Nature子刊再登我司基因工程小鼠

我司为上海交大医学院上海市免疫学研究所王宏林教授课题组构建了MicroRNA-31转基因小鼠和Gprc5a条件敲除小鼠，相关研究成果同时在线发表在《Nature》子刊《Nature Communications》（影响因子11.47）上。这两篇论文分别揭示了微小RNA(microRNA, miR)-31在多发性硬化和银屑病发生发展中的作用及其分子机制，为自身免疫性疾病的治疗提供重要理论基础。

在CD4+ T 细胞中条件性剔除 miR-31，可以促进多发性硬化的小鼠模型外周调节性T细胞的产生，进而减缓多发性硬化病的发生发展。进一步的研究表明，miR-31 通过靶向 G蛋白偶联受体家族中的Gprc5a的 3‘UTR 区域发挥其生物学作用。Gprc5a 缺失会影响诱导性调节性T细胞的形成，并且会加重多发性硬化病的发生发展，研究提出miR-31可以通过靶向Gprc5a负向调节外周调节性T细胞的分化。这一发现揭示了表观遗传调控调节性T细胞的新机制，可能为包括多发性硬化病在内的自身免疫性疾病的临床治疗提供新的靶标。

      在另一项研究中发现miR-31也是银屑病治疗的潜在靶点。在银屑病病人和银屑病小鼠模型中，表皮中高度活化的NF- B信号分子促进角质形成细胞中miR-31的转录进而使之呈现高表达，高表达的miR-31直接靶向作用于细胞周期负向调控元件Ppp6c，导致角质形成细胞分裂加快进而过度增殖，从而促进了银屑病皮损区域表皮增生的病理过程。在小鼠表皮中条件性剔除miR-31，小鼠银屑病样皮损减轻，表皮增生状况缓解，真皮炎症细胞浸润数减少。

 

原文链接：MicroRNA-31 Negatively Regulates Peripherally Derived Regulatory T Cell Generation by Repressing Retinoic Acid-Inducible Protein 3

http://www.nature.com/ncomms/2015/150713/ncomms8639/full/ncomms8639.html

Abstract

Peripherally derived regulatory T (pTreg) cell generation requires T-cell receptor (TCR) signalling and the cytokines TGF-β1 and IL-2. Here we show that TCR signalling induces the microRNA miR-31, which negatively regulates pTreg-cell generation. miR-31 conditional deletion results in enhanced induction of pTreg cells, and decreased severity of experimental autoimmune encephalomyelitis (EAE). Unexpectedly, we identify Gprc5a as a direct target of miR-31. Gprc5a is known as retinoic acid-inducible protein 3, and its deficiency leads to impaired pTreg-cell induction and increased EAE severity. By generating miR-31 and Gprc5a double knockout mice, we show that miR-31 promotes the development of EAE through inhibiting Gprc5a. Thus, our data identify miR-31 and its target Gprc5a as critical regulators for pTreg-cell generation, suggesting a previously unrecognized epigenetic mechanism for dysfunctional Treg cells in autoimmune diseases.

原文链接：NF-κB-induced microRNA-31 promotes epidermal hyperplasia by repressing protein phosphatase 6 in psoriasis

http://www.nature.com/ncomms/2015/150703/ncomms8652/full/ncomms8652.html

Abstract

NF-κB is constitutively activated in psoriatic epidermis. However, how activated NF-κB promotes keratinocyte hyperproliferation in psoriasis is largely unknown. Here we report that the NF-κB activation triggered by inflammatory cytokines induces the transcription of microRNA (miRNA) miR-31, one of the most dynamic miRNAs identified in the skin of psoriatic patients and mouse models. The genetic deficiency of miR-31 in keratinocytes inhibits their hyperproliferation, decreases acanthosis and reduces the disease severity in psoriasis mouse models. Furthermore, protein phosphatase 6 (ppp6c), a negative regulator that restricts the G1 to S phase progression, is diminished in human psoriatic epidermis and is directly targeted by miR-31. The inhibition of ppp6c is functionally important for miR-31-mediated biological effects. Moreover, NF-κB activation inhibits ppp6c expression directly through the induction of miR-31, and enhances keratinocyte proliferation. Thus, our data identify NF-κB-induced miR-31 and its target, ppp6c, as critical factors for the hyperproliferation of epidermis in psoriasis.