Pathogenic Mechanisms of Secondary Organic Aerosols.

Air pollution represents a major health problem and an economic burden. In recent years, advances in air pollution research has allowed particle fractionation and identification of secondary organic aerosol (SOA). SOA is formed from either biogenic or anthropogenic emissions, through a mass transfer from the gaseous mass to the particulate phase in the atmosphere. They can have deleterious impact on health and the mortality of individuals with chronic inflammatory diseases. The pleiotropic effects of SOA could involve different and interconnected pathogenic mechanisms ranging from oxidative stress, inflammation, and immune system dysfunction. The purpose of this review is to present recent findings about SOA pathogenic roles and potential underlying mechanisms focusing on the lungs; the latter being the primary exposed organ to atmospheric pollutants.

A Synthetic Circuit Empowering Reprogrammed B Cells for Therapeutic Proteins Expression Regulated by Tumor Detection.

Cancer remains a leading cause of death worldwide, but immunotherapies hold promises to cure it by awaking the patient's immune system to provide long-term protection. Cell therapies, involving the infusion of immune cells, either directly or genetically modified, are being developed to recognize and destroy cancer cells. Here, we explored the potential of a new synthetic circuit to reprogram B cells to cure cancers. This circuit consists in a sensor (a membrane-anchored IgG1), a transducer (a fragment of the NR4A1 promoter) and an effector molecule. Upon recognition of its target, this sensor triggers signaling pathways leading to the activation of the transducer and to effector expression (here, a reporter molecule). We showed that this circuit could discriminate tumors expressing the target antigen from those that did not, in a dose dependent manner in vitro. Going further, we replaced the original membrane-anchored sensor by an immunoglobulin expression cassette that can not only be membrane-anchored but also be secreted depending on B-cell maturation status. This allowed concomitant activation of the circuit and secretion of transgenic antibodies directed against the targeted antigen. Of note, these antibodies could correctly bind their target and were recognized by FcR expressed at the surface of immune cells, which should synergically amplify the action of the effector. The potential of reprogrammed B cells remains to be assessed in vivo by implementing a therapeutic effector. In the future, B-cell reprogramming platforms should allow personalized cancer treatment by adapting both the sensor and the therapeutic effectors to patients.

Engineering B cells with customized therapeutic responses using a synthetic circuit.

The expansion of genetic engineering has brought a new dimension for synthetic immunology. Immune cells are perfect candidates because of their ability to patrol the body, interact with many cell types, proliferate upon activation, and differentiate in memory cells. This study aimed at implementing a new synthetic circuit in B cells, allowing the expression of therapeutic molecules in a temporally and spatially restricted manner that is induced by the presence of specific antigens. This should enhance endogenous B cell functions in terms of recognition and effector properties. We developed a synthetic circuit encoding a sensor (a membrane-anchored B cell receptor targeting a model antigen), a transducer (a minimal promoter induced by the activated sensor), and effector molecules. We isolated a 734-bp-long fragment of the NR4A1 promoter, specifically activated by the sensor signaling cascade in a fully reversible manner. We demonstrate full antigen-specific circuit activation as its recognition by the sensor induced the activation of the NR4A1 promoter and the expression of the effector. Overall, such novel synthetic circuits offer huge possibilities for the treatment of many pathologies, as they are completely programmable; thus, the signal-specific sensors and effector molecules can be adapted to each disease.

Characterization of Lung Inflammatory Response to Aspergillus fumigatus Spores.

The airway exposure to Aspergillus fumigatus spores (AFsp) is associated with an inflammatory response, potentially leading to allergic and/or chronic pulmonary aspergillosis. The aim of our study is to better understand the host response, first in vitro, then in vivo, following the chronic exposure of mice to AFsp. We investigated the inflammatory response to AFsp in cell mono- and co-culture systems with murine macrophages and alveolar epithelial cells. The mice were subjected to two intranasal instillations using 105 AFsp. Their lungs were processed for inflammatory and histopathological analyses. In cell culture, the gene expressions significantly increased for TNF-α, CXCL-1, CXCL-2, IL-1ß, IL-1α and GM-CSF in macrophages, with these increases being limited for TNF-α, CXCL-1 and IL-1α in epithelial cells. In co-culture, increases in the TNF-α, CXCL-2 and CXCL-1 gene expressions were observed to be associated with increased protein levels. The in vivo lung histological analyses of mice challenged by AFsp showed cellular infiltrates in the peribronchial and/or alveolar spaces. A Bio-Plex approach on the bronchoalveolar lavage revealed significant increases in the protein secretion of selected mediators of the challenged mice compared to the unchallenged mice. In conclusion, the exposure to AFsp resulted in a marked inflammatory response of macrophages and epithelial cells. These inflammatory findings were confirmed in mouse models associated with lung histologic changes.

Magnetic Resonance Imaging of Protease-Mediated Lung Tissue Inflammation and Injury.

Pulmonary inflammation usually involves strong neutrophil recruitment with a marked release of proteases such as neutrophil elastase (NE). Noninvasive in vivo assessment of unregulated elastase activity in the lungs would provide a valuable diagnostic tool. Here, it is proposed to use Overhauser-enhanced magnetic resonance imaging (OMRI) in mice where inflammation was induced by the instillation of lipopolysaccharide (LPS). OMRI contrast in the lungs was generated by a dedicated NE free radical substrate. The free radical decayed more rapidly in LPS-treated mouse lungs than in control mice, indicating the occurrence of increased proteolysis under inflammation. Preclinical detection of abnormal proteolysis opens the way for new diagnosis modality and antiprotease testing in vivo.