Diet-Induced Alterations in Gut Microflora Contribute to Lethal Pulmonary Damage in TLR2/TLR4-Deficient Mice

SummaryChronic intake of Western diet has driven an epidemic of obesity and metabolic syndrome, but how it induces mortality remains unclear. Here, we show that chronic intake of a high-fat diet (HFD), not a low-fat diet, leads to severe pulmonary damage and mortality in mice deficient in Toll-like receptors 2 and 4 (DKO). Diet-induced pulmonary lesions are blocked by antibiotic treatment and are transmissible to wild-type mice upon either cohousing or fecal transplantation, pointing to the existence of bacterial pathogens. Indeed, diet and innate deficiency exert significant impact on gut microbiota composition. Thus, chronic intake of HFD promotes severe pulmonary damage and mortality in DKO mice in part via gut dysbiosis, a finding that may be important for immunodeficient patients, particularly those on chemotherapy or radiotherapy, where gut-microbiota-caused conditions are often life threatening

Microglia and Microglia-Like Cell Differentiated from DC Inhibit CD4 T Cell Proliferation

The central nervous system (CNS) is generally regarded as a site of immune privilege, whether the antigen presenting cells (APCs) are involved in the immune homeostasis of the CNS is largely unknown. Microglia and DCs are major APCs in physiological and pathological conditions, respectively. In this work, primary microglia and microglia-like cells obtained by co-culturing mature dendritic cells with CNS endothelial cells in vitro were functional evaluated. We found that microglia not only cannot prime CD4 T cells but also inhibit mature DCs (maDCs) initiated CD4 T cells proliferation. More importantly, endothelia from the CNS can differentiate maDCs into microglia-like cells (MLCs), which possess similar phenotype and immune inhibitory function as microglia. Soluble factors including NO lie behind the suppression of CD4 T cell proliferation induced by both microglia and MLCs. All the data indicate that under physiological conditions, microglia play important roles in maintaining immune homeostasis of the CNS, whereas in a pathological situation, the infiltrated DCs can be educated by the local microenvironment and differentiate into MLCs with inhibitory function

Mechanisms of inflammatory responses in obese adipose tissue

The fields of immunology and metabolism are rapidly converging on adipose tissue. During obesity, many immune cells infiltrate or populate in adipose tissue and promote a low-grade chronic inflammation. Studies to date have suggested that perturbation of inflammation is critically linked to nutrient metabolic pathways and to obesity-associated complications such as insulin resistance and type 2 diabetes. Despite these advances, however, many open questions remain including how inflammatory responses are initiated and maintained, how nutrients impact the function of various immune populations, and how inflammatory responses affect systemic insulin sensitivity. Here we review recent studies on the roles of various immune cells at different phases of obesity and discuss molecular mechanisms underlying obesity-associated inflammation. Better understanding of the events occurring in adipose tissue will provide insights into the pathophysiological role of inflammation in obesity and shed light on the pathogenesis of obesity-associated metabolic syndrome

The ATP-P2X7 signaling axis is dispensable for obesity-associated inflammasome activation in adipose tissue

Inflammasome activation in adipose tissue has been implicated in obesity-associated insulin resistance and type 2 diabetes. However, when and how inflammasome is activated in adipose tissue remains speculative. Here we test the hypothesis that extracellular ATP, a potent stimulus of inflammasome in macrophages via purinergic receptor P2X, ligand-gated ion channel, 7 (P2X7), may play a role in inflammasome activation in adipose tissue in obesity. Our data show that inflammasome is activated in adipose tissue upon 8-week feeding of 60% HFD, coinciding with the onset of hyperglycemia and hyperinsulinemia as well as the induction of P2X7 in adipose tissue. Unexpectedly, P2X7-deficient animals on HFD exhibit no changes in metabolic phenotypes, nor in inflammatory responses or inflammasome activation when compared to the wildtype controls. Similar observations have been obtained in hematopoietic cell-specific P2X7-deficient animals generated by bone marrow transplantation. Thus, we conclude that inflammasome activation in adipose tissue in obesity coincides with the onset of hyperglycemia and hyperinsulinemia, but unexpectedly, is not mediated by the ATP-P2X7 signaling axis. The nature of the inflammasome-activating danger signal(s) in adipose tissue in obesity remains to be characterized

The ATP-P2X7 signaling axis is dispensable for obesity-associated inflammasome activation in adipose tissue

Inflammasome activation in adipose tissue has been implicated in obesity-associated insulin resistance and type 2 diabetes. However, when and how inflammasome is activated in adipose tissue remains speculative. Here we test the hypothesis that extracellular ATP, a potent stimulus of inflammasome in macrophages via purinergic receptor P2X, ligand-gated ion channel, 7 (P2X7), may play a role in inflammasome activation in adipose tissue in obesity. Our data show that inflammasome is activated in adipose tissue upon 8-week feeding of 60% HFD, coinciding with the onset of hyperglycemia and hyperinsulinemia as well as the induction of P2X7 in adipose tissue. Unexpectedly, P2X7-deficient animals on HFD exhibit no changes in metabolic phenotypes, nor in inflammatory responses or inflammasome activation when compared to the wildtype controls. Similar observations have been obtained in hematopoietic cell-specific P2X7-deficient animals generated by bone marrow transplantation. Thus, we conclude that inflammasome activation in adipose tissue in obesity coincides with the onset of hyperglycemia and hyperinsulinemia, but unexpectedly, is not mediated by the ATP-P2X7 signaling axis. The nature of the inflammasome-activating danger signal(s) in adipose tissue in obesity remains to be characterized

Developing Robust, Hydrogel-Based, Nanofiber-Enabled Encapsulation Devices (Needs) For Cell Therapies

Cell encapsulation holds enormous potential to treat a number of hormone deficient diseases and endocrine disorders. We report a simple and universal approach to fabricate robust, hydrogel-based, nanofiber-enabled encapsulation devices (NEEDs) with macroscopic dimensions. In this design, we take advantage of the well-known capillary action that holds wetting liquid in porous media. By impregnating the highly porous electrospun nanofiber membranes of pre-made tubular or planar devices with hydrogel precursor solutions and subsequent crosslinking, we obtained various nanofiber-enabled hydrogel devices. This approach is broadly applicable and does not alter the water content or the intrinsic chemistry of the hydrogels. The devices retained the properties of both the hydrogel (e.g. the biocompatibility) and the nanofibers (e.g. the mechanical robustness). The facile mass transfer was confirmed by encapsulation and culture of different types of cells. Additional compartmentalization of the devices enabled paracrine cell co-cultures in single implantable devices. Lastly, we provided a proof-of-concept study on potential therapeutic applications of the devices by encapsulating and delivering rat pancreatic islets into chemically-induced diabetic mice. The diabetes was corrected for the duration of the experiment (8 weeks) before the implants were retrieved. The retrieved devices showed minimal fibrosis and as expected, live and functional islets were observed within the devices. This study suggests that the design concept of NEEDs may potentially help to overcome some of the challenges in the cell encapsulation field and therefore contribute to the development of cell therapies in future

Material Flow and Mechanical Properties of a Non-Keyhole Friction Stir Welded Aluminum Alloy with Improved Sleeve Bottom Geometry

Non-keyhole friction stir welding (N-KFSW) is a technique that can fabricate a welding joint without a keyhole through a one-time welding process. The Al–Mg–Si alloy was chosen as a research object, and the N-KFSW technique was investigated by numerical and experimental methods. Firstly, the sleeve bottoms of the N-KFSW welding tool system were innovatively optimized in this study. The optimal sleeve bottom with an 80° angle between the spiral groove and the sleeve inner side wall allowed avoiding the incomplete root penetration defect at the bottom of the stir zone (SZ), which was verified by numerical results and the C-shaped line height. Then, using a 3 mm-thick aluminum alloy as the experimental material, the material flow and joint formation characteristics and mechanical properties at 110, 150 and 190 mm/min welding speeds were studied and compared. The results showed that the SZ presented a drum shape due to the action of the clamping ring and the threads on the side wall of the sleeve. The SZ width decreased from 7.17 to 6.91 mm due to the decreased heat input. From 70 to 210 mm/min welding speed, the maximum tensile strength of the joint was 250 MPa at 190 mm/min, and the joint with relatively higher strength fractured at the heat-affected zone

Material Flow and Mechanical Properties of a Non-Keyhole Friction Stir Welded Aluminum Alloy with Improved Sleeve Bottom Geometry

Non-keyhole friction stir welding (N-KFSW) is a technique that can fabricate a welding joint without a keyhole through a one-time welding process. The Al–Mg–Si alloy was chosen as a research object, and the N-KFSW technique was investigated by numerical and experimental methods. Firstly, the sleeve bottoms of the N-KFSW welding tool system were innovatively optimized in this study. The optimal sleeve bottom with an 80° angle between the spiral groove and the sleeve inner side wall allowed avoiding the incomplete root penetration defect at the bottom of the stir zone (SZ), which was verified by numerical results and the C-shaped line height. Then, using a 3 mm-thick aluminum alloy as the experimental material, the material flow and joint formation characteristics and mechanical properties at 110, 150 and 190 mm/min welding speeds were studied and compared. The results showed that the SZ presented a drum shape due to the action of the clamping ring and the threads on the side wall of the sleeve. The SZ width decreased from 7.17 to 6.91 mm due to the decreased heat input. From 70 to 210 mm/min welding speed, the maximum tensile strength of the joint was 250 MPa at 190 mm/min, and the joint with relatively higher strength fractured at the heat-affected zone

Anisotropic Shear Strength Behavior of Soil–Geogrid Interfaces

This paper presents an experimental study on the anisotropic shear strength behavior of soil–geogrid interfaces. A new type of interface shear test device was developed, and a series of soil–geogrid interface shear tests were conducted for three different biaxial geogrids and three different triaxial geogrids under the shear directions of 0°, 45° and 90°. Clean fine sand, coarse sand, and gravel were selected as the testing materials to investigate the influence of particle size. The experimental results for the interface shear strength behavior, and the influences of shear direction and particle size are presented and discussed. The results indicate that the interface shear strength under the same normal stress varies with shear direction for all the biaxial and triaxial geogrids investigated, which shows anisotropic shear strength behavior of soil–geogrid interfaces. The soil–biaxial geogrid interfaces show stronger anisotropy than that of the soil–triaxial geogrid interfaces under different shear directions. Particle size has a great influence on the anisotropy shear strength behavior of soil–geogrid interfaces