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.

BackgroundTumor-associated macrophages (TAMs) remodel the colorectal cancer (CRC) microenvironment. Yet, findings on the role of TAMs in CRC seem to be contradictory compared with other cancers. FoxP3+ regulatory T (Treg)-cells dominantly infiltrate CRC. However, the underlying molecular mechanism in which TAMs may contribute to the trafficking of Treg-cells to the tumor mass remains unknown.Methodology/Principal FindingsCRC was either induced by N-methyl-N-nitrosourea (MNU) and H. pylori or established by subcutaneous injection of mouse colorectal tumor cell line (CMT93) in mice. CMT93 cells were co-cultured with primary macrophages in a transwell apparatus. Recruitment of FoxP3 green fluorescence protein positive (FoxP3GFP+) Treg-cells was assessed using the IVIS Imaging System or immunofluorescence staining. A role for macrophages in trafficking of Treg-cells and in the development of CRC was investigated in CD11b diphtheria toxin receptor (CD11b-DTR) transgenic C57BL/6J mice in which macrophages can be selectively depleted. Treg-cells remarkably infiltrated solid tumor, and predominantly expressed the homing chemokine receptor (CCR) 6 in the induced CRC model. Both CMT93 cancer cells and macrophages produced a large amount of CCL20, the sole ligand of CCR6 in vitro and in vivo. Injection of recombinant mouse CCL20 into tumor sites promoted its development with a marked recruitment of Treg-cells in the graft CRC model. Conditional macrophage ablation decreased CCL20 levels, blocked Treg-cell recruitment and inhibited tumor growth in CD11b-DTR mice grafted with CMT93.Conclusions/SignificanceTAMs recruit CCR6+ Treg-cells to tumor mass and promote its development via enhancing the production of CCL20 in a CRC mouse model.

BackgroundHealth workforce turnover remains a global concern, particularly in rural and remote areas. Western rural areas are the least developed in China, where it faces the serious challenge on the rural health worker (RHW) management. This study aimed to investigate job satisfaction, work stress, and turnover intentions of RHWs, and to explore prominent factors associated with turnover intentions of RHWs in rural western China.MethodsFrom June to September 2013, based on a three-stage random sampling method, a cross-sectional survey was conducted among RHWs in 11 western provinces in China. A brief, structured questionnaire filled in by RHWs was used for data collection. A total of 5046 RHWs participated in the study. The response rate was approximately 93.1%. Exploratory factor analyses, Pearson’s chi-squared tests, one-way ANOVA, binary logistic regression analyses, and mediating effect tests were performed for data analyses.ResultsApproximately 29.1% of the 5046 RHWs indicated turnover intentions. Most of the RHWs disclosed low educational levels, income levels, and professional technical titles. The RHWs expressed slight job satisfaction (mean 3.20) and moderate work stress (mean 3.22). Age, income, medical institution, and job satisfaction (i.e., organizational management, reward, and occupation satisfaction) were significant predictors of the RHWs’ turnover intentions. The RHWs, who were younger (less than 41 years), receiving an income of $326.8–$490.1 per month, working in township hospitals, and having low job satisfaction, were more likely to have turnover intentions. Work stress had an indirect and positive effect on RHWs’ turnover intentions. Job satisfaction weakened the positive effect of work stress on turnover intentions of RHWs by playing a total mediating role. Reward satisfaction was the strongest mediator.ConclusionsThe turnover intentions of RHWs in western China are significantly associated with job satisfaction, work stress, age, income, and medical institution. Appropriate strategies should be implemented to improve RHWs’ job satisfaction and reduce their work stress. Meanwhile, providing more attractive wages and non-monetary support, improving working conditions, etc. could be effective to reduction in RHWs’ turnover intentions.Electronic supplementary materialThe online version of this article (10.1186/s12875-019-0904-0) contains supplementary material, which is available to authorized users.

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.