Immunology and Infectious Disease Commons^™

The Influence Of Tert-Butylhydroquinone (Tbhq) On Acod1/Irg1-Driven Inflammatory Pathways, Alyssa M. Whisel

All Dissertations

The demand for processed foods has led to increased use of synthetic phenolic antioxidants (SPAs), notably tert-butylhydroquinone (TBHQ), to inhibit lipid oxidation and prolong shelf life. While TBHQ is deemed safe at regulated levels, concerns arise from studies indicating potential adverse effects such as oxidative stress, genotoxicity, and impaired immune function. To investigate TBHQ's immunomodulatory effects, RAW 264.7 murine macrophages were pre-treated with TBHQ and subsequently stimulated with lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid (poly I:C, PIC) to simulate bacterial or viral challenges. Results demonstrated that TBHQ at high non-cytotoxic doses reduced nitric oxide and IL-10 production while promoting phagocytosis and …

Immune Regulation In Fungal Airway Inflammation And Host Defense, Ruoning Wang

Biomedical Sciences ETDs

Asthma is a chronic inflammatory disease of the lungs characterized by complex pathophysiological mechanisms and diverse endotypes, primarily categorized as T helper type 2 cell (Th2)-high and Th2-low asthma. Despite significant advances in understanding asthma pathogenesis, the mechanisms governing the pulmonary immune system’s response to external challenges have not been fully understood. To address these gaps, this comprehensive project was designed to investigate the interplay between fungal infections and specific CD4⁺ T cell populations in asthma. Our findings suggest that fungal infections can contribute to neutrophilic asthma by promoting the migration of platelet-myeloid aggregates into the lungs. We also …

Proteolytic Manipulation Of Neutrophil Responses And The Efferocytic Synapse By Porphyromonas Gingivalis., Kelley N. Cooper

Electronic Theses and Dissertations

Porphyromonas gingivalis (Pg) is etiologically associated with chronic periodontitis, a highly prevalent chronic inflammatory disease characterized by the destruction of hard and soft tissues of the periodontium. Pg is adapted to live in the human oral subgingival niche, a hostile environment dominated by excessive numbers of activated neutrophils and antimicrobial mediators. Its survival is contingent upon prompt and effective inactivation of neutrophil effector functions. In this dissertation, I uncover a novel pathogenic mechanism employed by Pg that disarms the antimicrobial capacity of live neutrophils and simultaneously sequesters them within macrophages. Mechanistically, RgpB, a cysteine protease produced by Pg …

The Role Of Ganglioside Gd2 And Gd3 Synthase (St8sia1) In The Regulation Of Immune Suppression In Breast Cancer, Bolutyfe Oderinde

Dissertations and Theses (Open Access)

Gangliosides are acidic glycosphingolipids involved in cell adhesion, proliferation, and modulation of signal transduction pathways. It has been reported that tumor-shed gangliosides influence the activity of immune cells including macrophages, NK cells, and T cells. GD3 synthase (GD3S) is the key enzyme that regulates the biosynthesis of the b and c series gangliosides, particularly GD3 and GD2, and studies have shown that GD3S is upregulated in most tumors and plays a role in tumor progression. Similarly, we have previously found GD3S to be significantly upregulated in GD2+ breast cancer stem cells (BCSC) compared to GD2- cells, and the knockdown of …

Role Of Toll-Like Receptor 2 In Macrophage Recognition And Response To Borrelia Burgdorferi, Yukiye A. Koide

Master's Theses

Lyme disease is the most common vector-borne disease in the US and will experience an uptick as the insect host, the ixodid tick, gains habitat with climate change. The causative agent of Lyme disease, Borrelia burgdorferi, is recognized by Toll-like receptor 2 (TLR2), which initiates the innate immune response. Here, I used ELISA and SEAP detection assays to determine that knocking out TLR2 in THP-1 macrophages reduces the amount of NFkB activation, as well as IL-10 and IL-1β secretion. Then, I used fluorescence microscopy and Incucyte assays to quantify the amount of phagocytosis performed by wild-type and knock-out THP-1 cells. …

Staphylococcus Aureus Oleate Hydratase Produces Ligands That Activate Host Ppara, Christopher D. Radka, Matthew W. Frank, Tyler S. Simmons, Cydney N. Johnson, Jason W. Rosch, Charles O. Rock

Markey Cancer Center Faculty Publications

Commensal gut bacteria use oleate hydratase to release a spectrum of hydroxylated fatty acids using host-derived unsaturated fatty acids. These compounds are thought to attenuate the immune response, but the underlying signaling mechanism(s) remain to be established. The pathogen Staphylococcus aureus also expresses an oleate hydratase and 10- hydroxyoctadecanoic acid (h18:0) is the most abundant oleate hydratase metabolite found at Staphylococcal skin infection sites. Here, we show h18:0 stimulates the transcription of a set of lipid metabolism genes associated with the activation of peroxisome proliferator activated receptor (PPAR) in the RAW 264.7 macrophage cell line and mouse primary bone marrow-derived …

Endogenous Glucocorticoid Signaling Is Required For Normal Macrophage Response To H. Pylori Infection, Stuti Khadka

Graduate Theses, Dissertations, and Problem Reports (ETD)

Gastric cancer is the fifth leading cause of cancer-related deaths worldwide, affecting millions of people. H. pylori is the strongest risk factor for gastric cancer, with about 90% of the cases strongly associated with H. pylori infection. Half of the world's population is infected with this bacterium. However, only a small subset of the infected population (1-3 %) go on to develop gastric cancer. Diagnosis of the disease at an early stage is the biggest challenge because of the widespread prevalence of H. pylori infection and a long asymptomatic phase before the advanced stages. Patients are left with limited treatment …

Localized Delivery Of Gm-Csf In The Regulation Of Breast Tumor Oxygen And Anti-Tumor Immunity Through Macrophages, Nicole E. Mihalik

Graduate Theses, Dissertations, and Problem Reports (ETD)

GM-CSF has been employed as an adjuvant to cancer immunotherapies in solid tumors due to its ability to drive immune stimulatory macrophages and other myeloid cells that promote anti-tumor responses. However, GM-CSF does not always exert immune stimulatory effects on myeloid cells, and sometimes even drives immune suppressive phenotypes. GM-CSF effects on myeloid cells and the tumor microenvironment (TME) appear to vary across dosages and even cancer types. However, an optimal dosing regimen for GM-CSF has yet to be determined to-date, and this is further complicated by the fact that GM-CSF is often administered via oncolytic viruses or tumor vaccines …

Mechanistic Insights Into The Therapeutic Potential Of Adjunctive Thymosin Beta-4 Treatment In Pseudomonas Aeruginosa-Induced Keratitis, Yuxin Wang

Wayne State University Dissertations

Tβ4, a naturally occurring 43-amino acid protein, has been found to promote wound healing and reduce corneal inflammation. Topical Tβ4 as a therapeutic agent in conjunction with ciprofloxacin improves the outcome of Pseudomonas aeruginosa-induced keratitis by regulating the cellular functions of PMNs and MΦs and enhancing the production of SPMs. Understanding the mechanisms of Tβ4 provides valuable insights and novel therapeutic potential for resolving disease pathogenesis not only in the cornea but also in other infectious and immune-regulated inflammatory conditions.

Functional Comparison Of Raw 264.7 Cells And Murine Bone Marrow-Derived Macrophages (Bmdm), Quinn Harker

Undergraduate Theses and Capstone Projects

RAW 264.7 cells are an immortalized line of mouse cells that are commonly used in immunological research. They will be used to compare against murine bone marrow-derived macrophages (BMDM) to see if the two lines of cells are experimentally comparable in basic inflammatory testing. A standard method of measuring cell activity is through the analysis of nitric oxide production, which can be accomplished using a Griess reaction. Cell counts will be standardized to account for differing growth rates between the two cell lines. A similar output of nitric oxide concentration as an indicator of cellular activity between the RAW 264.7 …

The Allergy Mediator Histamine Confers Resistance To Immunotherapy In Cancer Patients Via Activation Of The Macrophage Histamine Receptor H1, Hongzhong Li, Yi Xiao, Qin Li, Jun Yao, Xiangliang Yuan, Yuan Zhang, Xuedong Yin, Yohei Saito, Huihui Fan, Ping Li, Wen-Ling Kuo, Angela Halpin, Don L Gibbons, Hideo Yagita, Zhongming Zhao, Da Pang, Guosheng Ren, Cassian Yee, J Jack Lee, Dihua Yu

Faculty, Staff and Student Publications

Reinvigoration of antitumor immunity remains an unmet challenge. Our retrospective analyses revealed that cancer patients who took antihistamines during immunotherapy treatment had significantly improved survival. We uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction. Mechanistically, HRH1-activated macrophages polarize toward an M2-like immunosuppressive phenotype with increased expression of the immune checkpoint VISTA, rendering T cells dysfunctional. HRH1 knockout or antihistamine treatment reverted macrophage immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response. Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. …

Il-10 And Tgf-Beta Increase Connexin-43 Expression And Membrane Potential Of Hl-1 Cardiomyocytes Coupled With Raw 264.7 Macrophages, Cora B. Cox

Browse all Theses and Dissertations

Cardiomyocytes and macrophages have been found to interact via connexin-43 hemichannels. The role of connexin-43, however, is not fully understood. This study shows that these interactions aid in increasing the membrane potential of cardiomyocytes allowing contraction of the cells. HL-1 cardiomyocytes and RAW 264.7 macrophages in coculture increased expression of connexin-43 compared to cardiomyocytes alone. Co-cultures also increased the fluorescence of Di-8-ANEPPS potentiometric dye indicating an increase in cardiomyocyte membrane potential. Treatment with IL-10 and TGF-beta further increased connexin-43 expression and membrane potential. Treatment with SOCS3 inhibited the effects of TGF-beta and IL-10 while having no effect on its own. …

Myelin, Cpla2, And Azithromycin: Modulation Of Macrophage Activation In Spinal Cord Injury Inflammation, Timothy J. Kopper

Theses and Dissertations--Physiology

Spinal cord injury (SCI) produces a chronic inflammatory state primarily mediated by macrophages consisting of resident microglia and infiltrating monocytes. These chronically activated SCI macrophages adopt a pro-inflammatory, pathological state that continues to cause additional damage after the initial injury and inhibits recovery. While the roles of macrophages in SCI pathophysiology are well documented, the factors contributing to this maladaptive response are poorly understood. Here, we identify the detrimental effects of myelin debris on macrophage physiology and demonstrate a novel, activation state-dependent role for cytosolic phospholipase-A2 (cPLA₂) in myelin- mediated potentiation of pro-inflammatory macrophage activation. Macrophage- mediated inflammatory …

Il-10 And Tgf-Beta Increase Connexin-43 Expression And Membrane Potential Of Hl-1 Cardiomyocytes Coupled With Raw 264.7 Macrophages, Cora B. Cox

Browse all Theses and Dissertations

Cardiomyocytes and macrophages have been found to interact via connexin-43 hemichannels. The role of connexin-43, however, is not fully understood. This study shows that these interactions aid in increasing the membrane potential of cardiomyocytes allowing contraction of the cells. HL-1 cardiomyocytes and RAW 264.7 macrophages in coculture increased expression of connexin-43 compared to cardiomyocytes alone. Co-cultures also increased the fluorescence of Di-8-ANEPPS potentiometric dye indicating an increase in cardiomyocyte membrane potential. Treatment with IL-10 and TGF-beta further increased connexin-43 expression and membrane potential. Treatment with SOCS3 inhibited the effects of TGF-beta and IL-10 while having no effect on its own. …

Regulation Of Osseous Healing By Macrophage-Derived Wnt Ligands, Jefferson Overlin Abaricia

Theses and Dissertations

Osseous healing is regulated by various classes of cells and signaling mechanisms. Of these, Wnt signaling has long been known to be critically important in directing the differentiation of mesenchymal stem cells (MSCs) into osteoblasts during bone healing. However, the source of these Wnt ligands is not known. Recently, a body of literature has arisen finding both beneficial and detrimental effects of macrophage-derived Wnt ligands on the regeneration of other tissues (liver, kidney, heart, and intestine), often by regulating inflammatory activation and stem cell behavior. As macrophages have been well-characterized as orchestrators of healing, their use of Wnt signaling to …

Impact Of Physical Activity And Cardiorespiratory Fitness On Vascular Homeostasis In Premenopausal Women Consuming A Westernized High-Fat Meal, Lauren N. Pedersen

Theses and Dissertations

A large percentage of adults in industrialized nations consume a Westernized dietary pattern, which contributes to fasting dyslipidemia and increased risk for atherosclerotic cardiovascular disease. Evidence suggests that a single Westernized meal containing high saturated fat may induce alterations in blood lipids as well as disturb multiple factors regulating peripheral vascular homeostasis, including innate immune cell function, oxidative stress, and vascular function. Conversely, participation in acute and chronic exercise may beneficially impact an individual’s postprandial response. Therefore, this dissertation contains three manuscripts seeking to describe how acute exercise, cardiorespiratory fitness, and physical activity level impact the lipemic and vascular homeostatic …

Roles Of Endothelial Cell Heat Shock Protein A12b And Β-Glucan, A Reagent For Trained Immunity In The Regulation Of Inflammation In Sepsis, Fei Tu

Electronic Theses and Dissertations

Sepsis is dysregulated host immune response to infection causing life-threatening organ dysfunction. Endothelial cell dysfunction and uncontrolled inflammatory responses are two contributors for sepsis-induced mortality. The crosstalk between endothelial and immune cells plays a critical role in the pathophysiology of sepsis. Therefore, understanding the mechanism of interaction between endothelial and immune cells will provide novel information to develop therapeutic strategies for sepsis.

Pathogen associated moleculear patterns (PAMPs) and/or damage associated molecular patterns (DAMPs) produced during sepsis, activate endothelial cells to increase the expression of adhesion molecules, attracting immune cell infiltration into the tissues. Uncontrolled inflammatory responses during the early phase …

Identification Of Imiquimod As A Potential Combination For Anti-Cd47 Antibodies In Cancer Therapy, Nicole Brittaney Pang

Scripps Senior Theses

The avenues of targeted immunotherapy offers a promise of less toxic treatment options for those battling different forms of cancer. Specifically, the process of hijacking a patient’s own immune system to fight cancer from within versus using external treatments like chemotherapy which is extremely damaging to the patient. One such avenue includes the usage of monoclonal antibodies as an effective modality for immunotherapy. Cluster of Differentiation 47 (CD47), also known as the ‘don’t eat me signal’, aids in cell proliferation and evasion of phagocytosis and has been found to be a target for stopping tumorigenesis. Previous research has been successful …

The Impact Of Aging And Mechanical Injury On Alveolar Epithelial And Macrophage Responses In Acute Lung Injury And Inflammation, Michael S. Valentine

Theses and Dissertations

Patients with severe lung pathologies, such as Acute Respiratory Distress Syndrome (ARDS), often require mechanical ventilation as a clinical intervention; however, this procedure frequently exacerbates the original pulmonary issue and produces an exaggerated inflammatory response that potentially leads to sepsis, multisystem organ failure, and mortality. This acute lung injury (ALI) condition has been termed Ventilator-Induced Lung Injury (VILI). Alveolar overdistension, cyclic atelectasis, and biotrauma are the primary injury mechanisms in VILI that lead to the loss of alveolar barrier integrity and pulmonary inflammation. Stress and strains during mechanical ventilation are believed to initiate alveolar epithelial mechanotransduction signaling mechanisms that contribute …

The Distinct Expressions Of Integrins Αdβ2 And Αmβ2 Differently Regulate Macrophage Migration In 3d Matrix In Vitro And In Tissue During Inflammation, Kui Cui

Electronic Theses and Dissertations

Chronic inflammation is an essential mechanism during the development of cardiovascular and metabolic diseases. The outcome of diseases depends on the balance between the migration and accumulation of macrophages in damaged tissues. Macrophage motility is highly regulated by adhesive receptors, integrins. Namely, intermediate expression of integrin supports macrophage migration, while a high integrin density inhibits it. Our studies are focused on evaluation of the contribution of related integrins α_Dβ₂ and α_Mβ₂ to macrophage migration and development of chronic inflammation.

We found that integrin α_Dβ₂ is upregulated on M1-macrophages in vitro and …

Regulation Of Immune Cell Activation And Functionby The Nbmpp2 Protein Andthe Cd5 Co-Receptor, Claudia Mercedes Freitas

Theses and Dissertations

According to the centers for disease control and prevention (CDC) and the world healthorganization (WHO), heart disease and immune related diseases such as diabetes and cancer areamong the leading causes of death around the world. Thus, the regulation of the function ofimmune cell plays a key role in health and disease. Calcium (Ca2+) ions play a critical role inimmune cell activation, function and in a robust immune response. Defects in Ca2+ signalinginfluences the development of cardiac disease, Alzheimer disease, immune cell metabolism,muscle dysfunction, and cancer. Each immune cell is unique in its activation and function,making it relevant to understand how …

The Response Of M0, M1, And M2 Raw246.7 Macrophage Cell Line To Hsv-1 Infection In Vitro, Amani Mohammed Alhazmi

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Herpes Simplex Virus Type 1 (HSV-1) infection occurs through the epithelial cells of the skin or mucous membranes. The beginning of the primary infection is rapid and is characterized by pain in the mouth, salivation, and submandibular lymphadenitis. The infected mucosa produces numerous, small and red lesions known as cold sores, however, many cases are asymptomatic. After the primary infection HSV-1 moves through the nerve to stay in trigeminal ganglia and to cause a recurrent infection from time to time. In the early hours of the HSV-1 infection, the cytokines produced by infected cells are critical in the stimulation of …

The Effects Of Socs1 And Socs3 Peptide Mimetics On Macrophage Phagocytosis Of Malignant Cells, Tahirah M. Madkhali

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Macrophages are essential phagocytic cells involved in both innate and adaptive immune systems and play vital roles in the host defense and inflammation. Macrophages have a remarkably high capacity to clear unnecessary cellular materials in interstitial environment through a process called “phagocytosis”, which is affected by many factors including suppressors of cytokine signaling (SOCS). SOCSs are a group of intracellular proteins that downregulate the cytokine signals involved in various JAK/STAT pathways through a negative feedback loop. This study focuses on investigating the effects of SOCS1 and SOCS3 on the phagocytic ability of RAW 264.7 macrophages polarized into M2a with IL-4/IL-13 …

Macrophages But Not Astrocytes Harbor Hiv Dna In The Brains Of Hiv-1-Infected Aviremic Individuals On Suppressive Antiretroviral Therapy, Allen Ko, Guobin Kang, Julian B. Hattler, Hadiza I. Galadima, Junfeng Zhang, Qingsheng Li, Woong-Ki Kim

Community & Environmental Health Faculty Publications

The question of whether the human brain is an anatomical site of persistent HIV-1 infection during suppressive antiretroviral therapy (ART) is critical, but remains unanswered. The presence of virus in the brains of HIV patients whose viral load is effectively suppressed would demonstrate not only the potential for CNS to act as an anatomical HIV reservoir, but also the urgent need to understand the factors contributing to persistent HIV behind the blood-brain barrier. Here, we investigated for the first time the presence of cells harboring HIV DNA and RNA in the brains from subjects with undetectable plasma viral load and …

Microbial Co-Infection Alters Macrophage Polarization, Phagosomal Escape, And Microbial Killing, Nikita H. Trivedi, Jieh-Juen Yu, Chiung-Yu Hung, Richard P. Doelger, Christopher S. Navara, Lisa Y. Armitige, Janakiram Seshu, Anthony P. Sinai, James P. Chambers, M. Neal Guentzel, Bernard P. Arulanandam

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Macrophages are important innate immune cells that respond to microbial insults. In response to multi-bacterial infection, the macrophage activation state may change upon exposure to nascent mediators, which results in different bacterial killing mechanism(s). In this study, we utilized two respiratory bacterial pathogens, Mycobacterium bovis (Bacillus Calmette Guẻrin, BCG) and Francisella tularensis live vaccine strain (LVS) with different phagocyte evasion mechanisms, as model microbes to assess the influence of initial bacterial infection on the macrophage response to secondary infection. Non-activated (M0) macrophages or activated M2-polarized cells (J774 cells transfected with the mouse IL-4 gene) were first infected with BCG for …

Virus Production And Cell Viability Of Hsv-1-Infected Murine Keratinocytes (Hel-30) Co-Cultured With Murine Macrophages (Raw 264.7), Barry Graffagna

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Keratinocytes are the most abundant type of cell in the outer layer of skin, the epidermis, and provide barrier against pathogens from invading. However, Herpes Simplex Virus Type 1 (HSV-1) targets these keratinocytes for infection, and later infects neurons to establish lifelong latency. The keratinocytes stimulate the innate immune system to engage and to destroy the virus. Among the cells of the innate immune system to respond to the viral invasion is the macrophage. In this study, RAW 264.7 macrophage and HEL-30 keratinocyte monolayers were challenged in vitro with HSV-1 at a multiplicity of infection (MOI) of 0.1 to investigate …

Antibody Dependent Enhancement Of Visceral Leishmaniasis, Alan K. Mcnolty

All Master's Theses

Leishmaniasis is a parasitic disease caused by protozoans of the genus Leishmania. This vector-born disease, transmitted by biting phlebotomine sandflies, typically manifests in one of three ways. The cutaneous form of the disease is characterized by localized lesions of the skin and is by far the most common manifestation. The visceral form of the disease is caused by parasitic infiltration of internal organs, particularly the spleen, liver, and bone marrow. The mucocutaneous form is caused by parasitic infection of the mucosa in the nose or mouth. While cutaneous leishmaniasis (CL) is often self-healing, visceral leishmaniasis (VL) is fatal if …

Hsv-1 Replication In Different Raw 264.7 And J774.1 Macrophage Phenotypes And Macrophage Viability Following Hsv-1 Infection, Yousef Nifaj Alanazi

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HSV-1 is a ubiquitous virus capable of causing lifelong latent infection. The virus contains a large double strand DNA genome covered by an icosahedral capsid. HSV-1 is a cytolytic virus which can cause a lethal infection. The virus possesses critical protein ICP0 which is capable of interfering with host cell signaling and eventually prevent cell apoptosis. Innate immunity plays a crucial role in defense against HSV-1 infection and macrophage plays a significant role in the innate immune system. Macrophage cells can alter their behavior depending upon certain stimuli and tissue environments. Naive macrophage (M0) cells can be polarized to a …

Engineering Surface Properties To Modulate Inflammation And Stem Cell Recruitment Through Macrophage Activation, Kelly M. Hotchkiss

Theses and Dissertations

Biomaterials are becoming the most commonly used therapeutic method for treatment of lost or damaged tissue in the body. Metallic materials are chosen for high strength orthopaedic and dental applications. Titanium (Ti) implants are highly successful in young, healthy patients with the ability to fully integrate to surrounding tissue. However the main population requiring these corrective treatments will not be healthy or young, therefore further research into material modifications have been started to improve outcomes in compromised patients. The body’s immune system will generate a response to any implanted material, and control the final outcome. Among the first and most …

Ticks, Ixodes Scapularis, Feed Repeatedly On White-Footed Mice Despite Strong Inflammatory Response: An Expanding Paradigm For Understanding Tick-Host Interactions, Jennifer M. Anderson, Ian N. Moore, Bianca M. Nagata, José M.C. Ribeiro, Jesus G. Valenzuela, Daniel E. Sonenshine

Biological Sciences Faculty Publications

Ticks transmit infectious agents including bacteria, viruses and protozoa. However, their transmission may be compromised by host resistance to repeated tick feeding. Increasing host resistance to repeated tick bites is well known in laboratory animals, including intense inflammation at the bite sites. However, it is not known whether this also occurs in wild rodents such as white-footed mice, Peromyscus leucopus, and other wildlife, or if it occurs at all. According to the "host immune incompetence" hypothesis, if these mice do not have a strong inflammatory response, they would not reject repeated tick bites by Ixodes scapularis. To test …