MicroRNA-155–deficient dendritic cells cause less severe GVHD through reduced migration and defective inflammasome activation
Blood, The Journal of the American Society of Hematology, 2015•ashpublications.org
The successful treatment of acute leukemias with allogeneic hematopoietic cell
transplantation (allo-HCT) is limited by acute graft-versus-host disease (GVHD). Because
microRNA-155 (miR-155) regulates activation of the innate immune system, we aimed to
determine its function in dendritic cells (DCs) during GVHD in an experimental model. We
observed that miR-155 deficiency of the recipient led to improved survival, reduced serum
levels of proinflammatory cytokines, and lower GVHD histopathology scores. In addition …
transplantation (allo-HCT) is limited by acute graft-versus-host disease (GVHD). Because
microRNA-155 (miR-155) regulates activation of the innate immune system, we aimed to
determine its function in dendritic cells (DCs) during GVHD in an experimental model. We
observed that miR-155 deficiency of the recipient led to improved survival, reduced serum
levels of proinflammatory cytokines, and lower GVHD histopathology scores. In addition …
Abstract
The successful treatment of acute leukemias with allogeneic hematopoietic cell transplantation (allo-HCT) is limited by acute graft-versus-host disease (GVHD). Because microRNA-155 (miR-155) regulates activation of the innate immune system, we aimed to determine its function in dendritic cells (DCs) during GVHD in an experimental model. We observed that miR-155 deficiency of the recipient led to improved survival, reduced serum levels of proinflammatory cytokines, and lower GVHD histopathology scores. In addition, miR-155−/− bone marrow chimeric mice receiving allo-HCT and miR-155−/− DCs showed that miR-155 deficiency in the DC compartment was responsible for protection from GVHD. Activated miR-155−/− DCs displayed lower expression of various purinergic receptors and impaired migration toward adenosine triphosphate (ATP). Microarray analysis of lipopolysaccharide/ATP-stimulated miR-155−/− DCs revealed mitogen-activated protein kinase pathway dysregulation and reduced inflammasome-associated gene expression. Consistent with this gene expression data, we observed reduced ERK activation, caspase-1 cleavage, and IL-1β production in miR-155−/− DCs. The connection between miR-155 and inflammasome activation was supported by the fact that Nlrp3/miR-155 double-knockout allo-HCT recipient mice had no increased protection from GVHD compared with Nlrp3−/− recipients. This study indicates that during GVHD, miR-155 promotes DC migration toward sites of ATP release accompanied by inflammasome activation. Inhibiting proinflammatory miR-155 by antagomir treatment could help reduce this complication of allo-HCT.
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