Innate immune regulates cutaneous sensory IL-13 receptor alpha 2 to promote atopic dermatitis.

The clinical significance and regulators of IL-13Rα2 in itch and atopic dermatitis (AD) remain unclear. To identify disease-driven regulatory circuits of IL-13Rα2, transcriptomic/pathological analysis was performed in skin from patients with AD, psoriasis, healthy subjects, and murine AD model. Functionality was investigated in sensory neurons, keratinocytes and animal model, by using knockdown (KD), calcium imaging, RNA-seq, cytokine arrays, pharmacological assays, and behavioural investigations. In our study, an upregulated IL-13Rα2 expression was revealed in skin of AD patients, but not psoriasis, in a disease activity-dependent manner. In cultured human keratinocytes, IL-13 increased IL-13Rα2 transcription levels, and this were downregulated by IL-13Rα1KD. IL-13Rα2KD reduced transcription levels of EDNRA, CCL20, CCL26. In contrast, sensory neuron-derived IL-13Rα2 was upregulated by TLR2 heterodimer agonists, Pam3CSK4 and FSL-1. In a mouse cheek model, pre-administration of Pam3CSK4 and FSL-1 enhanced IL-13-elicited scratching behaviour. Consistently, in cultured sensory neurons Pam3CSK4 enhanced IL-13-elicted calcium transients, increased number of responders, and orchestrated chemerin, CCL17 and CCL22 release. These release was inhibited by IL-13Rα2KD. Collectively, IL-13 regulates keratinocyte-derived IL-13Rα2 and TLR2 to modulate neuronal IL-13Rα2, thereby promoting neurogenic inflammation and exacerbating AD and itch. Thus, the cutaneous IL-13-IL-13Rα2 and neuronal TLR2-IL-13Rα2 pathway represent important targets to treat AD and itch.

Selective Expression of a SNARE-Cleaving Protease in Peripheral Sensory Neurons Attenuates Pain-Related Gene Transcription and Neuropeptide Release.

Chronic pain is a leading health and socioeconomic problem and an unmet need exists for long-lasting analgesics. SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) are required for neuropeptide release and noxious signal transducer surface trafficking, thus, selective expression of the SNARE-cleaving light-chain protease of botulinum neurotoxin A (LCA) in peripheral sensory neurons could alleviate chronic pain. However, a safety concern to this approach is the lack of a sensory neuronal promoter to prevent the expression of LCA in the central nervous system. Towards this, we exploit the unique characteristics of Pirt (phosphoinositide-interacting regulator of TRP), which is expressed in peripheral nociceptive neurons. For the first time, we identified a Pirt promoter element and cloned it into a lentiviral vector driving transgene expression selectively in peripheral sensory neurons. Pirt promoter driven-LCA expression yielded rapid and concentration-dependent cleavage of SNAP-25 in cultured sensory neurons. Moreover, the transcripts of pain-related genes (TAC1, tachykinin precursor 1; CALCB, calcitonin gene-related peptide 2; HTR3A, 5-hydroxytryptamine receptor 3A; NPY2R, neuropeptide Y receptor Y2; GPR52, G protein-coupled receptor 52; SCN9A, sodium voltage-gated channel alpha subunit 9; TRPV1 and TRPA1, transient receptor potential cation channel subfamily V member 1 and subfamily A member 1) in pro-inflammatory cytokines stimulated sensory neurons were downregulated by viral mediated expression of LCA. Furthermore, viral expression of LCA yielded long-lasting inhibition of pain mediator release. Thus, we show that the engineered Pirt-LCA virus may provide a novel means for long lasting pain relief.

Preliminary study of the source apportionment and diversity of microplastics: Taking floating microplastics in the South China Sea as an example.

At present, the study of microplastic sources is in a relatively preliminary stage due to the complexity of microplastic features in the environment. Based on a literature review, we developed a source-specific classification system for the quantitative analysis of microplastic sources. The classification system includes ten types of microplastics based on morphology and composition and can identify their main sources and the associated probabilities. To reflect the complexity of types and sources in the regional combination of microplastics, we first propose a microplastic diversity index (D1-D'(MP)). We use the South China Sea as an example to carry out quantitative source analysis and calculate the diversity index. Eight types of microplastics were found, mainly consisting of maritime coatings (type "Gran_coat") (33.0%) and synthetic fibers (type "Fib_thin") (29.6%). We also found that the diversity increased with offshore distance. In addition, we partitioned surface microplastics globally according to a two-dimensional microplastic abundance-diversity index. We believe that these indicators can effectively reflect pollution status and ultimately lead to different types of control measures. In the future, additional indicators for the characterization of microplastics must be included in the classification system to establish a one-to-one source analysis system for microplastic characteristics and source apportionment. In general, our study may provide new insights into the establishment of more accurate and quantitative source apportionment techniques and effective pollution control.

MicroRNA-195 inhibits epithelial-mesenchymal transition via downregulating CDK4 in bladder cancer.

Bladder cancer is one of the most common cancers in the world. Despite advanced development made to improve the diagnosis and therapy techniques for bladder cancer, patients always have a poor outcome based on its high potential for metastasis. MiR-195 was reported to have close relevance with the process of bladder cancer. However, the molecular mechanism of miR-195 underlying bladder cancer metastasis and epithelial-mesenchymal transition (EMT) remains unclear. The present study was done to explore the function of miR-195 on EMT and cell migration in bladder cancer. In the present study, we detected the level of miR-195 in 25 matched human bladder cancer tissues and normal adjacent tissues, as well as bladder cancer cell lines or normal cells. Additionally, we determined the effects of miR-195 on expression of CDK4, and the miR-195/CKD4 signaling cascade on cell cycle, invasion, migration, and viability. Results showed that miR-195 was down expressed in bladder cancer tissues and cell lines, which inhibited EMT, cell migration, and invasion. We identify CDK4, an early G1 cell cycle regulator, as a downstream target of miR-195. Also, we found that miR-195 could induce G1-phase arrest, inhibit cell invasion, migration, and viability through down-regulation of CDK4 expression in 5637 and BIU-87 cells. Our experimental data suggest an important role for miR-195/CDK4 in bladder tumorigenesis and provide a potential therapeutic strategy for bladder cancer.