Browsing by Subject "Inflammation"
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Item CARDIOMYOPATHY IN MALES DRIVEN BY CHRONIC IFN-G EXPOSURE IN A MOUSE MODEL OF AUTOIMMUNE DISEASE(2022-01-01) Fenimore, John Maxwell; Starz-Gaiano, Michelle; Young, Howard A; Biological Sciences; Biological SciencesCardiovascular diseases have been associated with a chronic inflammatory response and activated cell-mediated immunity. However, modeling these chronic inflammatory diseases has been difficult. Systemic lupus erythematosus (SLE), a disease that is driven by high expression of interferons (IFNs), notably both IFN-� and IFN-g, has a strong association with idiopathic cardiovascular disease. Lupus patients show a male prominence in heart disease and posthumously demonstrate indications of apparent myocarditis, a difficult to diagnose form of heart disease. We have developed a mouse model of male biased autoimmune cardiomyopathy showing a functional loss in cardiac muscle. AU nucleotide Rich Element replacement (ARE) mice have a genetic change that results in a chronic, elevated level of IFN-g in the circulation due to a substitution of the AU rich regulatory element within the IFN-g mRNA 3? UTR with random nucleotides. ARE mice present a novel model for lupus cardiomyopathy and show that the decline in cardiac function may be independent of infiltrate in myocarditis, highlighting it as being potentially a cytokine driven cardiomyopathy. Here I demonstrate male mice with our model of chronic IFN-g exposure have more severe symptoms than females where a heart failure with preserved ejection fraction develops acutely in response to stress, with an associated defect in glucose metabolism. Fatigue, a symptom often associated with autoimmune diseases and cardiomyopathies is also tied to this skeletal and cardiac muscle defect of metabolism. Furthermore, I show that chronic IFN-g exposure in males plays a role in the development of the observed fatigue and cardiomyopathy. The work in this thesis examines the effect of chronic interferon expression and sex hormones impact on the muscle cell mitochondrial pathways involving energetic metabolism and function to gain insight involved in the stress response to adrenaline and how it may impact fatigue and the development of cardiomyopathy. This study provides new insight into and offers new approaches towards the treatment of these diseases as a result of metabolic dysfunction in the host.Item HIGH MOBILITY GROUP BOX 1 (HMGB1) ENHANCES IMMUNE SUPPRESSION BY REGULATING MYELOID-DERIVED SUPPRESSOR CELL (MDSC) DIFFERENTIATION, FUNCTION, AND SURVIVAL(2015-01-01) Parker, Katherine; Ostrand-Rosenberg, Suzanne; Biological Sciences; Biological SciencesChronic inflammation is associated with malignant transformation and tumor progression. The immune system also plays a role in tumor progression, with tumor immune escape recognized as a hallmark of cancer. During tumor immune escape, tumor cells produce inflammatory molecules that promote the accumulation and function of myeloid-derived suppressor cells (MDSC). Therefore, inflammation promotes tumor progression through the induction of MDSC, which inhibits the development of anti-tumor immunity. Since the damage associated molecular pattern molecule (DAMP) and alarmin high mobility group box protein 1 (HMGB1) are pro-inflammatory and are binding partners, inducers, and/or chaperones for many of the pro-inflammatory molecules that drive MDSC, we examined HMGB1 as a potential regulator of MDSC. Using murine tumor systems, this dissertations demonstrates that HMGB1 is ubiquitously present in the tumor microenvironment, that HMGB1 can activate MDSC via the NF-?B signal transduction pathway, and that HMGB1 regulates MDSC quantity, quality, and survival. HMGB1 drives MDSC development from bone marrow progenitor cells and promotes MDSC accumulation in the tumor, spleen, and blood of tumor-bearing mice. Additionally, HMGB1 helps MDSC suppress antigen-driven activation of CD4+ and CD8+ T cells, increases MDSC production of the type 2 cytokine IL-10, enhances crosstalk between MDSC and macrophages, and facilitates MDSC'sability to down-regulate expression of the homing receptor L-selectin on naive T cells. It is well appreciated that HMGB1 facilitates tumor cell survival by inducing autophagy. Therefore, we sought to determine if HMGB1 regulates MDSC survival through the induction of autophagy. Inhibition of autophagy or HMGB1 increased the quantity of apoptotic MDSC, demonstrating that autophagy and HMGB1 prolong the survival of tumor-induced MDSC. Circulating tumor-induced MDSC have a default autophagic phenotype, while tumor-infiltrating MDSC are more autophagic. This heightened autophagic state is consistent with the notion that inflammatory conditions within the microenvironment of solid tumors contributes to tumor progression by enhancing immune suppressive MDSC. Taken together, these results demonstrate that the inflammatory molecule HMGB1 contributes to tumor progression by driving the development, function, and viability of MDSC. Therefore, the immunosuppressive activities of HMGB1 must be considered when designing cancer immunotherapies.Item Reversing Breast Cancer-Induced Immune Suppression(2015-01-01) Beury, Daniel Wirth; Ostrand-Rosenberg, Suzanne; Biological Sciences; Biological SciencesThe immune system is capable of eradicating transformed cells. However, tumor cells and host cells present in the tumor secrete pro-inflammatory mediators that promote the accumulation and activity of myeloid-derived suppressor cells (MDSC), which potently suppress anti-tumor immunity. MDSC and macrophages are present in most solid tumors and it is established that cross-talk between MDSC and macrophages impacts anti-tumor immunity; however, interactions between tumor cells and MDSC or macrophages are less well studied. Using four murine tumor cell lines, we examined potential interactions between these cells in vitro and in vivo. In vitro studies demonstrated that MDSC-secreted IL-10 decreased macrophage-derived IL-6 and TNFα, and increased nitric oxide (NO). IL-6 indirectly decreased MDSC IL-10. Tumor cells increased MDSC IL-6 and vice versa; and increased macrophage IL-6 and NO, and decreased macrophage TNFα. Tumor-cell-driven macrophage IL-6 was reduced by MDSC, and tumor cells and MDSC enhanced macrophage NO. In vivo studies identified that IL-6 and IL-10 were produced by stromal cells in the tumor. These results demonstrate that MDSC, macrophage, and tumor cell interactions potentially alter the inflammatory milieu within the tumor microenvironment and drive tumor growth. Release of reactive oxygen species (ROS) is one of the mechanisms used by MDSC to suppress anti-tumor immunity. Although ROS are toxic to most cells, MDSC survive despite their elevated content and release of ROS. Nuclear factor erythroid derived 2-like 2 (Nrf2) is a transcription factor that regulates a battery of genes which attenuate oxidative stress. Therefore, we hypothesized that MDSC resistance to ROS may be due to their up-regulation of Nrf2. Murine studies demonstrated that Nrf2 enhanced MDSC suppressive activity and increased the quantity of tumor-infiltrating MDSC by reducing their oxidative stress and rate of apoptosis. Nrf2 did not affect circulating levels of MDSC in tumor-bearing mice since the decreased apoptotic rate of tumor-infiltrating MDSC was balanced by a decreased rate of differentiation from bone marrow progenitor cells. These results demonstrate that Nrf2 regulates the generation, survival and suppressive potency of MDSC, and that a feedback homeostatic mechanism maintains a steady-state level of circulating MDSC in tumor-bearing individuals.