title: Dynamic modulation of thymic microRNAs in response to stress.
abstract: Physiological stress evokes rapid changes in both the innate and adaptive immune response. Immature αβ T cells developing in the thymus are particularly sensitive to stress, with infections and/or exposure to lipopolysaccharide or glucocorticoids eliciting a rapid apoptotic program. MicroRNAs are a class of small, non-coding RNAs that regulate global gene expression by targeting diverse mRNAs for degradation. We hypothesized that a subset of thymically encoded microRNAs would be stress responsive and modulate thymopoiesis. We performed microRNA profiling of thymic microRNAs isolated from control or stressed thymic tissue obtained from mice. We identified 18 microRNAs that are dysregulated >1.5-fold in response to lipopolysaccharide or the synthetic corticosteroid dexamethasone. These included the miR-17-90 cluster, which have anti-apoptotic functions, and the miR-181 family, which contribute to T cell tolerance. The stress-induced changes in the thymic microRNAs are dynamically and distinctly regulated in the CD4(-)CD8(-), CD4(+)CD8(+), CD4(+)CD8(-), and CD4(-)CD8(+) thymocyte subsets. Several of the differentially regulated murine thymic miRs are also stress responsive in the heart, kidney, liver, brain, and/or spleen. The most dramatic thymic microRNA down modulated is miR-181d, exhibiting a 15-fold reduction following stress. This miR has both similar and distinct gene targets as miR-181a, another member of miR-181 family. Many of the differentially regulated microRNAs have known functions in thymopoiesis, indicating that their dysregulation will alter T cell repertoire selection and the formation of naïve T cells. This data has implications for clinical treatments involving anti-inflammatory steroids, ablation therapies, and provides mechanistic insights into the consequences of infections.
authors: The Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors: Serkan
authors: S
authors: Belkaya
authors: Robert L
authors: RL
authors: Silge
authors: Ashley R
authors: AR
authors: Hoover
authors: Jennifer J
authors: JJ
authors: Medeiros
authors: Jennifer L
authors: JL
authors: Eitson
authors: Amy M
authors: AM
authors: Becker
authors: M Teresa
authors: MT
authors: de la Morena
authors: Rhonda S
authors: RS
authors: Bassel-Duby
authors: Nicolai S C
authors: NS
authors: van Oers
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D009928:Organ Specificity; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics*; D060168:Thymocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D013997:Time Factors; D059467:Transcriptome / Q000187:drug effects
chemical_list: D016827:CD8 Antigens; D053605:Leukemia Inhibitory Factor; D008070:Lipopolysaccharides; D035683:MicroRNAs; D003907:Dexamethasone; D008156:Luciferases