a-label-free-segmentation-approach-for-intravital-imaging-mammary

A Label-Free Segmentation Approach for Intravital Imaging of Mammary Tumor Microenvironment

The ability to visualize complex and dynamic physiological interactions between numerous cell types and the extracellular matrix (ECM) within a live tumor ...

University of Wisconsin-Madison

Exposure to particulate matter (PM) has been associated with increased incidence and severity of autoimmune disease. Diesel PM is primarily composed of an elemental carbon core and adsorbed organic compounds such as polycyclic aromatic hydrocarbons (PAHs) and contributes up to 40% of atmospheric PM. The organic fraction (OF) of PM excludes all metals and inorganics and retains most organic compounds, such as PAHs. Both PM and OF increase inflammation in vitro and aggravate autoimmune disease in humans. PAHs are known aryl hydrocarbon receptor (AHR) ligands. The AHR modulates T cell differentiation and effector function in vitro and in experimental autoimmune encephalomyelitis (EAE), a murine model of autoimmune disease. This study aims to identify whether the total mass or active components of PM are responsible for activating pathways associated with exposure to PM and autoimmune disease. This study tests the hypothesis that active components present in diesel PM and their OF enhance effector T cell differentiation and aggravate autoimmune disease.

Differential effects of diesel exhaust particles on T cell differentiation and autoimmune disease.

Autoimmune diseases have increased in incidence and prevalence worldwide. While genetic predispositions play a role, environmental factors are a major contributor. Atmospheric particulate matter (PM) is a complex mixture composed of metals, nitrates, sulfates and diverse adsorbed organic compounds like polycyclic aromatic hydrocarbons (PAHs) and dioxins. Exposure to atmospheric PM aggravates autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, among others. PAHs and dioxins are known aryl hydrocarbon receptor (AHR) ligands. The AHR modulates T cell differentiation and directs the balance between effector and regulatory T cells in vitro and in experimental autoimmune encephalomyelitis (EAE), a murine model of autoimmune disease. This study aims to identify pathways that contribute to autoimmune disease and their potential use as therapeutic targets to alleviate symptoms and the need for global immunosuppression. This study tests the hypothesis that atmospheric PM enhances effector T cell differentiation and aggravates autoimmune disease.

Ambient urban dust particulate matter reduces pathologic T cells in the CNS and severity of EAE.

Atmospheric particulate matter (PM) is a complex component of air pollution that is a composed of inorganic and organic constituents. The chemically-extracted organic fraction (OF) of PM excludes inorganics but retains most organic constituents like polycyclic aromatic hydrocarbons (PAHs). PAHs are ubiquitous environmental toxicants and known aryl hydrocarbon receptor (AHR) ligands. The AHR is a ligand activated transcription factor that responds to endogenous ligands and exogenous ligands including PAHs. Activation of the AHR leads to upregulation of cytochrome P450 (CYP) metabolizing enzymes which are important for the biotransformation of toxicants to less toxic, or in the case of PAHs, more toxic intermediates. Additionally, the AHR plays an important role in balancing regulatory and effector T cell responses. This study aimed to determine whether PAHs present in PM aggravate inflammation by driving inflammatory T cell and dendritic cell (DC) responses and their mechanism of action. This study tests the hypothesis that PAHs present in PM activate the AHR and alter the immune balance shifting from regulation to inflammation. To test this, the effects of SRM1649b OF on T cell differentiation and DC function were measured in vitro. SRM1649b OF enhanced Th17 differentiation in an AHR and CYP-dependent manner and increased the percent of IFNγ positive DCs in an AHR-dependent manner. SRM1649b PAH mixtures enhanced Th17 differentiation in an AHR-dependent but CYP-independent manner and increased the percent of IFNγ positive DCs. Cumulatively, these results suggest that PAHs present in PM are active components that contribute to immune responses in both T cells and BMDCs through the AHR and CYP metabolism. Understanding the role of AHR and CYP metabolism of PAHs in immune cells after PM exposure will shed light on new targets that will shift the immune balance from inflammation to regulation.

Polycyclic aromatic hydrocarbons (PAHs) present in ambient urban dust drive proinflammatory T cell and dendritic cell responses via the aryl hydrocarbon receptor (AHR) in vitro.

Alterations in extracellular matrix composition and organization are known to promote tumor growth and metastatic progression in breast cancer through interactions with tumor cells as well as stromal cell populations. Macrophages display a spectrum of behaviors from tumor-suppressive to tumor-promoting, and their function is spatially and temporally dependent upon integrated signals from the tumor microenvironment including, but not limited to, cytokines, metabolites, and hypoxia. Through years of investigation, the specific biochemical cues that recruit and activate tumor-promoting macrophage functions within the tumor microenvironment are becoming clear. In contrast, the impact of biomechanical stimuli on macrophage activation has been largely underappreciated, however there is a growing body of evidence that physical cues from the extracellular matrix can influence macrophage migration and behavior. While the complex, heterogeneous nature of the extracellular matrix and the transient nature of macrophage activation make studying macrophages in their native tumor microenvironment challenging, this review highlights the importance of investigating how the extracellular matrix directly and indirectly impacts tumor-associated macrophage activation. Additionally, recent advances in investigating macrophages in the tumor microenvironment and future directions regarding mechano-immunomodulation in cancer will also be discussed.

Article	Year
Differential effects of diesel exhaust particles on T cell differentiation and autoimmune disease. Particle and fibre toxicology\| PubMed ID: 30143013	2018
Ambient urban dust particulate matter reduces pathologic T cells in the CNS and severity of EAE. Environmental research\| PubMed ID: 30316103	2019
Polycyclic aromatic hydrocarbons (PAHs) present in ambient urban dust drive proinflammatory T cell and dendritic cell responses via the aryl hydrocarbon receptor (AHR) in vitro. PloS one\| PubMed ID: 30576387	2018
Biomechanical Contributions to Macrophage Activation in the Tumor Microenvironment. Frontiers in oncology\| PubMed ID: 32509583	2020

Erica J. Hoffmann

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