Polymerization of misfolded protein lowers CX3CR1 expression in human PBMCs

AbstractThe CX3CR1 (chemokine (C-X3-C motif) receptor 1) expression levels on immune cells have significant importance in maintaining tissue homeostasis under physiological and pathological conditions. The factors implicated in the regulation of CX3CR1 and its specific ligand CX3CL1 (fractalkine) expression remain largely unknown. Recent studies provide evidence that host‘s misfolded proteins occurring in the forms of polymers or amyloid fibrils can regulate CX3CR1 expression. Herein, we present a novel example that polymers of human ZZ alpha1-antitrypsin (Z-AAT) protein, resulting from its conformational misfolding due to the Z (Glu342Lys) mutation in SERPINA1 gene, strongly lower CX3CR1 expression in human PBMCs. We also show that extracellular polymers of Z-AAT are internalized by PBMCs, which parallels with increased intracellular levels of CX3CR1 protein. Our findings support the role of extracellular misfolded proteins in CX3CR1 regulation and encourage conducting further studies on this issue.

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Polymerization of misfolded Z alpha-1antitrypin protein lowers CX3CR1 expression in human PBMCs

eLife ◽

10.7554/elife.64881 ◽

2021 ◽

Vol 10 ◽

Author(s):

Srinu Tumpara ◽

Matthias Ballmaier ◽

Sabine Wrenger ◽

Mandy König ◽

Matthias Lehmann ◽

...

Keyword(s):

Immune Cells ◽

Amyloid Fibrils ◽

Tissue Homeostasis ◽

Misfolded Proteins ◽

Human Pbmcs ◽

Pathological Conditions ◽

Alpha 1 Antitrypsin ◽

Specific Ligand ◽

Cx3cr1 Expression

The CX3CR1 (chemokine (C-X3-C motif) receptor 1) expression levels on immune cells have significant importance in maintaining tissue homeostasis under physiological and pathological conditions. The factors implicated in the regulation of CX3CR1 and its specific ligand CX3CL1 (fractalkine) expression remain largely unknown. Recent studies provide evidence that host`s misfolded proteins occurring in the forms of polymers or amyloid fibrils can regulate CX3CR1 expression. Herein, a novel example demonstrates that polymers of human ZZ alpha-1 antitrypsin (Z-AAT) protein, resulting from its conformational misfolding due to the Z (Glu342Lys) mutation in SERPINA1 gene, strongly lower CX3CR1 mRNA expression in human PBMCs. This parallels with increase of intracellular levels of CX3CR1 and Z-AAT proteins. Presented data indicate the involvement of the CX3CR1 pathway in the Z-AAT-related disorders and further support the role of misfolded proteins in CX3CR1 regulation.

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Role of Leptin in the Activation of Immune Cells

Mediators of Inflammation ◽

10.1155/2010/568343 ◽

2010 ◽

Vol 2010 ◽

pp. 1-8 ◽

Cited By ~ 201

Author(s):

Patricia Fernández-Riejos ◽

Souad Najib ◽

Jose Santos-Alvarez ◽

Consuelo Martín-Romero ◽

Antonio Pérez-Pérez ◽

...

Keyword(s):

Immune Response ◽

Immune Cells ◽

Energy Homeostasis ◽

Humoral Factors ◽

Endocrine Organ ◽

Pathological Conditions ◽

Immune Mediated ◽

Infection Susceptibility

Adipose tissue is an active endocrine organ that secretes various humoral factors (adipokines), and its shift to production of proinflammatory cytokines in obesity likely contributes to the low-level systemic inflammation that may be present in metabolic syndrome-associated chronic pathologies such as atherosclerosis. Leptin is one of the most important hormones secreted by adipocytes, with a variety of physiological roles related to the control of metabolism and energy homeostasis. One of these functions is the connection between nutritional status and immune competence. The adipocyte-derived hormone leptin has been shown to regulate the immune response, innate and adaptive response, both in normal and pathological conditions. The role of leptin in regulating immune response has been assessed in vitro as well as in clinical studies. It has been shown that conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders such as autoimmune diseases are associated with increased secretion of leptin and production of proinflammatory pathogenic cytokines. Thus, leptin is a mediator of the inflammatory response.

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The Role of Immune Cells in the Brain during Physiological and Pathological Conditions

Psychiatric Annals ◽

10.3928/00485713-20150501-05 ◽

2015 ◽

Vol 45 (5) ◽

pp. 232-239 ◽

Cited By ~ 1

Author(s):

Tina C. Franklin ◽

Eric S. Wohleb ◽

Ronald S. Duman

Keyword(s):

Immune Cells ◽

Pathological Conditions ◽

The Brain

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The Detrimental and Beneficial Functions of Macrophages After Cochlear Injury

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.631904 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yuan Zhang ◽

Yiyuan Li ◽

Xiaolong Fu ◽

Pengjun Wang ◽

Qin Wang ◽

...

Keyword(s):

Immune Cells ◽

Spiral Ganglion ◽

Morphological Characteristics ◽

Acoustic Trauma ◽

Spiral Ganglion Neuron ◽

Exact Role ◽

Pathological Conditions ◽

Age Related ◽

Ototoxic Drug

Macrophages are the main intrinsic immune cells in the cochlea; they can be activated and play a complicated role after cochlear injury. Many studies have shown that the number of macrophages and their morphological characteristics within the major cochlear partitions undergo significant changes under various pathological conditions including acoustic trauma, ototoxic drug treatment, age-related cochlear degeneration, selective hair cell (HC) and spiral ganglion neuron (SGN) elimination, and surgery. However, the exact role of these macrophages after cochlear injury is still unclear. Regulating the migration and activity of macrophages may be a therapeutic approach to reduce the risk or magnitude of trauma-induced hearing loss, and this review highlights the role of macrophages on the peripheral auditory structures of the cochlea and elucidate the mechanisms of macrophage injury and the strategies to reduce the injury by regulating macrophage.

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Emerging Role of Angiotensin AT2 Receptor in Anti-Inflammation: An Update

Current Pharmaceutical Design ◽

10.2174/1381612826666200115092015 ◽

2020 ◽

Vol 26 (4) ◽

pp. 492-500 ◽

Cited By ~ 1

Author(s):

Sanket N. Patel ◽

Naureen Fatima ◽

Riyasat Ali ◽

Tahir Hussain

Keyword(s):

Nitric Oxide ◽

Angiotensin Ii ◽

Cell Survival ◽

Immune Cells ◽

Therapeutic Target ◽

At2 Receptor ◽

Pathological Conditions ◽

Promote Cell Survival ◽

Anti Inflammation

The hyperactive RAS and inflammation are closely associated. The angiotensin-II/AT1R axis of the RAS has been explored extensively for its role in inflammation and a plethora of pathological conditions. Understanding the role of AT2R in inflammation is an emerging area of research. The AT2R is expressed on a variety of immune and non-immune cells, which upon activation triggers the release of a host of cytokines and has multiple effects that coalesce to anti-inflammation and prevents maladaptive repair. The anti-inflammatory outcomes of AT2R activation are linked to its well-established signaling pathways involving formation of nitric oxide and activation of phosphatases. Collectively, these effects promote cell survival and tissue function. The consideration of AT2R as a therapeutic target requires further investigations.

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Roles of IL-1 in Cancer: From Tumor Progression to Resistance to Targeted Therapies

International Journal of Molecular Sciences ◽

10.3390/ijms21176009 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6009

Author(s):

Valerio Gelfo ◽

Donatella Romaniello ◽

Martina Mazzeschi ◽

Michela Sgarzi ◽

Giada Grilli ◽

...

Keyword(s):

Immune Response ◽

Tumor Cells ◽

Immune Cells ◽

Feedback Loop ◽

Innate Immune ◽

Critical Function ◽

Positive Feedback Loop ◽

Pathological Conditions ◽

Cancer Initiation

IL-1 belongs to a family of 11 members and is one of the seven receptor-agonists with pro-inflammatory activity. Beyond its biological role as a regulator of the innate immune response, IL-1 is involved in stress and chronic inflammation, therefore it is responsible for several pathological conditions. In particular, IL-1 is known to exert a critical function in malignancies, influencing the tumor microenvironment and promoting cancer initiation and progression. Thus, it orchestrates immunosuppression recruiting pro-tumor immune cells of myeloid origin. Furthermore, new recent findings showed that this cytokine can be directly produced by tumor cells in a positive feedback loop and contributes to the failure of targeted therapy. Activation of anti-apoptotic signaling pathways and senescence are some of the mechanisms recently proposed, but the role of IL-1 in tumor cells refractory to standard therapies needs to be further investigated.

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PD-L1 Inhibitors for the Treatment of Prostate Cancer

Current Drug Targets ◽

10.2174/1389450121666200609142219 ◽

2020 ◽

Vol 21 (15) ◽

pp. 1558-1565

Author(s):

Matteo Santoni ◽

Francesco Massari ◽

Liang Cheng ◽

Alessia Cimadamore ◽

Marina Scarpelli ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trials ◽

T Lymphocytes ◽

Chronic Inflammation ◽

Immune Cells ◽

Response To Therapy ◽

Complex Series

The carcinogenesis of prostate cancer (PCa) results from a complex series of events. Chronic inflammation and infections are crucial in this context. Infiltrating M2 type macrophages, as well as neutrophils and T lymphocytes, contribute to PCa development, progression and response to therapy. The preliminary findings on the efficacy of immunotherapy in patients with PCa were not encouraging. However, a series of studies investigating anti-PD-L1 agents such as Atezolizumab, Avelumab and Durvalumab used alone or in combination with other immunotherapies, chemotherapy or locoregional approaches are in course in this tumor. In this review, we illustrate the role of immune cells and PD-L1 expression during PCa carcinogenesis and progression, with a focus on ongoing clinical trials on anti-PD-L1 agents in this context.

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Dietary Carotenoids in Managing Metabolic Syndrome and Role of PPARs in the Process

Current Nutrition & Food Science ◽

10.2174/1573401315666190619111557 ◽

2020 ◽

Vol 16 (6) ◽

pp. 846-853

Author(s):

Raghunandan Purohith ◽

Nagendra P.M. Nagalingaswamy ◽

Nanjunda S. Shivananju

Keyword(s):

Metabolic Syndrome ◽

Dietary Intervention ◽

Bioactive Constituents ◽

Dietary Antioxidants ◽

Predisposing Factor ◽

Beneficial Effects ◽

Pathological Conditions ◽

Established Relationship ◽

Comprehensive Study

Metabolic syndrome is a collective term that denotes disorder in metabolism, symptoms of which include hyperglycemia, hyperlipidemia, hypertension, and endothelial dysfunction. Diet is a major predisposing factor in the development of metabolic syndrome, and dietary intervention is necessary for both prevention and management. The bioactive constituents of food play a key role in this process. Micronutrients such as vitamins, carotenoids, amino acids, flavonoids, minerals, and aromatic pigment molecules found in fruits, vegetables, spices, and condiments are known to have beneficial effects in preventing and managing metabolic syndrome. There exists a well-established relationship between oxidative stress and major pathological conditions such as inflammation, metabolic syndrome, and cancer. Consequently, dietary antioxidants are implicated in the remediation of these complications. The mechanism of action and targets of dietary antioxidants as well as their effects on related pathways are being extensively studied and elucidated in recent times. This review attempts a comprehensive study of the role of dietary carotenoids in alleviating metabolic syndromewith an emphasis on molecular mechanism-in the light of recent advances.

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