Dynamic Modulation of Thymic MicroRNAs in Response to Stress

Abstract

BackgroundPhysiological 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.

Histological and Immunohistochemical Study on the Effect of Constant Light Exposure on T Lymphocyte Subsets in the Thymus and Lymph Node of Male Albino Rats

“…Stress has a strong impact on thymopoiesis through the alteration of the expression of microRNA involved in apoptosis, tolerance, and proliferation. Many of these MicroRNA exhibited a different responsiveness in immature versus mature thymocyte subsets [44] . The moderate CD3 expression appeared in the medulla of group II might be due to their resistance to apoptosis and so escaping the negative selection occurred mostly in the medulla.…”

Transgenic Expression of MicroRNA-185 Causes a Developmental Arrest of T Cells by Targeting Multiple Genes Including Mzb1

“…After a 48-h culture period, IL-2 levels were measured using the mouse IL-2 ELISA MAX kit (BioLegend). RNA Analysis-Northern blotting was performed as described previously (9,20). For real-time PCR, RNA was isolated using the Ambion RNAqueous micro kit (Invitrogen) and treated with DNase.…”

“…miR-185 is a stress-responsive miR expressed in the thymus (9). It is encoded on human chromosome 22q11.2 and is haploinsufficient in 22q11.2/DiGeorge syndrome patients (10).…”

“…1A). It is expressed in immature thymocytes, mature CD4 ϩ CD8 Ϫ and CD4 Ϫ CD8 ϩ T cells, and B cells (5,9,21,22). To determine whether miR-185 levels impact T cell functions, we utilized a gain-of-function transgenic approach (23) in which the murine primary miR-185 (pri-miR-185) was overexpressed in thymocytes and peripheral T cells (Fig.…”

Acute Thymic Involution and Mechanisms for Recovery

“…miR-181d, which has analogous and exclusive gene targets similar to those of miR-181a, was strikingly down-regulated during LPSinduced stress. The dysregulation of other modulated miRNAs might alter the T cell repertoire, which could lead to defective formation of naïve T cells (Belkaya et al 2011). Enhanced expression of miR-181a in mature T cells leads to a higher affinity for peptide antigens, whereas decreased expression of this miR in immature T cells results in a lower sensitivity and loss of negative and positive selection.…”