
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI45021.

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. with turnover or promoting destabilization in some of its targets, through synergies with suppressive RBPs, microRNAs, and associated factors (18-22). Overexpression of HuR in mouse macrophages blocks the translation of selective inflammatory mRNAs, suggesting that it could act as negative regulator of pathologic inflammation (19). Furthermore, developmental deletions of HuR in mice demonstrated its involvement in cellular differentiation, maturation, and migration (23-25), potentially also affecting inflammatory responses. Here we aim to clarify the role of HuR in inflammation by genetic ablation in innate immune cells and to uncover its function in macrophage control and migration that is required for the maintenance of inflammatory homeostasis and protection against cancer.