Short-lived myeloid cell lifespan is regulated by a long non-coding RNA

Abstract

Abstract Neutrophils, eosinophils and “classical” monocytes collectively account for ~70% of blood leukocytes and are among the shortest-lived cells in the body. Precise regulation of the short lifespan of these myeloid cells is critical to maintain effective host responses to pathogens while minimizing the deleterious consequences of prolonged inflammation. However, how the lifespan of these cells is strictly controlled remains largely unknown. We identified a novel long non-coding RNA (lncRNA) that is highly and specifically expressed by neutrophils, eosinophils and “classical” monocytes in response to pro-survival cytokines. Ablation of this lncRNA in mice leads to a dramatic reduction in the survival of these myeloid cells, rendering these animals highly susceptible to bacterial infection and resistant to the development of immunopathology. To control the lifespan of these cells, this lncRNA epigenetically regulates the transcription of its neighboring pro-apoptotic gene in an allele-specific manner. Thus, in these highly inflammatory cells, changes in levels of this lncRNA provide a locus-specific regulatory mechanism that allows for rapid and dynamic control of apoptosis in response to extracellular signals. In concordance, expression of this lncRNA is significantly elevated in eosinophils from human patients with hypereosinophilic disorders, which are characterized by high plasma levels of the pro-survival cytokine IL-5. Our results indicate that locus-specific regulation of gene expression by lncRNAs is a powerful mechanism by which environmental cues are integrated to achieve optimal immune cell homeostasis. Moreover, this lncRNA may represent a potential therapeutic target for several inflammatory disorders.