The airway neuro-immune axis as a therapeutic target in allergic airway diseases

Abstract Recent evidence has increasingly underscored the importance of the neuro-immune axis in mediating allergic airway diseases, such as allergic asthma and allergic rhinitis. The intimate spatial relationship between neurons and immune cells suggests that their interactions play a pivotal role in regulating allergic airway inflammation. Upon direct activation by allergens, neurons and immune cells engage in interactions, during which neurotransmitters and neuropeptides released by neurons modulate immune cell activity. Meanwhile, immune cells release inflammatory mediators such as histamine and cytokines, stimulating neurons and amplifying neuropeptide production, thereby exacerbating allergic inflammation. The dynamic interplay between the nervous and immune systems suggests that targeting the neuro-immune axis in the airway could represent a novel approach to treating allergic airway diseases. This review summarized recent evidence on the nervous system’s regulatory mechanisms in immune responses and identified potential therapeutic targets along the peripheral nerve-immune axis for allergic asthma and allergic rhinitis. The findings will provide novel perspectives on the management of allergic airway diseases in the future

TNF stimulates nuclear export and secretion of IL-15 by acting on CRM1 and ARF6.

Interleukin (IL)-15 is a ubiquitously expressed cytokine that in the basal state is mainly localized intracellularly, including the nucleus. Unexpectedly, tumor necrosis factor-α (TNF) time-dependently induced nuclear export of IL-15Rα and IL15. This process was inhibited by leptomycine B (LMB), a specific inhibitor of nuclear export receptor chromosomal region maintenance 1 (CRM1). In the presence of TNF, LMB co-treatment led to accumulation of both IL-15Rα and IL-15 in the nucleus of HeLa cells, suggesting that CRM1 facilitates nuclear export and that TNF enhances CRM1 activity. Once in the cytoplasm, IL-15 showed partial co-localization with late endosomes but very little with other organelles tested 4 h after TNF treatment. IL-15Rα showed co-localization with both early and late endosomes, and to a lesser extent with endoplasmic reticulum and Golgi. This indicates different kinetics and possibly different trafficking routes of IL-15 from its specific receptor. The TNF-induced secretion of IL-15 was attenuated by pretreatment of cells by brefeldin A that inhibits ER-to-Golgi transport, or by use of domain negative ADP-ribosylation factor 6 (ARF6) that interferes with exocytotic sorting. We conclude that TNF abolishes nuclear localization of IL-15 and IL-15Rα by acting on CRM1, and it facilitates exocytosis of IL-15 with the involvement of ARF6

Accelerated progression of Hodgkin\u27s-like lymphomas in golli deficient SJL mice

Spontaneously occurring lymphomas in SJL mice have many pathological features similar to Hodgkin\u27s lymphoma in humans. The malignant growth of the tumor cells is dependent on the support of host FoxP3(+)CD4(+) regulatory T cells (Tregs). In this study, we report that the ablation of golli protein, a negative regulator of CRAC (calcium release activated calcium) channel, in SJL mice results in an accelerated progression of Hodgkin\u27s-like lymphoma which is accompanied by a facilitated conversion of FoxP3(+) Treg cells. Our results suggest that golli protein might affect the progression of Hodgkin\u27s-like lymphomas through regulating the induction of Treg cells

Efficient tuning of electroluminescence from sky-blue to deep-blue by changing the constitution of spirobenzofluorene derivatives

Two novel benzimidazole-attached spiro[benzofluorene] derivatives, 2,2'-(spiro[benzo[c]fluorine-7,9'-fluorene]-5,9-diylbis(4,1-phenylene))bis(1-phenyl-1H-benzo[d]imidazole) and 2,2'-(spiro[benzo-[de] anthracene-7,9'-fluorene]-2',3-diylbis(4,1-phenylene))bis(1-phenyl-1H-benzo[d]imidazole), were prepared by a Suzuki coupling reaction. Their photophysical and photochemical properties were studied systemically. The fluorescent organic light-emitting diodes were fabricated by using them as the emitters, all of them showed strong blue emission. Interestingly, from the benzoanthracene derived compound a high color purity was found with Commission de L'Eclairage 1931 chromaticity coordinates of (0.15, 0.10) and an efficiency of 1.96 cd/A. To the best of our knowledge, this is the first time to obtain a deep-blue emission with spiro[benzofluorene] derivative in a nondoped device. (C) 2014 Elsevier Ltd. All rights reserved

Saturated deep-blue emitter based on a spiro[benzoanthracene-fluorene]-linked phenanthrene derivative for non-doped organic light-emitting diodes

A spiro[benzoanthracene-fluorene] derivative containing a phenanthrene moiety, 2',3-di(phenanthren-9-yl)spiro(benzo[de]anthracene-7,9'-fluorene] (DPSBAF), was prepared by a Suzuki coupling reaction. The photophysical and photochemical properties were investigated systematically. A non-doped organic light-emitting diode using DPSBAF as the emitter achieved a luminance efficiency of 2.18 cd A(-1) with Commission Internationale de l'Ectairage 1931 chromaticity coordinates of (0.15, 0.09). The synthesized spiro[benzoanthracene-fluorene] derivative with a high thermal stability, a glass transition temperature of 210 degrees C and a decomposition temperature of 410 degrees C, shows potential for application in non-doped saturated deep-blue organic light-emitting diodes

ARF6 localizes to plasma membrane and endosomes and it is crucial to IL-15 secretion after TNF treatment.

<p>HeLa cells were transfected with pCDNA3.1 (control), WT-ARF6, or DN-ARF6 plasmids 48 h before the assay. (A) In control cells and those overexpressing WT-ARF6, TNF treatment for 4 h increased IL-15 release. The cells overexpressing DN-ARF6 did not show a response. In none of the groups did PBS vehicle treatment increase IL-15 release. Data are representative of three independent experiments. *: p<0.05 compared with the control. (B) The overexpression of WT-ARF6 and/or TNF treatment seemed to increase the expression of IL-15 and IL-15Rα, shown by WB of whole cell lysates. (C) The potential interaction of ARF6 with IL-15 was shown by ICC. The left panel is ARF6 immunoreactivity (red, stained with anti-ARF6 in control cells and anti-HA in cells overexpressing ARF6) and the right panel is IL-15 immunoreactivity (green). In control cells, endogenous ARF6 showed a diffuse vesicular pattern of cytoplasmic distribution. In cells overexpressing WT-ARF6 that increased overall expression as well as cell surface distribution of ARF6, IL-15 signal was also increased and showed cell surface distribution co-localizing with WT-ARF6. In cells overexpressing DN-ARF6, the small increase of ARF6 signal remained cytoplasmic, and did not show co-localization with IL-15. Bar: 10 μm. D) Intracellular distribution of IL-15 Rα (green) did not show co-localization with endogenous ARF6 in control cells (stained with an ARF6 Ab, red) or in those overexpressing WT-ARF6 (middle panel) or DN-ARF6 (lower panel, HA Ab staining, red). Bar: 10 μm.</p

Intracellular trafficking of IL-15 and IL-15Rα.

<p>(A and B) Distribution of IL-15 and IL-15Rα in intracellular vesicles. After TNF treatment for 4 h, IL-15 showed partial co-localization with late endosomes but very little with other organelles tested. IL-15Rα showed co-localization with both early and late endosomes, and to a lesser extent with endoplasmic reticulum and the Golgi complex. (C) WB showing IL-15 levels in the cell lysate after TNF (5 ng/mL) or BFA (2 μM) treatment. (D) Cell viability after TNF or LMB treatment shown by ATP production. (E) ELISA of cell culture medium showing IL-15 level in response to TNF or BFA treatment. *: p<0.05 from the non-stimulated control.</p

ARF6 interacts with IL-15Rα.

<p>(A) ARF6 was bound to IL-15Rα. Cells were transfected with ARF6-HA 24 h earlier. ARF6 protein was immunoprecipitated and subjected to WB for IL-15 and IL-15Rα. Immunoprecipitation with nonspecific IgGs was done as the control. (B) ARF6 co-localized with IL-15Rα in the plasma membrane and some organelles. After co-transfection, ARF6-HA (green) and IL-15Rα (red) were co-localized, as shown by confocal microscopy. Bar: 10 μm.</p

Co-localization analysis.

<p>M1: fraction of green fluorescence (IL15 or IL15Rα) overlapping with red fluorescence (EEA or Rab7).</p><p>M2: fraction of red fluorescence (EEA or Rab7) overlapping with green fluorescence (IL15 or IL15Rα).</p

IL-15Rα and IL-15 undergo CRM1-mediated nuclear export.

<p>(A) Mapping of the IL-15Rα sequence showing putative NES interacting sites, with comparison of the putative NES in IL-15Rα with the consensus sequence (cons) of leucine-rich NES in IL-15 Rα from human and other species. (B) Nuclear export of IL-15 (green) and IL-15Rα (red) was inhibited by LMB after TNF induction in a dose-dependent manner. IL-15Rα was located in both nucleus and cytoplasm before TNF treatment. After TNF stimulation for 4 h, IL-15Rα and IL-15 shuttled from nucleus to the cytoplasm. LMB (5 or 20 ng/mL) co-treatment in the last 2 h prevented the export of IL-15Rα and IL-15. DAPI stained nuclei are shown in blue. Bar: 10 μm. (C) WB of IL-15 and IL-15Rα in the nucleus and cytoplasm after vehicle, TNF (5 ng/mL), LMB (20 ng/mL), or combined treatment. The markers actin and histone were used to show efficient separation of nucleus and cytoplasm. (D) Cell viability in the matching treatment groups shown by ATP production. (E) IL-15 level in culture media of basal or stimulated cells, as quantified by ELISA. *: p<0.05 from the non-stimulated control.</p