978 research outputs found
Interview with Michal Raz, author, What’s Wrong with the Poor? Psychiatry, Race, and the War on Poverty
No full textIn What’s Wrong with the Poor: Psychiatry, Race, and the War on Poverty (University of North Carolina Press, 2016), Mical Raz offers a deep dive into the theoretical roots of the Head Start program, and offers a fascinating story of unexpected policy origins and of the interplay between psychiatric theory, race, and U.S. social welfare policy
Jamie Metzl Hacking Darwin: Genetic Engineering and the Future of Humanity. Naperville, IL: Sourcebooks, 2019, 352 pp.
No full textJamie Metzl is a geopolitical expert and science fiction writer. He is the author of a
book on the Cambodian genocide and three novels. Hacking Darwin is his first nonfiction book dealing with the topic of human genetic enhancement
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The role of ROR gamma and ROR gamma t in lung inflammation and lung cancer in mice
No full textLung cancer (LC) is the leading cause of cancer death worldwide. While smoking remains the predominant cause of LC, LC in never-smokers accounts for up to 25% of all LC incidents. Clinical Studies have shown that people diagnosed with a chronic inflammatory lung disease such as chronic obstructive pulmonary disease (COPD) and possibly asthma are at increased risk of LC. Previous studies in the lab have identified that chronic lung inflammation caused by long-term exposure to the allergen House Dust Mite (HDM) leads to the acceleration of LC in mice. This is due to an increase of a subtype of lung inflammation, in which the Nod-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome and interleukin-1 (IL-1β) signaling pathway is chronically activated in lung macrophages. The present study looked downstream of IL-1β signaling at the transcription factors RORγ and RORγt. Our results show that the pharmacological inhibition of RORγ/γt using digoxin decreased LC development in a KrasG12D-driven LC model. Additionally, we found that IL-1β signaling and RORγ inhibition do not affect LC cell proliferation and survival in vitro using the Lewis Lung Carcinoma (LLC) cells. Furthermore, the anti-tumor effect of digoxin is essentially inhibited in absence of T cells in Rag1 KO mice, suggesting that the observed effect is likely due to the inhibition of RORγt in Th17 cells and other RORγt-expressing immune cells (e.g., ILC3, NK cells) rather than a direct effect on LC cells
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The Effect of House Dust Mites and Allergic Airway Inflammation on Lung Carcinogenesis
No full textUnlike other lung diseases such as chronic obstructive pulmonary disorder (COPD), the relationship between asthma and lung cancer has not been well established. However, our studies conducted in mouse models of asthma suggest that asthma represent a potential risk for lung cancer. The mechanism behind how asthma promotes lung cancer development still needs further study; however, we found that chronic airway inflammation was important for this effect. Furthermore, adaptive immunity was found to not play a significant role in the initiation of lung cancer development but may impact the regulation of the growth of cancer cells. Finally, the consequences of allergic airway inflammation and its impact on lung cancer development are the subject of our current studies in our laboratory
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The Potential Effect of Chitin on Lung Inflammation and Lung Cancer Progression in Mice
No full textPrevious investigations in the laboratory demonstrated that chronic exposure to house dust mites (HDM), a common indoor aeroallergen associated with the development of asthma, accelerates lung cancer (LC) development in mice. The tumor-promoting effect of HDM was mainly due to NLRP3 inflammasome activation in macrophages and increased IL-1β production as the blockade of these molecules abrogated the effect of HDM on tumor development. Interestingly, the lung tumor-promoting effect of HDM was not completely abolished by heat treatment of the HDM extract, suggesting that the heat-insensitive factors play a role in its pro-tumorigenic effect. Chitin, a component of the HDM exoskeleton, is an abundant 1,4-beta blinked N-glucosamine polymer that is rigid and hard to degrade. Here we performed additional mechanistic studies using the RAW 264.7 mouse macrophage cell line and bone marrow-derived macrophages (BMDMs), and investigated the specific effect of chitin, a major constituent of HDM, on IL-1β production. We also test the effect of chronic exposure to chitin on LC development in a genetically engineered mouse model (GEMM) of mutated KRAS
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cAMP in dendritic cell alters the fate of Th2 and Th17 responses
No full textDendritic cells are professional antigen presenting cells that activate naïve T cell to promote specific T cell responses. Until recently, the DCs’ recognition of microbial or inflammatory stimuli through PRRs was solely recognized to initiate DCs’ maturation. On the other hand, the role of PRR-independent activation of DCs has remained largely unexplored. This thesis will focus on a recent discovery of cAMP dependent DCs’ maturation. We treated various types of DCs with GPCR ligands and other regulators affecting GPCR/cAMP pathway. Here, we show that DCs’ varying levels of cAMP determine DCs’ ability to promote either Th2 responses or Th17 responses. We discovered that the increased cAMP level reduced the expression of DC’s transcription factors like IRF4 and KLF4. Subsequently, DC’s increased cAMP level reduced Th2 responses and increased Th17 responses. In fact, this cAMP dependent DC maturation is so robust that inducing cAMP signaling alone allowed Th2-promoting DC to switch into Th17-promoting DC. Surprisingly, we discovered that DC’s expression of IRF5 and inhibition of IRF4 are essential in Th17 polarization. In addition, we also described the implication of GPCR/cAMP pathway’s role in the onset of neutrophilic asthma. Th2 response in the airway is known to promote eosinophilic asthma while additional Th17 response induce neutrophilic asthma. Here, we show that a long-term exposure to asthma’s common bronchodilator, LABA, also switches Th2 mediated eosinophilic asthma into Th17 mediated neutrophilic asthma by elevating DC’s cAMP level. These findings delineate an unforeseen contribution of cAMP signaling in the regulation of innate and adaptive immunity
Phosphorothioate backbone modification changes the pattern of responses to CpG
No full textBacterial DNA is immunostimulatory due to the presence of specific unmethylated CpG-containing sequences (1). The activity of bacterial DNA can be mimicked by oligonucletides (ODN) (2), and this has been critical in establishing the sequence requirements for activation. Both native phosphodiester oligonucleotides and phosphorothioate-modified oligonucleotides (PO-ODN and PS-ODN) of various sequences can activate macrophages, dendritic cells, and B lymphocytes. Although PO-ODN are the most relevant to the role of bacterial or viral DNA in the host response to infection, stabilized synthetic oligonucleotides have great potential in immunotherapy. Normal phosphodiester oligonucleotides are short-lived in vivo (3) and incapable of giving effective therapeutic immunostimulation. The most frequent means of stabilizing oligonucleotides is by phosphorothioate modification of the backbone, whereby one of the nonbridging oxygens of the phosphate group is converted to sulfur. Phosphorothioates are poor substrates for most cellular nucleases. CpG PS-ODN display many of the activities of bacterial DNA, but owing to evidence of phosphorothioate-specific activity, caution has been urged in their use as a model of bacterial DNA in infection (4,5). Although PS-ODN are now widely used in studies on the immunostimulatory effects of CpG-containing DNA, it is appropriate to ask whether they mimic all the actions of native phosphodiester DNA. In this article, we review literature on activities of PS-ODN and discuss our own comparisons of the action of PSand PO-ODN on macrophage activation
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Long-acting b2 adrenergic agonists (LABAs) provoke Th17-biased asthma
No full textAsthma is a heterogeneous disease with distinct features of airway hyper-responsiveness (AHR) and mucus secretion. In general, long-acting b2 adrenergic agonists (LABAs) are commonly recommended for asthma patients to reduce these symptoms. When LABAs act on airway smooth muscle (ASM), they bind to ASM’s b2 adrenergic receptors (b2ARs) to increase cAMP, which induces bronchodilation effect to ameliorate the AHR. In our previous study, we observed that the G protein-coupled receptors (GPCRs) in dendritic cells (DCs) triggers the Th17 differentiation of naïve T lymphocytes via cAMP signaling. Such a pro-Th17 activity is a serious response because it induces neutrophilic asthma with more severe inflammation. Thus, LABAs, which directly target b2AR of both ASM and lung DCs, need re-evaluation for their risk of causing severe inflammation. Therefore, we examined whether LABAs trigger b2AR of lung DCs and activate Th17 differentiation in asthma. Our results demonstrated that LABA treatment induced Th17 response in both murine DCs and human DC-like cell lines in vitro. Also, we observed that LABA inhalation triggered neutrophilic asthma in vivo. After we had confirmed the side-effect of LABAs, we further examined the combination of LABAs with Inhaled corticosteroids (ICS). Our results from LABA-ICS combination administration showed that the LABA-ICS combination inhibited both Th2 and Th17 response in asthma, supporting the anti-inflammatory effect of ICS with LABAs. Conclusively, we showed that LABAs have a side-effect of inducing neutrophilic asthma with its Th17 response, which suggests that the continuing use of LABAs may worsen the asthmatic symptoms of LABAs users
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A Single-Cell Transcriptomic Profiling of the Effects of House Dust Mite Exposure on the Murine Lung Microenvironment
No full textHouse Dust Mite (HDM) is a common aeroallergen that can induce asthma and allergic airway inflammation. The effects of acute exposure to HDM have been well studied in various mouse models asthma; however, the effects of chronic exposure have been much less investigated. Our studies identified that chronic exposure to HDM induces chronic lung inflammation and accelerates lung cancer development in two different mouse models of lung cancer. The lung cancer-promoting effect of HDM was mainly due to chronic activation of the NLRP3 inflammasome in lung macrophages and persistent production of IL-1β in the lungs. Based on these findings, we hypothesize that chronic exposure to HDM changes the lung microenvironment and makes it conducive to tumor growth by activating the IL-1β signaling pathway. To further evaluate the mechanisms by which HDM affects the lung microenvironment, we conducted a single-cell RNA sequencing (scRNA-seq) analysis and compared the effect of chronic HDM exposure in the lungs of wild-type (WT) and IL-1β knock out (KO) mice. Our findings suggest that HDM and IL-1β signaling affect various cell types such as macrophage, neutrophils, and T cells and their gene profiles that may contribute to the protumorigenic effects of HDM and IL-1β in the lungs. In conclusion, our study revealed the transcriptomic landscape of the murine lung microenvironment and uncovered the effects of chronic HDM exposure and IL-1β signaling
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ROR-gamma-t Inhibition Reduces Lung Cancer Development in Mice
No full textChronic inflammation has long been recognized as a driving factor for cancer, including lung cancer. However, the specific inflammatory cells and pathways involved in supporting tumor growth remain poorly understood. Here, we studied the effect ofdigoxin, an inhibitor of the Retinoic Acid Receptor-Related Orphan Receptor Gamma and Gamma t (RORγ/γt) transcription factors, in two mouse models of lung cancer. We found that digoxin significantly reduced tumor growth in the KrasG12D model and the urethane-induced lung cancer model. Mechanically, digoxin decreased lung infiltration by RORγt+ CD4+ lymphocytes (Th17 cells) and the secretion of pro-inflammatory cytokines like interleukin 17A (IL-17A), IL-17F, and IL-22 by these cells in the tumor microenvironment (TME). Notably, digoxin showed no direct cytotoxicity on tumor cells, suggesting an indirect mechanism of action through inhibition of RORγt+ immune cells. Furthermore, we found in Rag1−/− mice that digoxin also inhibited RORγt+ innate immune cells, such as type 3 innate lymphoid cells (ILC3s) and natural killer 17 (NK17) cells. In conclusion, our study suggests that inhibiting RORγt can reshape the TME by decreasing pro-tumor inflammation; therefore, providing a potential target for future cancer therapies
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