The Yin and Yang of microRNAs: leukemia and immunity

Abstract

Yin and Yang are two complementary forces that together describe the nature of real-world elements. Yin is the dark side; Yang is the light side. We describe microRNAs having both Yin and Yang characteristics because they can contribute to normal function (Yang) but also to autoimmunity, myeloproliferation, and cancer (Yin). We have been working on a number of microRNAs that have these dual characteristics and here we focus on two, miR-125b and miR-146a. We have concentrated on these two RNAs because we have very extensive knowledge of them, much of it from our laboratory, and also because they provide a strong contrast: the effects of overexpression of miR-125b are rapid, suggesting that it acts directly, whereas the effects of miR-146a are slow to develop, suggesting that they arise from chronic alterations in cellular behavior.

Fig. 1. Role of miR-125b in hematopoiesis

The figure displays a simplified diagram of the effect of miR-125b on hematopoietic development and immune cell function. (A) miR-125b enhances the repopulation of hematopoietic stem cells (HSCs). (B) miR-125b blocks the transition of common myeloid progenitors (CLPs) to pro-B cells. (C) The development of effector T cells is inhibited by miR-125b. (D) miR-125b drives the activation of macrophages. (E) Ectopic overexpression of miR-125b increases the common myeloid progenitor (CMP) pool.

Fig. 2. Expression of miR-146a is regulated by a set of transcriptional factors in a cell-lineage specific manner, involving such factors as PU.1, c-ETS, and PLZF, and in an activation-dependent manner, involving such factors as NF-κB

Validated targets of miR-146a include Irak1, Traf6, Stat1, and RelB, which are all involved in the NF-κB and STAT pathways, highlighting the role of miR-146a as a critical negative regulator of inflammatory and interferon signaling.

Fig. 3. A simplified schematic depiction of hematopoietic tree highlighting the role of miR-146a in hematopoiesis and immune cell function

(A). miR-146a negatively regulates myelopoiesis and myeloproliferation during inflammation and aging. In the absence of miR-146a, increased myeloproliferation is observed. (B). miR-146a negatively regulates megakaryopoiesis. Overexpression of miR-146a inhibits megakaryocyte proliferation and differentiation, while downregulation of miR-146a promotes megakaryocyte expansion and platelet production. However, in aging miR-146a-deficient mice with bone marrow fibrosis, thrombocytopenia is observed. MiR-146a is a negative regulator of monocyte and macrophage activation (C) and effector T-cell activation (D). (E). In regulatory T cells, miR-146a positively controls Treg functional competence. In the absence of miR-146a, Treg cells are defective in suppressing effector T-cell activation.