Stage-specific regulation of natural killer cell homeostasis and response against viral infection by microRNA-155

Abstract

Natural killer (NK) cells function in the recognition and destruction of host cells infected with pathogens. Many regulatory mechanisms govern the potent responses of NK cells, both at the cellular and molecular level. Ablation of microRNA (miRNA) processing enzymes demonstrated that miRNAs play critical roles in NK cell differentiation and function; however, the role of individual miRNAs requires further investigation. Using mice containing a targeted deletion of microRNA-155 (miR-155), we observed defects in NK cell maintenance and maturation at steady state, as well as in homeostatic proliferation in lymphopenic mice. In addition, we discovered that miR-155 is up-regulated in activated NK cells during mouse cytomegalovirus (MCMV) infection in response to signals from the proinflammatory cytokines IL-12 and IL-18 and through signal transducer and activator of transcription 4 (STAT4) signaling. Although miR-155 was found to be dispensable for cytotoxicity and cytokine production when triggered through activating receptors, NK cells lacking miR-155 exhibited severely impaired effector and memory cell numbers in both lymphoid and nonlymphoid tissues after MCMV infection. We demonstrate that miR-155 differentially targets Noxa and suppressor of cytokine signaling 1 (SOCS1) in NK cells at distinct stages of homeostasis and activation. NK cells constitutively expressing Noxa and SOCS1 exhibit profound defects in expansion during the response to MCMV infection, suggesting that their regulation by miR-155 promotes antiviral immunity.

Natural killer cell memory in infection, inflammation and cancer

“…Using ZBTB32-deficient mice, it was demonstrated that ZBTB32 facilitated proliferation by counteracting the anti-proliferative factor BLIMP1 (also known as PRDM1) 57 . In addition, NK cells lacking the microRNA miR-155 exhibited severely reduced effector and memory cell numbers after MCMV infection 58 . Although the genes encoding the known receptors expressed by NK cells do not require rearrangement, NK cells lacking RAG showed impaired expansion and persistence after MCMV infection, suggesting an important role for RAG in the optimal generation of MCMV-specific memory NK cells 59 .…”

NKp46‐mediated Dicer1 inactivation results in defective NK‐cell differentiation and effector functions in mice

“…Furthermore, the differentiation defect observed in miR15a/16-1 is phenocopied by cMyb overexpression and partially corrected upon cMyb knockdown [33]. In contrast, an increase in mature "NK-cell" numbers was reported in miR-155 −/− mice, but the relevant targets were not identified [34]. This underlines the pleiotropic role of microRNAs and suggests that more microRNA-target mRNA interactions are still to be discovered.…”

“…Suppressors of cytokine signaling 1 (SOCS1) negatively regulates this pathway. In addition, it is also a well-acknowledged miR-155 target in immune cells [34,37]. Indeed, miR-155Tg NK cells present an increased response to IL-2 [38] and miR-155 −/− Treg a defective one [39].…”

Down-Regulation of miR-141 Induced by Helicobacter Pylori Promotes the Invasion of Gastric Cancer by Targeting STAT4

“…Hirofumi et al postulated that miR-141 was a potential metastasis inhibitor in renal cancer and reported that upregulation of miR-141 inhibited migration of cancer cells. They demonstrated that miR-141 induced dysregulation of genes related to migration and invasion, including ZEB1 [17]. It was indicated that miR-141 was likely to have a number of targets through which it regulated biological functions on cancer cells.…”