scholarly journals Oxidative-Inflammatory Stress in Immune Cells from Adult Mice with Premature Aging

2019 ◽  
Vol 20 (3) ◽  
pp. 769 ◽  
Author(s):  
Antonio Garrido ◽  
Julia Cruces ◽  
Noemí Ceprián ◽  
Elena Vara ◽  
Mónica de la Fuente
Keyword(s):  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Premature Aging ◽  
Antioxidant Defenses ◽  
Inflammatory Stress ◽  
Adult Mice ◽  
Regulatory Systems ◽  
Peritoneal Leukocytes ◽  
B Mice ◽  
Cd1 Mice

Oxidative and inflammatory stresses are closely related processes, which contribute to age-associated impairments that affect the regulatory systems such as the immune system and its immunosenescence. Therefore, the aim of this work was to confirm whether an oxidative/inflammatory stress occurs in immune cells from adult mice with premature aging, similar to that shown in leukocytes from chronologically old animals, and if this results in immunosenescence. Several oxidants/antioxidants and inflammatory/anti-inflammatory cytokines were analyzed in peritoneal leukocytes from adult female CD1 mice in two models of premature aging—(a) prematurely aging mice (PAM) and (b) mice with the deletion of a single allele (hemi-zygotic: HZ) of the tyrosine hydroxylase (th) gene (TH-HZ), together with cells from chronologically old animals. Several immune function parameters were also studied in peritoneal phagocytes and lymphocytes. The same oxidants and antioxidants were also analyzed in spleen and thymus leukocytes. The results showed that the immune cells of PAM and TH-HZ mice presented lower values of antioxidant defenses and higher values of oxidants/pro-inflammatory cytokines than cells from corresponding controls, and similar to those in cells from old animals. Moreover, premature immunosenescence in peritoneal leukocytes from both PAM and TH-HZ mice was also observed. In conclusion, adult PAM and TH-HZ mice showed oxidative stress in their immune cells, which would explain their immunosenescence.

scholarly journals Downregulation of Morrbid in Tet2-Deficient Preleukemic Cells Overcomes Resistance to Inflammatory Stress and Mitigates Clonal Hematopoiesis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1288-1288
Author(s):  
Zhigang Cai ◽  
Jonathan Kotzin ◽  
Baskar Ramdas ◽  
Sisi Chen ◽  
Sai Nelanuthala ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Clinical Benefit ◽  
Myeloid Cells ◽  
Whole Body ◽  
Single Mutation ◽  
Hematopoietic Stem ◽  
Inflammatory Stress ◽  
Clonal Hematopoiesis ◽  
Cytokines And Chemokines

Abstract Myeloid malignancies including AML, CMML, MPN and MDS are considered clonal blood disorders. Hematopoietic stem and progenitor cells (HSPCs) with mutation(s) in AML-related genes such as TET2 or DNMT3A represent what are commonly defined as preleukemic HSPCs. The selection and expansion of preleukemic-HSPC clones precedes the development of AML. Additionally, preleukemic-HSPCs can transform through serial acquisition of additional somatic mutations over time and contribute to the development of full-blown AML. What is unclear is the nature of environmental signals that might contribute to the "switch" from a preleukemic state to a leukemic state in these cells. In this context, inflammation has been hypothesized to play an essential role, but precisely how inflammatory signals influence the growth, survival, differentiation and the overall engraftment potential of preleukemic-HSPCs is yet to be determined. Mouse models carrying loss of function alleles in Tet2 or Dnmt3a manifest an expanded HSPC pool, including a hematopoietic stem cell (HSC)-enriched fraction defined by cell surface markers Lineage-/Sca-1+/c-Kit+ (LSK). Some of these genetically modified mice go on to develop CMML or MPN with modest penetration when aged. Majority of pre-leukemic mutations on their own are insufficient to cause AML in mice, suggesting that a single mutation among the above-described mutations define a pre-leukemic state and perhaps additional cooperating mutations are necessary to provide a more effective selection advantage for preleukemic-HSPC leading to the development of full-blown leukemia. Inflammation has been linked to tumor induction and transformation in solid tissues. Inflammation caused by environmental exposure, infection, autoimmunity, or ageing may result in mutations and genomic instability in somatic cells as well as in reprogramming of the tumor microenvironment (i.e. through regulating angiogenesis and expression of cytokines and chemokines). Considering that both innate and adaptive immune cells are generated from HSPCs and are involved in regulating local as well as whole-body inflammatory processes, the relationship between inflammation and hematopoietic malignancies is likely to be complex. While the influence of inflammatory stress on normal HSPCs has recently gained significant attention, little is known about how preleukemic HSPCs respond to inflammation. Because HSPCs reside in the bone marrow and are surrounded by mature immune cells, the inflammatory microenvironment is likely to influence the growth and self-renewal of these cells in part by producing pro-inflammatory cytokines and chemokines. In support of this hypothesis are epidemiologic findings demonstrating that infection may act as a trigger for AML development in humans. In the present study, we asked whether Tet2-deficient HSPCs maintain growth and survival advantage during pathological stress by examining how Tet2-KO preleukemic-HSPCs respond to acute and chronic inflammation. We show a rapid increase in the frequency and absolute number of Tet2-deficient mature myeloid cells and HSPCs in response to acute inflammatory stress, which results in enhanced production of inflammatory cytokines, including IL-6, and resistance to apoptosis. Functionally, Tet2-deficient preleukemic-HSPCs showed resistance to inflammation-induced damage and apoptosis relative to controls. IL-6 induces hyperactivation of the Shp2-Stat3 signaling axis, resulting in increased expression of a novel anti-apoptotic lncRNA Morrbid in Tet2-KO myeloid cells and HSPCs. Expression of activated Shp2 in HSPCs phenocopies Tet2 loss, with regard to hyperactivation of Stat3 and Morrbid. In vivo, pharmacologic inhibition of Shp2 or Stat3 or genetic loss of Morrbid in Tet2-deficient mice rescues inflammatory stress-induced abnormalities in HSPCs and mature myeloid cells including clonal hematopoiesis. Our results suggest that the anti-inflammatory drugs E3330 and SHP099, which suppress the hyper-activation of Morrbid, could be of clinical benefit for TET2 mutations-induced clonal hematopoiesis and leukemogenesis. Our results provide insight into the selection advantage that might render Tet2-deficient HSPCs susceptible to transformation and suggest that anti-inflammation therapy could be of clinical benefit for individuals carrying TET2 mutations. Disclosures Kelley: Apexian Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Mohseni:Novartis Institutes of Biomedical Research: Employment.

Cancer stemness as a target for immunotherapy is shaped by pro-inflammatory stress.

2020 ◽  
Vol 15 ◽  
Author(s):  
Nese Unver
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Immune Cells ◽  
Tumor Recurrence ◽  
Inflammatory Factors ◽  
Cancer Stemness ◽  
Self Renewal ◽  
Inflammatory Stress ◽  
Factors Affecting

: Cancer stem cells represent a rare subpopulation of cancer cells carrying self-renewal and differentiation features in the multi-step tumorigenesis, tumor recurrence and metastasis. Pro-inflammatory stress is highly associated with cancer stemness via induction of cytokines, tumor-promoting immune cells and cancer stemness-related signaling pathways. This review summarizes the major pro-inflammatory factors affecting cancer stem cell characteristics and the critical immunotherapeutic strategies to eliminate cancer stem cells.

scholarly journals A novel application of bubble-eye strain of Carassius auratus for ex vivo fish immunological studies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hiroto Nakajima ◽  
Atsushi Miyashita ◽  
Hiroshi Hamamoto ◽  
Kazuhisa Sekimizu
Keyword(s):  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Ex Vivo ◽  
Large Bubble ◽  
Suitable Model ◽  
Bacterial Cells ◽  
Functional Impairments ◽  
Gene Expressions ◽  
Pro Inflammatory Cytokines

AbstractIn this study, we investigated a new application of bubble-eye goldfish (commercially available strain with large bubble-shaped eye sacs) for immunological studies in fishes utilizing the technical advantage of examining immune cells in the eye sac fluid ex vivo without sacrificing animals. As known in many aquatic species, the common goldfish strain showed an increased infection sensitivity at elevated temperature, which we demonstrate may be due to an immune impairment using the bubble-eye goldfish model. Injection of heat-killed bacterial cells into the eye sac resulted in an inflammatory symptom (surface reddening) and increased gene expression of pro-inflammatory cytokines observed in vivo, and elevated rearing temperature suppressed the induction of pro-inflammatory gene expressions. We further conducted ex vivo experiments using the immune cells harvested from the eye sac and found that the induced expression of pro-inflammatory cytokines was suppressed when we increased the temperature of ex vivo culture, suggesting that the temperature response of the eye-sac immune cells is a cell autonomous function. These results indicate that the bubble-eye goldfish is a suitable model for ex vivo investigation of fish immune cells and that the temperature-induced infection susceptibility in the goldfish may be due to functional impairments of immune cells.

scholarly journals The elected questions of condition of cellular factors of resistance during tick-borne mixed-infections

2006 ◽  
Vol 5 ◽  
pp. 144-150
Author(s):  
N. P. Pirogova ◽  
M. R. Karpova ◽  
V. V. Novitsky ◽  
A. P. Zima ◽  
O. V. Voronkova ◽  
...  
Keyword(s):  
Immune Response ◽  
Borrelia Burgdorferi ◽  
Inflammatory Cytokines ◽  
Mixed Infection ◽  
Immune Cells ◽  
Peripheral Blood ◽  
Mixed Infections ◽  
Tick Borne Encephalitis ◽  
Cellular Factors ◽  
Tick Borne Encephalitis Virus

The authors of the article are trying to generalize the literary data that characterizing proinflammatory and anti-inflammatory cytokines production of peripheral blood immune cells during tick-borne neuroinfections: Lyme borreliosis, associated with tick- borne encephalitis. The immune response development to antigens of a tick-borne encephalitis virus and Borrelia burgdorferi in pa- tients with a mixed-infection essentially differs from those during monoinfections.

scholarly journals Benznidazole Anti-Inflammatory Effects in Murine Cardiomyocytes and Macrophages Are Mediated by Class I PI3Kδ

2021 ◽  
Vol 12 ◽  
Author(s):  
Ágata C. Cevey ◽  
Paula D. Mascolo ◽  
Federico N. Penas ◽  
Azul V. Pieralisi ◽  
Aldana S. Sequeyra ◽  
...  
Keyword(s):  
Cell Line ◽  
Chagas Disease ◽  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Macrophage Polarization ◽  
Catalytic Subunit ◽  
M2 Macrophage ◽  
Socs3 Expression ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Benznidazole (Bzl), the drug of choice in many countries for the treatment of Chagas disease, leads to parasite clearance in the early stages of infection and contributes to immunomodulation. In addition to its parasiticidal effect, Bzl inhibits the NF-κB pathway. In this regard, we have previously described that this occurs through IL-10/STAT3/SOCS3 pathway. PI3K pathway is involved in the regulation of the immune system by inhibiting NF-κB pathway through STAT3. In this work, the participation of PI3K in the immunomodulatory effects of Bzl in cardiac and immune cells, the main targets of Chagas disease, was further studied. For that, we use a murine primary cardiomyocyte culture and a monocyte/macrophage cell line (RAW 264.7), stimulated with LPS in presence of LY294002, an inhibitor of PI3K. Under these conditions, Bzl could neither increase SOCS3 expression nor inhibit the NOS2 mRNA expression and the release of NOx, both in cardiomyocytes and macrophages. Macrophages are crucial in the development of Chronic Chagas Cardiomyopathy. Thus, to deepen our understanding of how Bzl acts, the expression profile of M1-M2 macrophage markers was evaluated. Bzl inhibited the release of NOx (M1 marker) and increased the expression of Arginase I (M2 marker) and a negative correlation was found between them. Besides, LPS increased the expression of pro-inflammatory cytokines. Bzl treatment not only inhibited this effect but also increased the expression of typical M2-macrophage markers like Mannose Receptor, TGF-β, and VEGF-A. Moreover, Bzl increased the expression of PPAR-γ and PPAR-α, known as key regulators of macrophage polarization. PI3K directly regulates M1-to-M2 macrophage polarization. Since p110δ, catalytic subunit of PI3Kδ, is highly expressed in immune cells, experiments were carried out in presence of CAL-101, a specific inhibitor of this subunit. Under this condition, Bzl could neither increase SOCS3 expression nor inhibit NF-κB pathway. Moreover, Bzl not only failed to inhibit the expression of pro-inflammatory cytokines (M1 markers) but also could not increase M2 markers. Taken together these results demonstrate, for the first time, that the anti-inflammatory effect of Bzl depends on PI3K activity in a cell line of murine macrophages and in primary culture of neonatal cardiomyocytes. Furthermore, Bzl-mediated increase expression of M2-macrophage markers involves the participation of the p110δ catalytic subunit of PI3Kδ.

scholarly journals Inflammatory Cytokines, Immune Cells, and Organ Interactions in Heart Failure

2021 ◽  
Vol 12 ◽  
Author(s):  
Huihui Li ◽  
Chen Chen ◽  
Dao Wen Wang
Keyword(s):  
Heart Failure ◽  
Clinical Trials ◽  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Therapeutic Targets ◽  
Pathophysiological Mechanisms

Despite mounting evidence demonstrating the significance of inflammation in the pathophysiological mechanisms of heart failure (HF), most large clinical trials that target the inflammatory responses in HF yielded neutral or even worsening outcomes. Further in-depth understanding about the roles of inflammation in the pathogenesis of HF is eagerly needed. This review summarizes cytokines, cardiac infiltrating immune cells, and extracardiac organs that orchestrate the complex inflammatory responses in HF and highlights emerging therapeutic targets.

scholarly journals Ontogeny of arterial macrophages defines their functions in homeostasis and inflammation

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Tobias Weinberger ◽  
Dena Esfandyari ◽  
Denise Messerer ◽  
Gulce Percin ◽  
Christian Schleifer ◽  
...  
Keyword(s):  
Tissue Regeneration ◽  
Immune Cells ◽  
Transcriptional Response ◽  
Developmental Origins ◽  
Adult Mice ◽  
Single Cell Rna Sequencing ◽  
Mapping Analysis ◽  
Health And Disease ◽  
Arterial Inflammation ◽  
Cellular Identity

Abstract Arterial macrophages have different developmental origins, but the association of macrophage ontogeny with their phenotypes and functions in adulthood is still unclear. Here, we combine macrophage fate-mapping analysis with single-cell RNA sequencing to establish their cellular identity during homeostasis, and in response to angiotensin-II (AngII)-induced arterial inflammation. Yolk sac erythro-myeloid progenitors (EMP) contribute substantially to adventitial macrophages and give rise to a defined cluster of resident immune cells with homeostatic functions that is stable in adult mice, but declines in numbers during ageing and is not replenished by bone marrow (BM)-derived macrophages. In response to AngII inflammation, increase in adventitial macrophages is driven by recruitment of BM monocytes, while EMP-derived macrophages proliferate locally and provide a distinct transcriptional response that is linked to tissue regeneration. Our findings thus contribute to the understanding of macrophage heterogeneity, and associate macrophage ontogeny with distinct functions in health and disease.

scholarly journals Roles of Pro- and Anti-Inflammatory Cytokines in the Pathogenesis of SLE

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Ding-Lei Su ◽  
Zhi-Min Lu ◽  
Min-Ning Shen ◽  
Xia Li ◽  
Ling-Yun Sun
Keyword(s):  
Complex Network ◽  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Inflammatory Disease ◽  
Immune Homeostasis ◽  
Adaptive Immune ◽  
Adaptive Immune Cells ◽  
Autoimmune Inflammatory Disease ◽  
Anti Inflammatory

SLE is an autoimmune inflammatory disease in which various pro- and anti-inflammatory cytokines, including TGF-β, IL-10, BAFF, IL-6, IFN-α, IFN-γ, IL-17, and IL-23, play crucial pathogenic roles. Virtually, all these cytokines can be generated by both innate and adaptive immune cells and exert different effects depending on specific local microenvironment. They can also interact with each other, forming a complex network to maintain delicate immune homeostasis. In this paper, we elaborate on the abnormal secretion and functions of these cytokines in SLE, analyze their potential pathogenic roles, and probe into the possibility of them being utilized as targets for therapy.

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