Abstract
IL-10-producing regulatory B (IL-10+ Breg) cells promote tolerance in autoimmune diseases and transplantation. However, it remains unclear whether microRNAs are involved in the development of IL-10+ Breg cells. Here, we found that microRNA-21 (miR-21) acts as an upstream regulator of IL-10 by targeting the 3' untranslated region of IL-10 mRNA. We also demonstrated that IL-10+ Breg cells exhibit lower miR-21 expression than non-Breg cells and that miR-21 acts as a potent negative regulator of the differentiation of IL-10+ Breg cells. Accordingly, specific inhibition of miR-21 using antisense oligonucleotides markedly promoted B cell IL-10 expression. Thus, IL-10 is a direct target of miR-21. Moreover, silencing of miR-21 significantly alleviated the severity of experimental autoimmune encephalomyelitis (EAE), and this change was associated with an increase in the number of IL-10+ Breg cells. Finally, we demonstrated that miR-21-silenced B cells exert their suppressive activity through effector T cells in an IL-10-dependent manner.Thus, we characterized a B cell-intrinsic microRNA pathway that inhibits the differentiation of IL-10+ Breg cells and promotes autoimmunity. miR-21 silencing therefore represents a new therapeutic strategy for the treatment of autoimmune diseases.
Highlights
IntroductionMicroRNAs (miRNAs) are small (~22-nucleotide) non-coding RNAs that regulate gene expression through translational repression and mRNA degradation [1]
MicroRNAs are small (~22-nucleotide) non-coding RNAs that regulate gene expression through translational repression and mRNA degradation [1]. miRNAs can recognize their target mRNAs via a ‘seed region’, which consists of the 2nd through 8th nucleotides of the miRNA.MiRNAs play important roles in many biological processes, including hematopoietic development, immunity, and carcinogenesis
For efficient analysis of mouse miR-21 expression, CD19+ B and CD4+ T cells were purified from the splenocytes of EAE mice at the disease-onset stage by magnetic-activated cell sorting (MACS, StemCell) for quantitative reverse transcription (RT) PCR analysis
Summary
MicroRNAs (miRNAs) are small (~22-nucleotide) non-coding RNAs that regulate gene expression through translational repression and mRNA degradation [1]. MiRNAs play important roles in many biological processes, including hematopoietic development, immunity, and carcinogenesis. The term ‘oncomiRs’ refers to a series of specific miRNAs that function as oncogenes or tumor suppressor genes. OncomiR miRNA-21 (miR21) has been found to be significantly overexpressed in tumors, such as breast, lung, colon, gastric and pancreatic cancers [3]. Another target of miR-21 is PTEN, which is a known tumor suppressor [4]. MiR-21 plays an important role in tumor development
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