Cathepsin K Deficiency Reduces Elastase Perfusion-Induced Abdominal Aortic Aneurysms in Mice

Objective: Cathepsin K (CatK) is one of the most potent mammalian elastases. We have previously shown increased expression of CatK in human abdominal aortic aneurysm (AAA) lesions. Whether this protease participates directly in AAA formation, however, remains unknown. Methods and Results: Mouse experimental AAA was induced with aortic perfusion of a porcine pancreatic elastase. Using this experimental model, we demonstrated that absence of CatK prevented AAA formation in mice 14 days postperfusion. CatK deficiency significantly reduced lesion CD4 T-cell content, total lesion and medial cell proliferation and apoptosis, medial smooth muscle cell (SMC) loss, elastinolytic CatL and CatS expression, and elastin fragmentation, but it did not affect AAA lesion Mac-3 macrophage accumulation or CD31 microvessel numbers. In vitro studies revealed that CatK contributed importantly to CD4 T-cell proliferation, SMC apoptosis, and other cysteinyl cathepsin and matrix metalloproteinase expression and activities in SMCs and endothelial cells but played negligible roles in microvessel growth and monocyte migration. AAA lesions from CatK-deficient mice showed reduced elastinolytic cathepsin activities compared with those from wild-type control mice. Conclusion: This study demonstrates that CatK plays an essential role in AAA formation by promoting T-cell proliferation, vascular SMC apoptosis, and elastin degradation and by affecting vascular cell protease expression and activities.Other Research Uni

IgE actions on CD4+ T cells, mast cells, and macrophages participate in the pathogenesis of experimental abdominal aortic aneurysms

Immunoglobulin E (IgE) activates mast cells (MCs). It remains unknown whether IgE also activates other inflammatory cells, and contributes to the pathogenesis of abdominal aortic aneurysms (AAAs). This study demonstrates that CD4+ T cells express IgE receptor FcεR1, at much higher levels than do CD8+ T cells. IgE induces CD4+ T-cell production of IL6 and IFN-γ, but reduces their production of IL10. FcεR1 deficiency (Fcer1a−/−) protects apolipoprotein E-deficient (Apoe−/−) mice from angiotensin-II infusion-induced AAAs and reduces plasma IL6 levels. Adoptive transfer of CD4+ T cells (but not CD8+ T cells), MCs, and macrophages from Apoe−/− mice, but not those from Apoe−/− Fcer1a−/− mice, increases AAA size and plasma IL6 in Apoe−/− Fcer1a−/− recipient mice. Biweekly intravenous administration of an anti-IgE monoclonal antibody ablated plasma IgE and reduced AAAs in Apoe−/− mice. Patients with AAAs had significantly higher plasma IgE levels than those without AAAs. This study establishes an important role of IgE in AAA pathogenesis by activating CD4+ T cells, MCs, and macrophages and supports consideration of neutralizing plasma IgE in the therapeutics of human AAAs

Pyramidal Feature Shrinking for Salient Object Detection

Recently, we have witnessed the great progress of salient object detection (SOD), which benefits from the effectiveness of various feature aggregation strategies. However, existing methods usually aggregate the low-level features containing details and the high-level features containing semantics over a large span, which introduces noise into the aggregated features and generate inaccurate saliency map. To address this issue, we propose pyramidal feature shrinking network (PFSNet), which aims to aggregate adjacent feature nodes in pairs with layer-by-layer shrinkage, so that the aggregated features fuse effective details and semantics together and discard interference information. Specifically, pyramidal shrinking decoder (PSD) is proposed to aggregate adjacent features hierarchically in an asymptotic manner. Unlike other methods that aggregate features with significantly different information, this method only focuses on adjacent feature nodes in each layer and shrinks them to a final unique feature node. Besides, we propose adjacent fusion module (AFM) to perform mutual spatial enhancement between the adjacent features so as to dynamically weight the features and adaptively fuse the appropriate information. In addition, scale-aware enrichment module (SEM) based on the features extracted from backbone is utilized to obtain rich scale information and generate diverse initial features with dilated convolutions. Extensive quantitative and qualitative experiments demonstrate that the proposed intuitive framework outperforms 14 state-of-the-art approaches on 5 public datasets

Enhanced development of CD4+ γδ T cells in the absence of Itk results in elevated IgE production

The Tec kinase Itk is critical for the development of αβ T cells as well as differentiation of CD4+ T cells into Th2 cells. Itk null mice have defects in the production of Th2 cytokines; however, they paradoxically have significant elevations in serum IgE. Here we show that Itk null mice have increased numbers of γδ T cells in the thymus and spleen. This includes elevated numbers of CD4+ γδ T cell, the majority of which carry the Vγ1.1 and Vδ6.2/3 γδ T-cell receptor with a distinct phenotype. The development of these CD4+ γδ T cells is T cell intrinsic, independent of either major histocompatibility complex class I or class II, and is favored during development in the absence of Itk. Itk null CD4+ γδ T cells secrete significant amounts of Th2 cytokines and can induce the secretion of IgE by wild-type B cells. Our data indicate that Itk plays important role in regulating γδ T-cell development and function. In addition, our data indicate that the elevated IgE observed in Itk-deficient mice is due in part to the enhanced development of CD4+ γδ T cells in the absence of Itk