The mechanisms associated with the induction of systemic immune responses by nanoparticles are not fully understood, but their elucidation is critical to address safety issues associated with the broader medical application of nanotechnology. In this study, a key role of nanoparticle-induced exosomes (extracellularly secreted membrane vesicles) as signaling mediators in the induction of T helper cell type 1 (Th1) immune activation is demonstrated. In vivo exposure to magnetic iron oxide nanoparticles (MIONs) results in significant exosome generation in the alveolar region of Balb/c mice. These act as a source of nanoparticle-induced, membrane-bound antigen/signaling cargo, which transfer their components to antigen-presenting cells (APCs) in the reticuloendothelial system. Through exosome-initiated signals, immature dendritic cells (iDCs) undergo maturation and differentiation to the DC1 subtype, while macrophages go through classical activation and differentiation to the M1 subtype. Simultaneously, iDCs and macrophages release various Th1 cytokines (including interleukin-12 and tumor necrosis factor α) driving T-cell activation and differentiation. Activated APCs (especially DC1 and M1 subtypes) consequently prime T-cell differentiation towards a Th1 subtype, thereby resulting in an orchestrated Th1-type immune response. Th1-polarized immune activation is associated with delayed-type hypersensitivity, which might underlie the long-term inflammatory effects frequently associated with nanoparticle exposure. These studies suggest that nanoparticle-induced exosomes provoke the immune activation and inflammatory responses that can accompany nanoparticle exposure.

Tumor-associated macrophages (TAM) play pivotal roles in cancer initiation and progression. Monocytes, the precursors of TAMs, normally undergo spontaneous apoptosis within 2 days, but can subsist in the inflammatory tumor microenvironment for continuous survival and generation of sufficient TAMs. The mechanisms underlying tumor-driving monocyte survival remain obscure. Here we report that cancer cell-derived exosomes were crucial mediators for monocyte survival in the inflammatory niche. Analysis of the survival-promoting molecules in monocytes revealed that cancer cell-derived exosomes activated Ras and extracellular signalregulated kinases in the mitogen-activated protein kinase (MAPK) pathway, resulting in the prevention of caspase cleavage. Phosphorylated receptor tyrosine kinases (RTKs), such as phosphorylated epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2), were abundantly expressed in cancer cell-derived exosomes. Knock-out of EGFR or/and HER-2, or alternatively, inhibitors against their phosphorylation significantly disturbed the exosome-mediated activation of the MAPK pathway, inhibition of caspase cleavage, and increase in survival rate in monocytes. Moreover, the deprived survival-stimulating activity of exosomes due to null expression of EGFR and HER-2 could be restored by activation of another RTK, insulin receptor. Overall, our study uncovered a mechanism of tumor-associated monocyte survival and demonstrated that cancer cell-derived exosomes can stimulate the MAPK pathway in monocytes through transport of functional RTKs, leading to inactivation of apoptosis-related caspases. This work provides insights into the long sought question on monocyte survival prior to formation of plentiful TAMs in the tumor microenvironment.Clinical and experimental evidences suggest that a particular type of macrophage population is present within the tumor microenvironment (1). Tumor-associated macrophages (TAMs) 4 are derived from recruited monocytes or resident tissue macrophages (2), and play essential roles in tumor initiation, progression, and metastasis (3). Monocyte recruitment, survival, and differentiation are fundamental steps for continuous generation of TAMs. Previous studies are focused on understanding the complicated mechanisms of monocyte recruitment and differentiation within tumor tissues (2). However, investigations regarding how monocytes maintain survival before differentiation into sufficient TAMs have never been reported.As key components of the innate immune system, monocytes are continuously produced by bone marrow but normally undergo spontaneous apoptosis within 48 h in blood circulation (4, 5). Monocyte apoptosis can be prevented in vitro by serum at high concentrations (Ͼ20%), differentiation factors, and a wide range of inflammatory stimuli such as lipopolysaccharide (LPS) and interferon-␥ (IFN-␥), all of which reduce the activation of caspases and trigger the differentiation of monocytes into macrophages or dendritic cells (5-10). However, i...

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This research has focused on the source identification, concentration, and ecological risk assessment of eight heavy metals in the largest karst wetland (Huixian) of south China. Numerous samples from superficial soil and sediment within ten representative landuse types were collected and examined, and the results were analyzed using multiple methods. Single pollution index (Pi) results were underpinned by the Geoaccumulation index (Igeo) method, in which Cd was observed as the priority pollutant with the highest contamination degree in this area. As for the most polluted landuse type, via applying Nemerow’s synthetical contamination index (PN) and Potential ecological risk index (RI), the river and rape field posed the highest ecological risks, while moderate for the rest. To quantify the drivers of the contaminants, a principal component analysis (PCA) was carried out and weathering of the watershed’s parent carbonate rocks was found to be the main possible origin, followed by anthropogenic sources induced by agricultural fertilizer. Considering the impacts of these potentially toxic elements on public health, the results of this study are essential to take preventive actions for environmental protection and sustainable development in the region.