scholarly journals Metabolic dysregulation induces impaired lymphocyte memory formation during severe SARS-CoV-2 infection

2021 ◽  
Author(s):  
Hung Nguyen ◽  
Sanjeev Gurshaney ◽  
Anamaria Morales Alvarez ◽  
Kevin Ezhakunnel ◽  
Andrew Manalo ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Memory Cell ◽  
Lung Epithelial Cells ◽  
Metabolic Reprogramming ◽  
Glycolytic Flux ◽  
Metabolic Dysregulation ◽  
Class 1 ◽  
Hla Class 1

Cellular metabolic dysregulation is a consequence of COVID-19 infection that is a key determinant of disease severity. To understand the mechanisms underlying these cellular changes, we performed high-dimensional immune cell profiling of PBMCs from COVID-19-infected patients, in combination with single cell transcriptomic analysis of COVID-19 BALFs. Hypoxia, a hallmark of COVID-19 ARDS, was found to elicit a global metabolic reprogramming in effector lymphocytes. In response to oxygen and nutrient-deprived microenvironments, these cells shift from aerobic respiration to increase their dependence on anaerobic processes including glycolysis, mitophagy, and glutaminolysis to fulfill their bioenergetic demands. We also demonstrate metabolic dysregulation of ciliated lung epithelial cells is linked to significant increase of proinflammatory cytokine secretion and upregulation of HLA class 1 machinery. Augmented HLA class-1 antigen stimulation by epithelial cells leads to cellular exhaustion of metabolically dysregulated CD8 and NK cells, impairing their memory cell differentiation. Unsupervised clustering techniques revealed multiple distinct, differentially abundant CD8 and NK memory cell states that are marked by high glycolytic flux, mitochondrial dysfunction, and cellular exhaustion, further highlighting the connection between disrupted metabolism and impaired memory cell function in COVID-19. Our findings provide novel insight on how SARS-CoV-2 infection affects host immunometabolism and anti-viral response during COVID-19.

Inhibition of amiloride-sensitive sodium-channel activity in distal lung epithelial cells by nitric oxide

1998 ◽  
Vol 274 (3) ◽  
pp. L378-L387 ◽  
Author(s):  
Jin Wen Ding ◽  
John Dickie ◽  
Hugh O’Brodovich ◽  
Yutaka Shintani ◽  
Bijan Rafii ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Epithelial Cells ◽  
Cell Function ◽  
Short Circuit ◽  
Short Circuit Current ◽  
Lung Epithelial Cells ◽  
Flufenamic Acid ◽  
Activated Macrophages ◽  
Lung Epithelial ◽  
Distal Lung

Distal lung epithelial cells (DLECs) play an active role in fluid clearance from the alveolus by virtue of their ability to actively transport Na+ from the alveolus to the interstitial space. The present study evaluated the ability of activated macrophages to modulate the bioelectric properties of DLECs. Low numbers of lipopolysaccharide (LPS)-treated macrophages were able to significantly reduce amiloride-sensitive short-circuit current ( I sc) without affecting total I sc or monolayer resistance. This was associated with a rise in the flufenamic acid-sensitive component of the I sc. The effect was reversed by the addition of N-monomethyl-l-arginine to the medium, implying a role for nitric oxide. We hypothesized that macrophages exerted their effect by expressing inducible nitric oxide synthase (iNOS) in DLECs. The products of LPS-treated macrophages increased the levels of iNOS protein and mRNA transcripts in DLECs as well as causing a rise in iNOS activity. Immunofluorescence microscopy of LPS-stimulated macrophage-DLEC cocultures with anti-nitrotyrosine antibodies provided evidence for the generation of peroxynitrite in macrophages but not in DLECs. These data indicate that activated macrophages in the lung may contribute to impaired resolution of acute respiratory distress syndrome and suggest a novel mechanism whereby nitric oxide might alter cell function by altering its ion-transporting phenotype.

scholarly journals Antigen presentation by lung epithelial cells directs CD4+ TRM cell function and regulates barrier immunity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Anukul T. Shenoy ◽  
Carolina Lyon De Ana ◽  
Emad I. Arafa ◽  
Isabelle Salwig ◽  
Kimberly A. Barker ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Antigen Presentation ◽  
Cell Function ◽  
Surface Expression ◽  
Surfactant Protein ◽  
Lung Epithelial Cells ◽  
Mhc Ii ◽  
Lung Epithelial ◽  
Barrier Immunity

AbstractBarrier tissues are populated by functionally plastic CD4+ resident memory T (TRM) cells. Whether the barrier epithelium regulates CD4+ TRM cell locations, plasticity and activities remains unclear. Here we report that lung epithelial cells, including distinct surfactant protein C (SPC)lowMHChigh epithelial cells, function as anatomically-segregated and temporally-dynamic antigen presenting cells. In vivo ablation of lung epithelial MHC-II results in altered localization of CD4+ TRM cells. Recurrent encounters with cognate antigen in the absence of epithelial MHC-II leads CD4+ TRM cells to co-express several classically antagonistic lineage-defining transcription factors, changes their cytokine profiles, and results in dysregulated barrier immunity. In addition, lung epithelial MHC-II is needed for surface expression of PD-L1, which engages its ligand PD-1 to constrain lung CD4+ TRM cell phenotypes. Thus, we establish epithelial antigen presentation as a critical regulator of CD4+ TRM cell function and identify epithelial-CD4+ TRM cell immune interactions as core elements of barrier immunity.

scholarly journals Metabolic Implications of Immune Checkpoint Proteins in Cancer

Cells ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 179
Author(s):  
Elizabeth R. Stirling ◽  
Steven M. Bronson ◽  
Jessica D. Mackert ◽  
Katherine L. Cook ◽  
Pierre L. Triozzi ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Cell Function ◽  
Immune Cell ◽  
Therapy Response ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Metabolic Reprogramming ◽  
Patient Response ◽  
Checkpoint Proteins ◽  
Immune Checkpoint Proteins

Expression of immune checkpoint proteins restrict immunosurveillance in the tumor microenvironment; thus, FDA-approved checkpoint inhibitor drugs, specifically PD-1/PD-L1 and CTLA-4 inhibitors, promote a cytotoxic antitumor immune response. Aside from inflammatory signaling, immune checkpoint proteins invoke metabolic reprogramming that affects immune cell function, autonomous cancer cell bioenergetics, and patient response. Therefore, this review will focus on the metabolic alterations in immune and cancer cells regulated by currently approved immune checkpoint target proteins and the effect of costimulatory receptor signaling on immunometabolism. Additionally, we explore how diet and the microbiome impact immune checkpoint blockade therapy response. The metabolic reprogramming caused by targeting these proteins is essential in understanding immune-related adverse events and therapeutic resistance. This can provide valuable information for potential biomarkers or combination therapy strategies targeting metabolic pathways with immune checkpoint blockade to enhance patient response.

scholarly journals Extracellular Lactate Acts as a Metabolic Checkpoint and Shapes Monocyte Function Time Dependently

2021 ◽  
Vol 12 ◽  
Author(s):  
Judith Schenz ◽  
Lena Heilig ◽  
Tim Lohse ◽  
Lucas Tichy ◽  
Katharina Bomans ◽  
...  
Keyword(s):  
Cytokine Production ◽  
Cell Function ◽  
Immune Cell ◽  
Cellular Respiration ◽  
Glycolytic Flux ◽  
Monocytic Cell ◽  
Monocytic Cell Line ◽  
Monocyte Function ◽  
Extracellular Lactate ◽  
Intracellular Energy

Elevated blood lactate levels are frequently found in critically ill patients and thought to result from tissue hypoperfusion and cellular oxygen shortage. Considering the close relationship between immune cell function and intracellular metabolism, lactate is more than a glycolytic waste molecule but able to regulate the immune response. Our aim was to elucidate the temporal and mechanistic effect of extracellular lactate on monocytes. To this end, primary human monocytes and the human monocytic cell line MonoMac6 were stimulated with various toll-like-receptor agonists after priming with Na-L-lactate under constant pH conditions. As readout, cytokine production was measured, real-time assessment of intracellular energy pathways was performed, and intracellular metabolite concentrations were determined. Irrespective of the immunogenic stimulus, short-term Na-lactate-priming strongly reduced cytokine production capacity. Lactate and hexoses accumulated intracellularly and, together with a decreased glycolytic flux, indicate a lactate-triggered impairment of glycolysis. To counteract intracellular hyperglycemia, glucose is shunted into the branching polyol pathway, leading to sorbitol accumulation. In contrast, long-term priming with Na-L-lactate induced cellular adaption and abolished the suppressive effect. This lactate tolerance is characterized by a decreased cellular respiration due to a reduced complex-I activity. Our results indicate that exogenous lactate shapes monocyte function by altering the intracellular energy metabolism and acts as a metabolic checkpoint of monocyte activation.

Immunometabolism in bladder cancer microenvironment

2022 ◽  
Vol 22 ◽  
Author(s):  
Mohammad Javad Fattahi ◽  
Mohammad Reza Haghshenas ◽  
Abbas Ghaderi
Keyword(s):  
Bladder Cancer ◽  
Immune Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Metabolic Reprogramming ◽  
Immune Cell Function ◽  
Complex Interactions ◽  
Metabolite Accumulation ◽  
And Migration

Abstract: The initiation and progression of bladder cancer (BC), is dependent on its tumor microenvironment (TME). On the other hand, cancer cells shape and train TME to support their development, respond to treatment and migration in an organism. Immune cells exert key roles in the BC microenvironment and have complex interactions with BC cells. These complicated interplays result in metabolic competition in the TME leading to nutrient deprivation, acidosis, hypoxia and metabolite accumulation, which impair immune cell function. Recent studies have demonstrated that immune cells functions are closely correlated with their metabolism. Immunometabolism describes the functional metabolic alterations that take place within immune cells and the role of these cells in directing metabolism and immune response in tissues or diseases such as cancer. Some molecules and their metabolites in the TME including glucose, fatty acids and amino acids can regulate the phenotype, function and metabolism of immune cells. Hence, here we describe some recent advances in immunometabolism and relate them to BC progression. A profound understanding of the metabolic reprogramming of BC cells and immune cells in the TME will offer novel opportunities for targeted therapies in future.

scholarly journals The cancer metabolic reprogramming and immune response

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Longzheng Xia ◽  
Linda Oyang ◽  
Jinguan Lin ◽  
Shiming Tan ◽  
Yaqian Han ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cells ◽  
Cancer Metabolism ◽  
Cell Function ◽  
Immune Cell ◽  
Metabolic Reprogramming ◽  
Antitumor Immune Response ◽  
Combination Treatments ◽  
Anticancer Immunotherapy ◽  
Limiting Nutrient

AbstractThe overlapping metabolic reprogramming of cancer and immune cells is a putative determinant of the antitumor immune response in cancer. Increased evidence suggests that cancer metabolism not only plays a crucial role in cancer signaling for sustaining tumorigenesis and survival, but also has wider implications in the regulation of antitumor immune response through both the release of metabolites and affecting the expression of immune molecules, such as lactate, PGE2, arginine, etc. Actually, this energetic interplay between tumor and immune cells leads to metabolic competition in the tumor ecosystem, limiting nutrient availability and leading to microenvironmental acidosis, which hinders immune cell function. More interestingly, metabolic reprogramming is also indispensable in the process of maintaining self and body homeostasis by various types of immune cells. At present, more and more studies pointed out that immune cell would undergo metabolic reprogramming during the process of proliferation, differentiation, and execution of effector functions, which is essential to the immune response. Herein, we discuss how metabolic reprogramming of cancer cells and immune cells regulate antitumor immune response and the possible approaches to targeting metabolic pathways in the context of anticancer immunotherapy. We also describe hypothetical combination treatments between immunotherapy and metabolic intervening that could be used to better unleash the potential of anticancer therapies.

scholarly journals Anti-inflammatory effects of long-chain n-3 PUFA in rhinovirus-infected cultured airway epithelial cells

2008 ◽  
Vol 101 (4) ◽  
pp. 533-540 ◽  
Author(s):  
Ahmad Saedisomeolia ◽  
Lisa G. Wood ◽  
Manohar L. Garg ◽  
Peter G. Gibson ◽  
Peter A. B. Wark
Keyword(s):  
Epithelial Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Fatty Acid Content ◽  
Interferon Γ ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Lactate Dehydrogenase Release ◽  
The Cost ◽  
Long Chain

Long-chain n-3 PUFA (LCn-3PUFA) including DHA and EPA, are known to decrease inflammation by inhibiting arachidonic acid (AA) metabolism to eicosanoids, decreasing the production of pro-inflammatory cytokines and reducing immune cell function. The aim of this study was to determine if EPA and DHA reduced the release of inflammatory mediators from airway epithelial cells infected with rhinovirus (RV). Airway epithelial cells (Calu-3) were incubated with EPA, DHA and AA for 24 h, followed by rhinovirus infection for 48 h. IL-6, IL-8 and interferon-γ-induced protein-10 (IP-10) released by cells were measured using ELISA. Viral replication was measured by serial titration assays. The fatty acid content of cells was analysed using GC. Cellular viability was determined by visual inspection of cells and lactate dehydrogenase release. DHA (400 μm) resulted in a significant 16 % reduction in IL-6 release after RV-43 infection, 29 % reduction in IL-6 release after RV-1B infection, 28 % reduction in IP-10 release after RV-43 infection and 23 % reduction in IP-10 release after RV-1B infection. Cellular DHA content negatively correlated with IL-6 and IP-10 release. None of the fatty acids significantly modified rhinovirus replication. DHA supplementation resulted in increased cellular content of DHA at the cost of AA, which may explain the decreased inflammatory response of cells. EPA and AA did not change the release of inflammatory biomarkers significantly. It is concluded that DHA has a potential role in suppressing RV-induced airway inflammation.

scholarly journals Immune Memory in Aging: a Wide Perspective Covering Microbiota, Brain, Metabolism, and Epigenetics

2021 ◽  
Author(s):  
Ozlem Bulut ◽  
Gizem Kilic ◽  
Jorge Domínguez-Andrés
Keyword(s):  
Immune System ◽  
Aging Process ◽  
Cell Function ◽  
Immune Cell ◽  
Immunological Memory ◽  
Metabolic Reprogramming ◽  
The Other ◽  
Immune Memory ◽  
Age Related ◽  
Wide Range

AbstractNon-specific innate and antigen-specific adaptive immunological memories are vital evolutionary adaptations that confer long-lasting protection against a wide range of pathogens. Adaptive memory is established by memory T and B lymphocytes following the recognition of an antigen. On the other hand, innate immune memory, also called trained immunity, is imprinted in innate cells such as macrophages and natural killer cells through epigenetic and metabolic reprogramming. However, these mechanisms of memory generation and maintenance are compromised as organisms age. Almost all immune cell types, both mature cells and their progenitors, go through age-related changes concerning numbers and functions. The aging immune system renders the elderly highly susceptible to infections and incapable of mounting a proper immune response upon vaccinations. Besides the increased infectious burden, older individuals also have heightened risks of metabolic and neurodegenerative diseases, which have an immunological component. This review discusses how immune function, particularly the establishment and maintenance of innate and adaptive immunological memory, regulates and is regulated by epigenetics, metabolic processes, gut microbiota, and the central nervous system throughout life, with a focus on old age. We explain in-depth how epigenetics and cellular metabolism impact immune cell function and contribute or resist the aging process. Microbiota is intimately linked with the immune system of the human host, and therefore, plays an important role in immunological memory during both homeostasis and aging. The brain, which is not an immune-isolated organ despite former opinion, interacts with the peripheral immune cells, and the aging of both systems influences the health of each other. With all these in mind, we aimed to present a comprehensive view of the aging immune system and its consequences, especially in terms of immunological memory. The review also details the mechanisms of promising anti-aging interventions and highlights a few, namely, caloric restriction, physical exercise, metformin, and resveratrol, that impact multiple facets of the aging process, including the regulation of innate and adaptive immune memory. We propose that understanding aging as a complex phenomenon, with the immune system at the center role interacting with all the other tissues and systems, would allow for more effective anti-aging strategies.

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