MicroRNA Regulation of Immune Cell Development and Function

Abstract SCI-31

The NF-kappa B pathway is a central mediator of inflammation and plays an important role in myeloid cell development. During activation of macrophages by LPS, three microRNAs (miRNAs) were initially identified as being upregulated in an NF-kappa B dependent manner. Subsequent efforts to characterize two of these miRNAs, namely miR-155 and miR-146a, have revealed important roles not only in inflammation but also in hematopoietic development. Curiously, these two miRNAs seem to play opposing roles in promoting immune cell and progenitor proliferation, and the phenotypes induced in gain and loss-of-function contexts will be discussed in detail. Specifically, miR-155 overexpression and miR-146a deficiency lead to myeloid proliferations with pathologic consequences. These differential roles are largely explained by the targets of these microRNAs, which include signal transduction regulators: SHIP1 and SOCS1 in the case of miR-155, and TRAF6 and IRAK1 in the case of miR-146a. The roles of these miRNAs as effector and feedback regulator of the NF-kappa B pathway, respectively, will be discussed in the context of myeloid development. More broadly, these studies, as well as studies of miRNAs in B-cell development, have revealed that understanding miRNA roles in these processes will illuminate new aspects of biology and pathology. For example, the regulation of hematopoietic development by these miRNAs has revealed important interconnections between pathways that previously may have been considered disparate. Moreover, these studies have begun to underscore the importance of identifying specific targets of a miRNA in a given physiologic or pathologic context.