<i>miR-146a</i> – <i>Traf6</i> regulatory axis controls autoimmunity and myelopoiesis, but is dispensable for hematopoietic stem cell homeostasis and tumor suppression

Abstract

<i>microRNA-146a</i> (<i>miR-146a</i>) has been previously implicated as an essential molecular brake, preventing immune overreaction and malignant transformation by attenuating NF-κB signaling, putatively via repression of the <i>Traf6</i> and <i>Irak1</i> genes. The exact contribution of <i>miR-146a</i>-mediated silencing of these genes to the control of immune activation is currently unknown. Therefore, we defined the role of the <i>miR-146a</i>-<i>Traf6</i> signaling axis in the regulation of immune homeostasis using a genetic epistasis analysis in <i>miR-146a</i>^<i>-/-</i> mice. We have uncovered a surprising separation of functions at the level of miR-146a targets. Lowering the <i>Traf6</i> gene dose and consequent attenuation of NF-κB activation rescued several significant <i>miR-146a</i>^<i>-/-</i> phenotypes, such as splenomegaly, aberrant myeloproliferation, and excessive inflammatory responses. In contrast, decreasing <i>Traf6</i> expression had no effect on the development of the progressive bone marrow failure phenotype, as well as lymphomagenesis in <i>miR-146a</i>^<i>-/-</i> mice, indicating that miR-146a controls these biological processes through different molecular mechanisms.