Targeting Immunoproteasome in Polarized Macrophages Ameliorates Experimental Emphysema Via Activating NRF1/2-P62 Axis and Suppressing IRF4 Transcription.

Chronic obstructive pulmonary disease (COPD) stands as the prevailing chronic airway ailment, characterized by chronic bronchitis and emphysema. Current medications fall short in treatment of these diseases, underscoring the urgent need for effective therapy. Prior research indicated immunoproteasome inhibition alleviated various inflammatory diseases by modulating immune cell functions. However, its therapeutic potential in COPD remains largely unexplored. Here, an elevated expression of immunoproteasome subunits LMP2 and LMP7 in the macrophages isolated from mouse with LPS/Elastase-induced emphysema and polarized macrophages in vitro is observed. Subsequently, intranasal administration of the immunoproteasome-specific inhibitor ONX-0914 significantly mitigated COPD-associated airway inflammation and improved lung function in mice by suppressing macrophage polarization. Additionally, ONX-0914 capsulated in PLGA nanoparticles exhibited more pronounced therapeutic effect on COPD than naked ONX-0914 by targeting immunoproteasome in polarized macrophages. Mechanistically, ONX-0914 activated autophagy and endoplasmic reticulum (ER) stress are not attribute to the ONX-0914 mediated suppression of macrophage polarization. Intriguingly, ONX-0914 inhibited M1 polarization through the nuclear factor erythroid 2-related factor-1 (NRF1) and NRF2-P62 axis, while the suppression of M2 polarization is regulated by inhibiting the transcription of interferon regulatory factor 4 (IRF4). In summary, the findings suggest that targeting immunoproteasome in macrophages holds promise as a therapeutic strategy for COPD.

Macrophages in immunoregulation and therapeutics.

Macrophages exist in various tissues, several body cavities, and around mucosal surfaces and are a vital part of the innate immune system for host defense against many pathogens and cancers. Macrophages possess binary M1/M2 macrophage polarization settings, which perform a central role in an array of immune tasks via intrinsic signal cascades and, therefore, must be precisely regulated. Many crucial questions about macrophage signaling and immune modulation are yet to be uncovered. In addition, the clinical importance of tumor-associated macrophages is becoming more widely recognized as significant progress has been made in understanding their biology. Moreover, they are an integral part of the tumor microenvironment, playing a part in the regulation of a wide variety of processes including angiogenesis, extracellular matrix transformation, cancer cell proliferation, metastasis, immunosuppression, and resistance to chemotherapeutic and checkpoint blockade immunotherapies. Herein, we discuss immune regulation in macrophage polarization and signaling, mechanical stresses and modulation, metabolic signaling pathways, mitochondrial and transcriptional, and epigenetic regulation. Furthermore, we have broadly extended the understanding of macrophages in extracellular traps and the essential roles of autophagy and aging in regulating macrophage functions. Moreover, we discussed recent advances in macrophages-mediated immune regulation of autoimmune diseases and tumorigenesis. Lastly, we discussed targeted macrophage therapy to portray prospective targets for therapeutic strategies in health and diseases.

BET proteins inhibitor JQ1 impairs GM-CSF-promoted peritoneal macrophage self-renewal and IL-4-induced alternative polarization.

Peritoneal macrophages (PMs), which resided in peritoneal cavity, are crucial to maintain tissue homeostasis and immunity. Macrophage self-renewal and polarization states are critical for PM population homeostasis and function. However, the underlying molecular mechanism that regulates self-renewal and polarization of PMs is still unclear and needs to be explored. Here, we demonstrated that PMs self-renewal was stimulated by granulocyte macrophage colony-stimulating factor (GM-CSF), but not by macrophage colony-stimulating factor (M-CSF). Pharmacological inhibition of Bromodomain & Extraterminal (BET) Proteins by either JQ1 or ARV-825 significantly reduced GM-CSF-dependent peritoneal macrophage self-renewal by abrogating cell proliferation and decreasing self-renewal-related gene expression, such as MYC and Klf4, at transcriptional and protein levels. In addition, transcriptomic analysis showed that JQ1 blocked alternative PMs polarization by downregulating key transcriptional factor IRF4 expression, but not the activation of AKT or STAT6 in PMs. These findings illustrated that the significance of BET family proteins in GM-CSF-induced PMs self-renewal and IL-4-induced alternative polarization.

Effect of Different Forms of Selenium on the Physiological Response and the Cadmium Uptake by Rice under Cadmium Stress.

Cadmium (Cd) is a pollutant toxic to plants and a potential threat to human health. Selenium (Se), though not essential for plants, has beneficial effects on plants under abiotic stress. A hydroponic experiment was conducted to investigate the impact of different forms of Se (Nano-Se, selenite, selenate, and SeMet) on accumulation, subcellular distribution, and chemical forms of Cd, as well as oxidative stress in rice seedlings. Cd (20 µmol·L-1) treatment significantly decreased biomass accumulation and chlorophyll content. The application of all Se forms, except selenate, mitigated the adverse effects of Cd on growth and chlorophyll content. The application of selenite, Nano-Se, and SeMet decreased root and shoot Cd concentrations as well as root-to-shoot Cd translocation in rice seedlings. Selenate application decreased shoot Cd concentration and root-to-shoot Cd translocation with no effect on root Cd concentration. Accordingly, Se increased the sequestration of Cd in the cell wall and vacuoles and decreased the active chemical form of Cd in rice seedlings. SeMet was the most effective supplement that decreased Cd concentration and enhanced Se concentration in the roots and shoots of rice seedlings. All forms of Se further enhanced catalase (CAT) and glutathione peroxidase (GSH-Px) activities and inhibited MDA accumulation. To conclude, Se influenced Cd accumulation and translocation in rice seedlings by altering the subcellular distribution, chemical forms, and antioxidant defense system under Cd stress. These effects were highly significant with SeMet treatment, probably due to better absorption and utilization by the plant.

Cytotoxic effects of polystyrene nanoplastics with different surface functionalization on human HepG2 cells.

Nanoplastics in the environment lead to the human exposure to these particles. However, the consequences of this exposure are not yet fully understood. Here, the cytotoxicity of polystyrene nanoparticles (PS-NPs) with a uniform size (50 nm) but distinct surface functionalization (pristine polystyrene, PS; carboxy and amino functionalized, PS-COOH and PS-NH2, respectively), and at an exposure dosage of 10, 50 and 100 µg/mL, were assessed in the human hepatocellular carcinoma (HepG2) cell line. Although all PS-NPs could be internalized by the HepG2 cells, according to the fluorescent intensities, more of PS-COOH and PS-NH2 than PS, accumulated in the cells. The cell viability was significantly affected in a positively dose-related manner. Functionalized PS-NPs exhibited greater inhibition of cell viability than PS, and the viability inhibition peaked (46%) at 100 µg/mL of PS-NH2 exposure. Superoxide dismutase (SOD) activity was maximum when HepG2 cells were exposed to 10 µg/mL of PS-COOH (1.8 folds higher than that without PS-COOH exposure). The glutathione (GSH) content was maximum when the cells were treated with 50 µg/mL of PS (3.75 fold increase compared to untreated cells). Although the difference in inhibition of cell viability was not significant between PS-NH2 and PS-COOH exposure, 100 µg/mL of PS-NH2 exposure caused the most severe oxidative stress due to dramatically increased accumulation of malondialdehyde (MDA); however, a decrease in the antioxidants levels as the SOD activity and GSH content were also found. The results demonstrated that the cellular oxidative damage occurred and that the antioxidation enzymes may not be able to maintain the balance between the generation of oxidant species and the antioxidant defense. Consequently, 100 µg/mL of PS-NH2 exposure triggered the destruction of antioxidant structures. This study defines the cytotoxic effects of PS-NPs on HepG2 cells and emphasizes the significance of investigating the cytotoxic outcomes of nanoplastics in humans.