Τίτλος:
Myeloid cell expression of the RNA-binding protein HuR protects mice from pathologic inflammation and colorectal carcinogenesis
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Συγγραφείς:
Yiakouvaki, A.
Dimitriou, M.
Karakasiliotis, I.
Eftychi, C.
Theocharis, S.
Kontoyiannis, D.L.
Περιοδικό:
JOURNAL OF CLINICAL INVESTIGATION
Λέξεις-κλειδιά:
chemokine receptor CCR2; cytokine; HuR protein; interleukin 10; messenger RNA; monocyte chemotactic protein 1; transforming growth factor beta; tumor necrosis factor, animal cell; animal experiment; animal model; animal tissue; article; bone marrow cell; cancer susceptibility; carcinogenesis; cell lineage; cell migration; chemotaxis; colitis; colorectal cancer; controlled study; cytokine production; disease association; disease course; disease exacerbation; endotoxemia; homeostasis; human; human cell; inflammation; innate immunity; macrophage; mouse; neoplasm; nonhuman; pathology; posttranscriptional gene silencing; priority journal; RNA translation; sensitivity analysis, Animals; Colitis; Colorectal Neoplasms; Cytokines; Disease Progression; DNA-Binding Proteins; Endosomal Sorting Complexes Required for Transport; Endotoxemia; Hu Paraneoplastic Encephalomyelitis Antigens; Immunity, Innate; Inflammation; Inflammation Mediators; Macrophage Activation; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Myeloid Cells; RNA Processing, Post-Transcriptional; RNA, Messenger; Signal Transduction; Transcription Factors
