MicroRNA-148a facilitates inflammatory dendritic cell differentiation and autoimmunity by targeting MAFB.

Yao Meng,Nan Shen,Jun Deng,Zhuojun Liao,Guanhua Li,Jun Li,Qing Sun,Zhihua Yin,Zhizhong Ye,Haibo Zhou,Yuqing Yu,Li Wu,Lu Liu

doi:10.1172/jci.insight.133721

Abstract

Monocyte-derived DCs (moDCs) have been implicated in the pathogenesis of autoimmunity, but the molecular pathways determining the differentiation potential of these cells remain unclear. Here, we report that microRNA-148a (miR-148a) serves as a critical regulator for moDC differentiation. First, miR-148a deficiency impaired the moDC development in vitro and in vivo. A mechanism study showed that MAFB, a transcription factor that hampers moDC differentiation, was a direct target of miR-148a. In addition, a promoter study identified that miR-148a could be transcriptionally induced by PU.1, which is crucial for moDC generation. miR-148a ablation eliminated the inhibition of PU.1 on MAFB. Furthermore, we found that miR-148a increased in monocytes from patients with psoriasis, and miR-148a deficiency or intradermal injection of antagomir-148a immensely alleviated the development of psoriasis-like symptoms in a psoriasis-like mouse model. Therefore, these results identify a pivotal role for the PU.1-miR-148a-MAFB circuit in moDC differentiation and suggest a potential therapeutic avenue for autoimmunity.

Highlights

DCs comprise a heterogeneous family of professional antigen-presenting cells that maintain the homeostasis of the immune system [1,2,3,4]
There was no difference in the number of lymphoid or myeloid cells (Supplemental Figure 2, B and D), indicating that miR-148a was dispensable for hematopoietic differentiation in the steady state
The differentiation of monocytes to DCs results in a rapid increase of PU.1, achieving high levels that precede the phenotypic changes, while MAFB expression is decreased during the differentiation

Summary

Introduction

DCs comprise a heterogeneous family of professional antigen-presenting cells that maintain the homeostasis of the immune system [1,2,3,4]. Two major subsets of conventional DCs (cDCs) have been characterized in the mouse nonlymphoid tissues, CD103+CD11b– cDCs and CD103–CD11b+ cDCs, whereas the epidermis contains Langerhans cells. An increased frequency and activation status of plasmacytoid DCs (pDCs), a potent type I IFN-producing DC subset, have been documented in early psoriatic lesions [8, 9]. Both cDCs and pDCs originate from DC precursors in a Fms-related tyrosine kinase 3 ligand (Flt3L)–dependent manner, whereas the generation of moDCs is GM-CSF dependent [1, 2]

Methods

Results

Conclusion