期刊
BLOOD
卷 126, 期 1, 页码 103-112出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-12-617258
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资金
- Deutsche Forschungsgemeinschaft, Germany [ZE 872/3-1]
- DFG [DFG ZE 872/1-2]
- Else Kroner-Fresenius-Stiftung [2013_A04]
- MOTI-VATE stipend (Else Kroner-Fresenius-Stiftung)
- Fulbright Grant (US)
- [SFB 850]
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-1 beta 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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