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Summary: Amino acid (aa) metabolism is closely correlated with the pathogenesis of psoriasis; however, details on aa transportation during this process are barely known. Here, we find that SLC38A5, a sodium-dependent neutral aa transporter that counter-transports protons, is markedly upregulated in the psoriatic skin of both human patients and mouse models. SLC38A5 deficiency significantly ameliorates the pathogenesis of psoriasis, indicating a pathogenic role of SLC38A5. Surprisingly, SLC38A5 is almost exclusively expressed in dendritic cells (DCs) when analyzing the psoriatic lesion and mainly locates on the lysosome. Mechanistically, SLC38A5 potentiates lysosomal acidification, which dictates the cleavage and activation of TLR7 with ensuing production of pro-inflammatory cytokines such as interleukin-23 (IL-23) and IL-1β from DCs and eventually aggravates psoriatic inflammation. In summary, this work uncovers an auxiliary mechanism in driving lysosomal acidification, provides inspiring insights for DC biology and psoriasis etiology, and reveals SLC38A5 as a promising therapeutic target for treating psoriasis.

We previously found that 19 microRNAs (miRNAs) significantly increased in the sera of hepatocellular carcinoma (HCC) patients. Here, we evaluated whether these miRNAs were secreted by HCC cells and contributed to tumor angiogenesis. High level of miR-210-3p (miR-210) was detected in the exosomes isolated from the sera of HCC patients and the conditioned media of hepatoma cells. Higher miR-210 level in serum was correlated with higher microvessel density in HCC tissues. Moreover, the HCC cell-secreted exosomes promoted in vitro tubulogenesis of endothelial cells, which was strengthened by overexpressing miR-210 in HCC cells but was attenuated by repressing miR-210 or DROSHA in HCC cells. This pro-tubulogenesis effect by HCC exosomes was also abrogated by antagonizing miR-210 in endothelial cells. Subsequent in vivo studies revealed that Matrigel plug and subcutaneous tumor xenografts treated with HCC cell-derived exosomal miR-210 displayed much more vessels. Furthermore, exosomal miR-210 could be delivered into endothelial cells and directly inhibited the expression of SMAD4 and STAT6, resulting in enhanced angiogenesis. Collectively, HCC cell-secreted exosomal miR-210 may be transferred into endothelial cells and thereby promotes tumor angiogenesis by targeting SMAD4 and STAT6. Our findings identify a novel mechanism of HCC angiogenesis and highlight the biological importance of exosomal miR-210.

Background: Previous studies showed that monocytes from patients with unstable coronary disease exhibit a greatly enhanced production of interleukin-6 (IL-6) in response to lipopolysaccharide and artery injury. Moreover, accumulating evidence suggest that C-reactive protein (CRP) may have direct proinflammatory effects on the cells of vascular wall. Whether this enhanced inflammatory response also exists, however, in cultured monocytes from patients with unstable angina, in response to CRP, has not been investigated., Methods: Monocytes were isolated from blood of 15 healthy volunteers (normal control), 15 patients with stable angina, and 15 patients with unstable angina by Ficoll density gradient and were stimulated by 20 microg/ml of CRP for 24 h. Measurements of IL-6 and tumor necrosis factor-a (tnf-alpha) were performed from supernatants of cultured medium in duplicate, using a commercial assay kit., Results: the data showed that IL-6 and tnf-alpha concentrations of spontaneous secretion (baseline) were higher in patients with unstable angina than in patients with stable angina and normal control (IL-6: 179+/-19 vs. 87+/-6 and 89+/-8 pg/ml, p<0.05, respectively; tnf-alpha: 69+/-13 vs. 30+/-4 and 27+/-3 pg/ml, p<0.05, respectively). CRP induced the enhanced release of IL-6 and tnf-alpha by 17-fold and 23-fold increase, respectively, in patients with unstable angina, while it did about 11-fold and 19-fold increase in patients with stable angina and normal group (IL-6: 3129+/-333 vs. 991+/-134 and 987+/-102 pg/ml, p<0.01, respectively; tnf-alpha: 1554+/-784 vs. 560+/-135 and 558+/-152 pg/ml, p<0.01, respectively)., Conclusions: Increased baseline concentrations of IL-6 and tnf-alpha can be a marker of the hyperresponsiveness of the inflammatory system in patients with unstable coronary disease. CRP could enhance even further this response, suggesting that a persisted and enhanced inflammatory responsiveness to CRP may be involved in the pathogenesis of unstable coronary disease.