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.

Conditional Knockout of the RNA-Binding Protein HuR in CD4+ T Cells Reveals a Gene Dosage Effect on Cytokine Production

“…By using a myeloid-specific HuR knockout mouse, the authors showed that macrophages deficient in HuR had increased expression of many cytokines, including those that are regulated by HuR. Additionally, these mice developed colitis-associated cancer, further supporting the notion that normal HuR expression is required for homeostasis (58). Taken together, both our data and data from other labs indicate that the effect of a HuR knockout in complex animal models differs from cell lines.…”

Arid5a controls IL-6 mRNA stability, which contributes to elevation of IL-6 level in vivo

“…In contrast, the role of RNA binding proteins in stabilization of IL-6 mRNA is not clearly understood. Although HuR, a member of Hu family, is known as a stability protein, which recognizes AREs of the 3′ UTR of cytokine mRNAs through RRMs (24,26), the role of HuR on the regulation of IL-6 mRNA stability remains unresolved, as it has been recently reported that IL-6 mRNA levels are elevated in HuR-deficient ( −/− ) nonstimulated macrophages compared with those of WT (27).…”

HuR Enhances Early Restitution of the Intestinal Epithelium by Increasing Cdc42 Translation

“…Although constitutive HuR inactivation in vivo is lethal to embryos (5), tissue-specific conditional HuR knockout mice have proven a useful tool to investigate the in vivo functions of HuR under biological and pathological conditions. It has been reported that myeloid deletion of HuR exacerbates the production of proinflammatory cytokines and increases the sensitivity to acute inflammatory reactions such as endotoxemia (25), whereas HuR deletion in germ cells leads to male but not female sterility (26). HuR is crucial for the maintenance of hematopoietic stem cells (27), the selection and chemotaxis of T cells (24), and B-cell development and activation/differentiation following an antigen encounter (28).…”