scholarly journals Immunometabolism governs dendritic cell and macrophage function

2015 ◽  
Vol 213 (1) ◽  
pp. 15-23 ◽  
Author(s):  
Luke A.J. O’Neill ◽  
Edward J. Pearce
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Metabolic Reprogramming ◽  
Environmental Cues ◽  
Direct Impact ◽  
Innate And Adaptive Immunity ◽  
Danger Signals ◽  
Intracellular Metabolism

Recent studies on intracellular metabolism in dendritic cells (DCs) and macrophages provide new insights on the functioning of these critical controllers of innate and adaptive immunity. Both cell types undergo profound metabolic reprogramming in response to environmental cues, such as hypoxia or nutrient alterations, but importantly also in response to danger signals and cytokines. Metabolites such as succinate and citrate have a direct impact on the functioning of macrophages. Immunogenicity and tolerogenicity of DCs is also determined by anabolic and catabolic processes, respectively. These findings provide new prospects for therapeutic manipulation in inflammatory diseases and cancer.

Cancer therapy with tumor cell lysate pulsed monocyte-derived dendritic cells in patients with metastastic colon cancer: Improvement by danger signals

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2563-2563
Author(s):  
T. Neβelhut ◽  
D. Lorenzen ◽  
D. Marx ◽  
R. Chang ◽  
J. Neβelhut ◽  
...  
Keyword(s):  
Cell Culture ◽  
Colon Cancer ◽  
Overall Survival ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Culture Conditions ◽  
Costimulatory Molecules ◽  
Danger Signals ◽  
Cell Lysate ◽  
Tumor Cell Lysate

2563 Background: The prognosis of colon cancers with hematogenous spread remains poor at 12–20 months. We report the use of a dendritic cell based immunotherapy to improve patient survival, especially with cell culture conditions mimicking infection. Methods: After isolating monocytes from the blood of 39 patients with metastasized colon cancer, dendritic cells were generated ex vivo in the presence of recombinant cytokines (IL-4; GM-CSF) and autologous serum. The DC loaded with tumor cell lysate were administered to the patients intradermally. Culture conditions were tested for upregulation of costimulatory molecules, downregulation of IL-10 and upregulation of IL-12 secretion by ELISPOT and fluorescence cytometry. Results: DC vaccination induced a clinical response in 9 (23%) patients with a median overall survival after onset of DC-therapy of 12 months (11–44 months for responders and 1–20 months for non-responders) and 23 months after diagnosis of metastases (16–63 months for responders and 1–23 months for non-responders). These data show that a dendritic cell based immunotherapy may prolong the patients overall survival. However, complete remissions are rare. This can be due to weak stimulation of CTL response due to insufficient antigen presentation, lack of costimulatory molecules as well as secretion of IL-10 rather than IL-12 by the DC’s. Here we could show that Toll-like receptors (TLR) ligands like Poly-I:C or lipopeptides as so called danger signals in combination with interferons can induce an upregulation of costimulatory molecules accompanied by inhibition of IL-10 and induction of IL-12 secretion in vitro. By using these culture conditions we induced a clinical complete remission of liver metastases after failure of standard therapy in one patient (overall survival after onset of DC-therapy 13 months, after diagnosis 24 months). Conclusions: According to Matzinger’s hypothesis an effective immune response occurs only by responding to a danger signal associated with infection or stress. Thus, cell culture condition should be used with TLR ligands mimicking a bacterial or viral infection. In general, a dendritic cell based immunotherapy can be successful in advanced stages of colon cancer patients. [Table: see text]

scholarly journals Effects of Fatty Acid Oxidation and Its Regulation on Dendritic Cell-Mediated Immune Responses in Allergies: An Immunometabolism Perspective

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Shanfeng Sun ◽  
Yanjun Gu ◽  
Junjuan Wang ◽  
Cheng Chen ◽  
Shiwen Han ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Fatty Acid ◽  
Dendritic Cell ◽  
Immune Responses ◽  
Fatty Acid Oxidation ◽  
Cell Activation ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Dendritic Cell Activation ◽  
Functional Changes

Type 1 allergies, involve a complex interaction between dendritic cells and other immune cells, are pathological type 2 inflammatory immune responses against harmless allergens. Activated dendritic cells undergo extensive phenotypic and functional changes to exert their functions. The activation, differentiation, proliferation, migration, and mounting of effector reactions require metabolic reprogramming. Dendritic cells are important upstream mediators of allergic responses and are therefore an important effector of allergies. Hence, a better understanding of the underlying metabolic mechanisms of functional changes that promote allergic responses of dendritic cells could improve the prevention and treatment of allergies. Metabolic changes related to dendritic cell activation have been extensively studied. This review briefly outlines the basis of fatty acid oxidation and its association with dendritic cell immune responses. The relationship between immune metabolism and effector function of dendritic cells related to allergic diseases can better explain the induction and maintenance of allergic responses. Further investigations are warranted to improve our understanding of disease pathology and enable new treatment strategies.

scholarly journals Attenuated Interferon and Proinflammatory Response in SARS-CoV-2–Infected Human Dendritic Cells Is Associated With Viral Antagonism of STAT1 Phosphorylation

2020 ◽  
Vol 222 (5) ◽  
pp. 734-745 ◽  
Author(s):  
Dong Yang ◽  
Hin Chu ◽  
Yuxin Hou ◽  
Yue Chai ◽  
Huiping Shuai ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Clinical Manifestations ◽  
Cell Types ◽  
Host Responses ◽  
Interferon Response ◽  
Proinflammatory Response ◽  
Innate And Adaptive Immunity ◽  
Virus Shedding ◽  
Human Dendritic Cells ◽  
Productive Virus

Abstract Clinical manifestations of coronavirus disease 2019 (COVID-19) vary from asymptomatic virus shedding, nonspecific pharyngitis, to pneumonia with silent hypoxia and respiratory failure. Dendritic cells and macrophages are sentinel cells for innate and adaptive immunity that affect the pathogenesis of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). The interplay between SARS-CoV-2 and these cell types remains unknown. We investigated infection and host responses of monocyte-derived dendritic cells (moDCs) and macrophages (MDMs) infected by SARS-CoV-2. MoDCs and MDMs were permissive to SARS-CoV-2 infection and protein expression but did not support productive virus replication. Importantly, SARS-CoV-2 launched an attenuated interferon response in both cell types and triggered significant proinflammatory cytokine/chemokine expression in MDMs but not moDCs. Investigations suggested that this attenuated immune response to SARS-CoV-2 in moDCs was associated with viral antagonism of STAT1 phosphorylation. These findings may explain the mild and insidious course of COVID-19 until late deterioration.

scholarly journals Dendritic cells star in Vancouver

2005 ◽  
Vol 202 (1) ◽  
pp. 5-10 ◽  
Author(s):  
Eynav Klechevsky ◽  
Hiroki Kato ◽  
Anne-Marit Sponaas
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Autoimmune Disease ◽  
Adaptive Immunity ◽  
Immune Regulation ◽  
Fast Moving ◽  
Molecular Mechanisms ◽  
Clinical Applications ◽  
Innate And Adaptive Immunity ◽  
Keystone Symposium

The fast-moving field of dendritic cell (DC) biology is hard to keep pace with. Here we report on advances from the recent Keystone Symposium, “Dendritic Cells at the Center of Innate and Adaptive Immunity,” organized in Vancouver, BC on Feb. 1–7, 2005 by Anne O'Garra, Jacques Banchereau, and Alan Sher. New insights into the molecular mechanisms of DC function and their influence on immune regulation, their role in infectious and autoimmune disease, and new clinical applications are highlighted.

Fascin and the Differential Diagnosis of Childhood Histiocytic Lesions

1998 ◽  
Vol 1 (3) ◽  
pp. 216-221 ◽  
Author(s):  
Ronald Jaffe ◽  
Donna DeVaughn ◽  
Erik Langhoff
Keyword(s):  
Dendritic Cells ◽  
Differential Diagnosis ◽  
Dendritic Cell ◽  
Langerhans Cells ◽  
False Negative ◽  
Cell Lineage ◽  
Large Cell ◽  
Cell Types ◽  
Large Numbers ◽  
Spitz Nevi

This is a descriptive screening of 46 examples of childhood histiocytic lesions and some of their look-alikes using a monoclonal antibody, p55, to fascin. Fascin, an actin-bundling protein, identifies dendritic cells in the blood and in tissues. Our aim was to test the diagnostic utility of the antibody in various lesions at different sites and to see whether the staining patterns give insight into the cell types involved. Fascin intensely stained the cells of juvenile xanthogranulomas (JXG), Rosai-Dorfman lesions, and soft tissue dendrocytomas. Normal Langerhans' cells and the cells of Langerhans' cell histiocytosis were unreactive. Their lack of fascin staining may be relevant to fascin being maturation as well as lineage related. Epithelioid and palisading granulomas were unstained, though an example of Kikuchi lymphadenitis had large numbers of dendritic-type cells that stained strongly. A reticulohistiocytoma of the skin was also unstained and look-alike lesions, Spitz nevi, and mast cell lesions did not stain. Two of three large-cell lymphomas (both CD30+) also had fascin reactivity. Even though fascin is not specific to dendritic cells, staining other cell types as well (false positive), and not entirely sensitive, dendritic cells such as tissue Langerhans' cells are unstained (false negative), there seems to be a consistency of staining in childhood histiocytic lesions. This may be of diagnostic use when read in the context of the tissue differential diagnosis. Whether fascin can serve as a marker for the dendritic cell lineage, or at least for some phases of dendritic cell lifecycle, is not answered by this survey.

scholarly journals Metabolism Is Central to Tolerogenic Dendritic Cell Function

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Wen Jing Sim ◽  
Patricia Jennifer Ahl ◽  
John Edward Connolly
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Cell Fate ◽  
Cell Function ◽  
Therapeutic Potential ◽  
Immunological Tolerance ◽  
Dendritic Cell Maturation ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Tolerogenic Dendritic Cell

Immunological tolerance is a fundamental tenant of immune homeostasis and overall health. Self-tolerance is a critical component of the immune system that allows for the recognition of self, resulting in hyporeactivity instead of immunogenicity. Dendritic cells are central to the establishment of dominant immune tolerance through the secretion of immunosuppressive cytokines and regulatory polarization of T cells. Cellular metabolism holds the key to determining DC immunogenic or tolerogenic cell fate. Recent studies have demonstrated that dendritic cell maturation leads to a shift toward a glycolytic metabolic state and preferred use of glucose as a carbon source. In contrast, tolerogenic dendritic cells favor oxidative phosphorylation and fatty acid oxidation. This dichotomous metabolic reprogramming of dendritic cells drives differential cellular function and plays a role in pathologies, such as autoimmune disease. Pharmacological alterations in metabolism have promising therapeutic potential.

Human plasmacytoid dendritic cells are unresponsive to bacterial stimulation and require a novel type of cooperation with myeloid dendritic cells for maturation

Blood ◽  
2009 ◽  
Vol 113 (18) ◽  
pp. 4232-4239 ◽  
Author(s):  
Diego Piccioli ◽  
Chiara Sammicheli ◽  
Simona Tavarini ◽  
Sandra Nuti ◽  
Elisabetta Frigimelica ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Immune Responses ◽  
Cross Talk ◽  
Bacterial Infections ◽  
Cell Types ◽  
Infectious Agents ◽  
Myeloid Dendritic Cells ◽  
Specific Induction ◽  
Bacterial Stimulation

Abstract Dendritic cell (DC) populations play unique and essential roles in the detection of pathogens, but information on how different DC types work together is limited. In this study, 2 major DC populations of human blood, myeloid (mDCs) and plasmacytoid (pDCs), were cultured alone or together in the presence of pathogens or their products. We show that pDCs do not respond to whole bacteria when cultured alone, but mature in the presence of mDCs. Using purified stimuli, we dissect this cross-talk and demonstrate that mDCs and pDCs activate each other in response to specific induction of only one of the cell types. When stimuli for one or both populations are limited, they synergize to reach optimal activation. The cross-talk is limited to enhanced antigen presentation by the nonresponsive population with no detectable changes in the quantity and range of cytokines produced. We propose that each population can be a follower or leader in immune responses against pathogen infections, depending on their ability to respond to infectious agents. In addition, our results indicate that pDCs play a secondary role to induce immunity against human bacterial infections, which has implications for more efficient targeting of DC populations with improved vaccines and therapeutics.

scholarly journals The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β

2021 ◽  
Vol 12 ◽  
Author(s):  
George A. Timmons ◽  
Richard G. Carroll ◽  
James R. O’Siorain ◽  
Mariana P. Cervantes-Silva ◽  
Lauren E. Fagan ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Molecular Clock ◽  
Inflammatory Diseases ◽  
Krebs Cycle ◽  
Glycolytic Enzyme ◽  
Metabolic Reprogramming ◽  
Inflammatory State ◽  
Intracellular Metabolism ◽  
Metabolic Sensor ◽  
Clock Protein

The transcription factor BMAL1 is a clock protein that generates daily or circadian rhythms in physiological functions including the inflammatory response of macrophages. Intracellular metabolic pathways direct the macrophage inflammatory response, however whether the clock is impacting intracellular metabolism to direct this response is unclear. Specific metabolic reprogramming of macrophages controls the production of the potent pro-inflammatory cytokine IL-1β. We now describe that the macrophage molecular clock, through Bmal1, regulates the uptake of glucose, its flux through glycolysis and the Krebs cycle, including the production of the metabolite succinate to drive Il-1β production. We further demonstrate that BMAL1 modulates the level and localisation of the glycolytic enzyme PKM2, which in turn activates STAT3 to further drive Il-1β mRNA expression. Overall, this work demonstrates that BMAL1 is a key metabolic sensor in macrophages, and its deficiency leads to a metabolic shift of enhanced glycolysis and mitochondrial respiration, leading to a heightened pro-inflammatory state. These data provide insight into the control of macrophage driven inflammation by the molecular clock, and the potential for time-based therapeutics against a range of chronic inflammatory diseases.

scholarly journals Defensins and Sepsis

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Guo-Hao Xie ◽  
Qi-Xing Chen ◽  
Bao-Li Cheng ◽  
Xiang-Ming Fang
Keyword(s):  
Dendritic Cells ◽  
Critical Illness ◽  
Inflammatory Diseases ◽  
Genetic Studies ◽  
Innate And Adaptive Immunity ◽  
Mortality And Morbidity ◽  
Disulphide Bonds ◽  
Inflammatory Processes

Sepsis is a leading cause of mortality and morbidity in the critical illness. Multiple immune inflammatory processes take part in the pathogenesis of sepsis. Defensins are endogenous antimicrobial peptides with three disulphide bonds created by six cysteine residues. Besides the intrinsic microbicidal properties, defensins are active players which modulate both innate and adaptive immunity against various infections. Defensins can recruit neutrophils, enhance phagocytosis, chemoattract T cells and dendritic cells, promote complement activation, and induce IL-1βproduction and pyrotosis. Previous publications have documented that defensins play important roles in a series of immune inflammatory diseases including sepsis. This review aims to briefly summarize in vitro, in vivo, and genetic studies on defensins’ effects as well as corresponding mechanisms within sepsis and highlights their promising findings which may be potential targets in future therapies of sepsis.

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