Dual mechanisms of posttranscriptional regulation of Tet2 by Let-7 microRNA in macrophages

Significance Macrophages function as sentinel cells, constantly monitoring the host environment for bacterial infection. They are activated by bacterial components and then secrete proinflammatory cytokines, such as interleukin (IL)-6. This is one of the body’s most effective weapons for fighting infections but must be rigidly controlled to avoid pathologic overresponse. Many factors have been shown to act as feedback regulators of inflammatory processes. Using both knockout and myeloid cell-specific transgenic mouse models, we report here that a physiological role of the microRNA let-7adf cluster is to promote IL-6 secretion by lipopolysaccharide-activated macrophages through down-regulating Tet2. This microRNA cluster represses Tet2 using two different mechanisms: direct targeting and indirect enhancement of succinate accumulation, a compound that represses Tet2.