Background IL-17 signaling has been implicated in lung and skin fibrosis. Here we examined the role of IL-17 signaling in the pathogenesis of liver fibrosis. Methods Using cholestatic and hepatotoxic models of liver injury, the development of liver fibrosis in wild type mice was compared to IL-17RA−/− mice, and to bone marrow chimeric mice devoid of IL-17 signaling in immune cells and Kupffer cells (IL-17RA−/−→wt and IL-17A−/− →wt mice), or in liver resident cells (Wt→ IL-17RA−/− mice). Results We determined that IL-17A and its receptor is highly induced in liver injury and has a strong pro-fibrogenic effect on both inflammatory and liver resident cells. IL-17 signaling facilitates production of IL-6, IL-1β, and TNF-α by inflammatory cells, and increases the expression of TGF-β1, the major pro-fibrogenic cytokine. IL-17 directly induces collagen Type I production in hepatic stellate cells (HSCs) via activation of the Stat3 signaling pathway. Mice devoid of Stat3 signaling in HSCs (GFAPStat3−/− mice) are less susceptible to fibrosis. Furthermore, deletion of IL-23 in immune cells results in attenuation of liver fibrosis, while deletion of IL-22 exacerbates fibrosis. Administration of IL-22 and IL-17E (IL-25, a negative regulator of IL-23) protects mice from BDL-induced liver fibrosis. Conclusions IL-17 induces liver fibrosis through multiple mechanisms and may serve as an attractive target for anti-fibrotic therapy.

Significance Liver resident activated hepatic stellate cells (aHSCs), and activated portal fibroblasts (aPFs) are the major source of the fibrous scar in the liver. aPFs have been implicated in liver fibrosis caused by cholestatic liver injury, whereas fibrosis in hepatotoxic liver injury is attributed to aHSCs. However, the contribution of aPFs to cholestatic fibrosis is not well characterized because of difficulties in cell purification and the lack of identified aPF-specific markers. We have developed a novel flow cytometry-based method of aPFs purification from the nonparenchymal cell fraction of collagen-α1(I)-GFP mice and have identified potential aPF-specific markers. The goal of this study is to determine whether aPFs contribute to cholestatic liver fibrosis and identify the mechanism(s) of their activation.

Microarrays with biomolecules (e.g., DNA and proteins), cells, and tissues immobilized on solid substrates are important tools for biological research, including genomics, proteomics, and cell analysis. In this paper, the current state of microarray fabrication is reviewed. According to spot formation techniques, methods are categorized as "contact printing" and "non-contact printing." Contact printing is a widely used technology, comprising methods such as contact pin printing and microstamping. These methods have many advantages, including reproducibility of printed spots and facile maintenance, as well as drawbacks, including low-throughput fabrication of arrays. Non-contact printing techniques are newer and more varied, comprising photochemistrybased methods, laser writing, electrospray deposition, and inkjet technologies. These technologies emerged from other applications and have the potential to increase microarray fabrication throughput; however, there are several challenges in applying them to microarray fabrication, including interference from satellite drops and biomolecule denaturization.

Peptide nanostructures are biodegradable and are suitable for many biomedical applications. However, to be useful imaging probes, the limited intrinsic optical properties of peptides must be overcome. Here we show the formation of tryptophan-phenylalanine dipeptide nanoparticles (DNPs) that can shift the peptide's intrinsic fluorescent signal from the ultraviolet to the visible range. The visible emission signal allows the DNPs to act as imaging and sensing probes. The peptide design is inspired by the red shift seen in the yellow fluorescent protein that results from π-π stacking and by the enhanced fluorescence intensity seen in the green fluorescent protein mutant, BFPms1, which results from the structure rigidification by Zn(II). We show that DNPs are photostable, biocompatible and have a narrow emission bandwidth and visible fluorescence properties. DNPs functionalized with the MUC1 aptamer and doxorubicin can target cancer cells and can be used to image and monitor drug release in real time.

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Because cytokine-priming signals direct CD8 + T cells to acquire unique profiles that affect their ability to mediate specific immune responses, here we generated IL-9-skewed CD8 + T (Tc9) cells by priming with Th9-polarized condition. Compared with type-I CD8 + cytotoxic T (Tc1) cells, Tc9 secreted different cytokines and were less cytolytic in vitro but surprisingly elicited greater antitumor responses against advanced tumors in OT-I/B16-OVA and Pmel-1/ B16 melanoma models. After adoptive transfer, Tc9 cells persisted longer and differentiated into IFN-γ-and granzyme-B (GrzB)-producing cytolytic Tc1-like effector cells. Phenotypic analysis revealed that adoptively transferred Tc9 cells secreted IL-2 and were KLRG-1 low and IL-7Rα high , suggesting that they acquired a signature of "younger" phenotype or became long-term lived cells with capacity of self-renewal. Our results also revealed that Tc9-mediated therapeutic effect critically depended on IL-9 production in vivo. These findings have clinical implications for the improvement of CD8 + T-cell-based adoptive immunotherapy of cancers.adoptive cell therapy | less-exhausted T cells | T-cell lineage plasticity

Quantum confined materials have been extensively studied for photoluminescent applications. Due to intrinsic limitations of low biocompatibility and challenging modulation, the utilization of conventional inorganic quantum confined photoluminescent materials in bio-imaging and bio-machine interface faces critical restrictions. Here, we present aromatic cyclo-dipeptides that dimerize into quantum dots, which serve as building blocks to further self-assemble into quantum confined supramolecular structures with diverse morphologies and photoluminescence properties. Especially, the emission can be tuned from the visible region to the near-infrared region (420 nm to 820 nm) by modulating the self-assembly process. Moreover, no obvious cytotoxic effect is observed for these nanostructures, and their utilization for in vivo imaging and as phosphors for light-emitting diodes is demonstrated. The data reveal that the morphologies and optical properties of the aromatic cyclo-dipeptide self-assemblies can be tuned, making them potential candidates for supramolecular quantum confined materials providing biocompatible alternatives for broad biomedical and opto-electric applications.

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