Exploiting immune cell metabolic machinery for functional HIV cure and the prevention of inflammaging

An emerging paradigm in immunology suggests that metabolic reprogramming and immune cell activation and functions are intricately linked. Viral infections, such as HIV infection, as well as cancer force immune cells to undergo major metabolic challenges. Cells must divert energy resources in order to mount an effective immune response. However, the fact that immune cells adopt specific metabolic programs to provide host defense against intracellular pathogens and how this metabolic shift impacts immune cell functions and the natural course of diseases have only recently been appreciated. A clearer insight into how these processes are inter-related will affect our understanding of several fundamental aspects of HIV persistence. Even in patients with long-term use of anti-retroviral therapies, HIV infection persists and continues to cause chronic immune activation and inflammation, ongoing and cumulative damage to multiple organs systems, and a reduction in life expectancy. HIV-associated fundamental changes to the metabolic machinery of the immune system can promote a state of “inflammaging”, a chronic, low-grade inflammation with specific immune changes that characterize aging, and can also contribute to the persistence of HIV in its reservoirs. In this commentary, we will bring into focus evolving concepts on how HIV modulates the metabolic machinery of immune cells in order to persist in reservoirs and how metabolic reprogramming facilitates a chronic state of inflammation that underlies the development of age-related comorbidities. We will discuss how immunometabolism is facilitating the changing paradigms in HIV cure research and outline the novel therapeutic opportunities for preventing inflammaging and premature development of age-related conditions in HIV+individuals.

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METABOLIC FLEXIBILITY IN CLASSICAL MONOCYTES IS NOT AFFECTED BY AGE

Innovation in Aging ◽

10.1093/geroni/igz038.392 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S105-S105

Author(s):

Johnathan Yarbro ◽

Brandt Pence

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Immune Cell ◽

Ex Vivo ◽

Inflammatory Cells ◽

Acid Oxidation ◽

Low Grade ◽

Glucose Starvation ◽

Cell Functions ◽

Age Related

Abstract Inflammaging is the chronic low-grade inflammation that occurs with age that contributes to the pathology of age-related diseases. Monocytes are innate immune cells that become dysregulated with age and which can contribute to inflammaging. Metabolism plays a key role in determining immune cell functions, with anti-inflammatory cells primarily relying on fatty acid oxidation and pro-inflammatory cells primarily relying on glycolysis. It was recently shown that lipopolysaccharide (LPS)-stimulated monocytes can compensate for a lack of glucose by utilizing fatty acid oxidation. Given that mitochondrial function decreases with age, we hypothesized that monocytes taken from aged individuals would have an impaired ability to upregulate oxidative metabolism and would have impaired effector functions. Aging did not impair LPS-induced oxygen consumption rate during glucose starvation as measured on a Seahorse XFp system. Additionally, aged monocytes maintained inflammatory gene expression responses and phagocytic capacity during LPS stimulation in the absence of glucose. In conclusion, aged monocytes maintain effector and metabolic functions during glucose starvation, at least in an ex vivo context.

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Metabolic substrate utilization in stress-induced immune cells

Intensive Care Medicine Experimental ◽

10.1186/s40635-020-00316-0 ◽

2020 ◽

Vol 8 (S1) ◽

Author(s):

Xiaomin Zhang ◽

Fabian Zink ◽

Felix Hezel ◽

Josef Vogt ◽

Ulrich Wachter ◽

...

Keyword(s):

Immune Cells ◽

Metabolic Pathways ◽

Cell Activation ◽

Immune Cell ◽

Tca Cycle ◽

Therapeutic Interventions ◽

Functional Changes ◽

Cell Functions ◽

Immune Cell Activation ◽

Metabolic Functions

AbstractImmune cell activation leads to the acquisition of new functions, such as proliferation, chemotaxis, and cytokine production. These functional changes require continuous metabolic adaption in order to sustain ATP homeostasis for sufficient host defense. The bioenergetic demands are usually met by the interconnected metabolic pathways glycolysis, TCA cycle, and oxidative phosphorylation. Apart from glucose, other sources, such as fatty acids and glutamine, are able to fuel the TCA cycle.Rising evidence has shown that cellular metabolism has a direct effect on the regulation of immune cell functions. Thus, quiescent immune cells maintain a basal metabolic state, which shifts to an accelerated metabolic level upon immune cell activation in order to promote key effector functions.This review article summarizes distinct metabolic signatures of key immune cell subsets from quiescence to activation and demonstrates a methodical concept of how to assess cellular metabolic pathways. It further discusses why metabolic functions are of rising interest for translational research and how they can be affected by the underlying pathophysiological condition and/or therapeutic interventions.

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Lipid-mediated insertion of Toll-like receptor (TLR) ligands for facile immune cell engineering

10.1101/840876 ◽

2019 ◽

Cited By ~ 1

Author(s):

Michael H. Zhang ◽

Emily M. Slaby ◽

Georgina Stephanie ◽

Chunsong Yu ◽

Darcy M. Watts ◽

...

Keyword(s):

Immune Cells ◽

Plasma Membranes ◽

Cell Activation ◽

Immune Cell ◽

Cell Lineage ◽

Genetic System ◽

Cell Engineering ◽

Toll Like Receptor ◽

Activated T Cells ◽

Cell Functions

AbstractCell-based immunotherapies have tremendous potential to treat many diseases, such as activating immunity in cancer or suppressing it in autoimmune diseases. Most cell-based cancer immunotherapies in the clinic provide adjuvant signals through genetic engineering to enhance T cell functions. However, genetically encoded signals have minimal control over dosing and persist for the life of a cell lineage. These properties make it difficult to balance increasing therapeutic efficacy with reducing toxicities. Here, we demonstrated the potential of phospholipid-coupled ligands as a non-genetic system for immune cell engineering. This system provides simple, controlled, non-genetic adjuvant delivery to immune cells via lipid-mediated insertion into plasma membranes. Lipid-mediated insertion (depoting) successfully delivered Toll-like receptor (TLR) ligands intracellularly and onto cell surfaces of diverse immune cells. These ligands depoted into immune cells in a dose-controlled fashion and did not compete during multiplex pairwise loading. Immune cell activation could be enhanced by autocrine and paracrine mechanisms depending on the biology of the TLR ligand tested. We determined that depoted ligands can functionally persist on plasma membranes for up to four days in naïve and activated T cells, enhancing their activation, proliferation, and skewing cytokine secretion. Depoted ligands provide a persistent yet non-permanent adjuvant signal to immune cells that may minimize the intensity and duration of toxicities compared to permanent genetic delivery. Altogether, these findings demonstrate potential for lipid-mediated insertion (depoting) as a universal cell engineering approach with unique, complementary advantages to other cell engineering methods.

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Molecular profiles and immunomodulatory activities of glioblastoma-derived exosomes

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa056 ◽

2020 ◽

Vol 2 (1) ◽

Cited By ~ 3

Author(s):

Juliana Hofstatter Azambuja ◽

Nils Ludwig ◽

Saigopalakrishna Yerneni ◽

Aparna Rao ◽

Elizandra Braganhol ◽

...

Keyword(s):

T Cells ◽

T Cell Activation ◽

Cd8 T Cells ◽

Immune Cells ◽

Cell Activation ◽

Immune Cell ◽

Size Exclusion ◽

Cell Functions

Abstract Background Glioblastoma is one of the most immunosuppressive human tumors. Emerging data suggest that glioblastoma-derived exosomes (GBex) reprogram the tumor microenvironment into a tumor-promoting milieu by mechanisms that not yet understood. Methods Exosomes were isolated from supernatants of glioblastoma cell lines by size exclusion chromatography. The GBex endosomal origin, size, protein cargos, and ex vivo effects on immune cell functions were determined. GBex were injected intravenously into mice to evaluate their ability to in vivo modulate normal immune cell subsets. Results GBex carried immunosuppressive proteins, including FasL, TRAIL, CTLA-4, CD39, and CD73, but contained few immunostimulatory proteins. GBex co-incubated with primary human immune cells induced simultaneous activation of multiple molecular pathways. In CD8+ T cells, GBex suppressed TNF-α and INF-γ release and mediated apoptosis. GBex suppressed natural killer (NK) and CD4+ T-cell activation. GBex activated the NF-κB pathway in macrophages and promoted their differentiation into M2 cells. Inhibition of the NF-κB pathway in macrophages reversed the GBex-mediated effects. GBex-driven reprogramming of macrophages involved the release of soluble factors that promoted tumor proliferation in vitro. In mice injected with GBex, the frequency of splenic CD8+ T cells, NK cells, and M1-like macrophages was reduced, while that of naïve and M2-like macrophages increased (P < .05). Conclusions GBex reprogrammed functions of all types of immune cells in vitro and altered their frequency in vivo. By creating and sustaining a highly immunosuppressive environment, GBex play a key role in promoting tumor progression.

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Amino acids: key sources for immunometabolites and immunotransmitters

International Immunology ◽

10.1093/intimm/dxaa019 ◽

2020 ◽

Vol 32 (7) ◽

pp. 435-446 ◽

Cited By ~ 2

Author(s):

Michio Miyajima

Keyword(s):

Amino Acids ◽

Immune Cells ◽

Nicotinamide Adenine Dinucleotide ◽

Cell Activation ◽

Immune Cell ◽

Nerve Cells ◽

Metabolic Reprogramming ◽

Functional Plasticity ◽

Immune Cell Activation ◽

Oxide Synthase

Abstract Immune-cell activation and functional plasticity are closely linked to metabolic reprogramming that is required to supply the energy and substrates for such dynamic transformations. During such processes, immune cells metabolize many kinds of molecules including nucleic acids, sugars and lipids, which is called immunometabolism. This review will mainly focus on amino acids and their derivatives among such metabolites and describe the functions of these molecules in the immune system. Although amino acids are essential for, and well known as, substrates for protein synthesis, they are also metabolized as energy sources and as substrates for functional catabolites. For example, glutamine is metabolized to produce energy through glutaminolysis and tryptophan is consumed to supply nicotinamide adenine dinucleotide, whereas arginine is metabolized to produce nitric acid and polyamine by nitric oxide synthase and arginase, respectively. In addition, serine is catabolized to produce nucleotides and to induce methylation reactions. Furthermore, in addition to their intracellular functions, amino acids and their derivatives are secreted and have extracellular functions as immunotransmitters. Many amino acids and their derivatives have been classified as neurotransmitters and their functions are clear as transmitters between nerve cells, or between nerve cells and immune cells, functioning as immunotransmitters. Thus, this review will describe the intracellular and external functions of amino acid from the perspective of immunometabolism and immunotransmission.

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Regulation of Immune Cell Functions by Metabolic Reprogramming

Journal of Immunology Research ◽

10.1155/2018/8605471 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 16

Author(s):

Jaehong Kim

Keyword(s):

T Cells ◽

Immune Cells ◽

Molecular Mechanisms ◽

Immune Cell ◽

Aerobic Glycolysis ◽

Metabolic Changes ◽

Metabolic Reprogramming ◽

Functional Plasticity ◽

Inflammatory Reactions ◽

Cell Functions

Recent findings show that the metabolic status of immune cells can determine immune responses. Metabolic reprogramming between aerobic glycolysis and oxidative phosphorylation, previously speculated as exclusively observable in cancer cells, exists in various types of immune and stromal cells in many different pathological conditions other than cancer. The microenvironments of cancer, obese adipose, and wound-repairing tissues share common features of inflammatory reactions. In addition, the metabolic changes in macrophages and T cells are now regarded as crucial for the functional plasticity of the immune cells and responsible for the progression and regression of many pathological processes, notably cancer. It is possible that metabolic changes in the microenvironment induced by other cellular components are responsible for the functional plasticity of immune cells. This review explores the molecular mechanisms responsible for metabolic reprogramming in macrophages and T cells and also provides a summary of recent updates with regard to the functional modulation of the immune cells by metabolic changes in the microenvironment, notably the tumor microenvironment.

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Aging Leukocytes and the Inflammatory Microenvironment of the Adipose Tissue

Diabetes ◽

10.2337/dbi21-0013 ◽

2021 ◽

Vol 71 (1) ◽

pp. 23-30

Author(s):

Korbyn J.V. Dahlquist ◽

Christina D. Camell

Keyword(s):

Metabolic Disease ◽

Adipose Tissue ◽

Immune System ◽

Immune Cells ◽

Cell Activation ◽

Immune Cell ◽

Inflammatory Factors ◽

Immune Cell Activation ◽

Age Related ◽

Increased Risk

Age-related immunosenescence, defined as an increase in inflammaging and the decline of the immune system, leads to tissue dysfunction and increased risk for metabolic disease. The elderly population is expanding, leading to a heightened need for therapeutics to improve health span. With age, many alterations of the immune system are observed, including shifts in the tissue-resident immune cells, increased expression of inflammatory factors, and the accumulation of senescent cells, all of which are responsible for a chronic inflammatory loop. Adipose tissue and the immune cell activation within are of particular interest for their well-known roles in metabolic disease. Recent literature reveals that adipose tissue is an organ in which signs of initial aging occur, including immune cell activation. Aged adipose tissue reveals changes in many innate and adaptive immune cell subsets, revealing a complex interaction that contributes to inflammation, increased senescence, impaired catecholamine-induced lipolysis, and impaired insulin sensitivity. Here, we will describe current knowledge surrounding age-related changes in immune cells while relating those findings to recent discoveries regarding immune cells in aged adipose tissue.

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Monocytes from Older Adults Maintain Capacity for Metabolic Compensation during Glucose Deprivation and Lipopolysaccharide Stimulation

10.1101/633354 ◽

2019 ◽

Author(s):

Johnathan R. Yarbro ◽

Brandt D. Pence

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Immune Cell ◽

Ex Vivo ◽

Glucose Deprivation ◽

Inflammatory Cells ◽

Acid Oxidation ◽

Low Grade ◽

Cell Functions ◽

Age Related

ABSTRACTInflammaging is the chronic low-grade inflammation that occurs with age that contributes to the pathology of age-related diseases. Monocytes are innate immune cells that become dysregulated with age and which can contribute to inflammaging. Metabolism plays a key role in determining immune cell functions, with anti-inflammatory cells primarily relying on fatty acid oxidation and pro-inflammatory cells primarily relying on glycolysis. It was recently shown that lipopolysaccharide (LPS)-stimulated monocytes can compensate for a lack of glucose by utilizing fatty acid oxidation. Given that mitochondrial function decreases with age, we hypothesized that monocytes taken from aged individuals would have an impaired ability to upregulate oxidative metabolism along with impaired effector functions. Aging did not impair LPS-induced oxygen consumption rate during glucose deprivation as measured on a Seahorse XFp system. Additionally, aged monocytes maintained inflammatory gene expression responses and phagocytic capacity during LPS stimulation in the absence of glucose. In conclusion, aged monocytes maintain effector and metabolic functions during glucose deprivation, at least in an ex vivo context.

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Dietary Fatty Acids at the Crossroad between Obesity and Colorectal Cancer: Fine Regulators of Adipose Tissue Homeostasis and Immune Response

Cells ◽

10.3390/cells10071738 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1738

Author(s):

Manuela Del Cornò ◽

Rosaria Varì ◽

Beatrice Scazzocchio ◽

Barbara Varano ◽

Roberta Masella ◽

...

Keyword(s):

Colorectal Cancer ◽

Fatty Acids ◽

Adipose Tissue ◽

Transcription Factors ◽

Immune Cells ◽

Immune Cell ◽

Response To Therapy ◽

Dietary Fatty Acids ◽

Low Grade ◽

Cell Functions

Colorectal cancer (CRC) is among the major threatening diseases worldwide, being the third most common cancer, and a leading cause of death, with a global incidence expected to increase in the coming years. Enhanced adiposity, particularly visceral fat, is a major risk factor for the development of several tumours, including CRC, and represents an important indicator of incidence, survival, prognosis, recurrence rates, and response to therapy. The obesity-associated low-grade chronic inflammation is thought to be a key determinant in CRC development, with the adipocytes and the adipose tissue (AT) playing a significant role in the integration of diet-related endocrine, metabolic, and inflammatory signals. Furthermore, AT infiltrating immune cells contribute to local and systemic inflammation by affecting immune and cancer cell functions through the release of soluble mediators. Among the factors introduced with diet and enriched in AT, fatty acids (FA) represent major players in inflammation and are able to deeply regulate AT homeostasis and immune cell function through gene expression regulation and by modulating the activity of several transcription factors (TF). This review summarizes human studies on the effects of dietary FA on AT homeostasis and immune cell functions, highlighting the molecular pathways and TF involved. The relevance of FA balance in linking diet, AT inflammation, and CRC is also discussed. Original and review articles were searched in PubMed without temporal limitation up to March 2021, by using fatty acid as a keyword in combination with diet, obesity, colorectal cancer, inflammation, adipose tissue, immune cells, and transcription factors.

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The Intersection of Metformin and Inflammation

AJP Cell Physiology ◽

10.1152/ajpcell.00604.2020 ◽

2021 ◽

Author(s):

Leena P. Bharath ◽

Barbara S. Nikolajczyk

Keyword(s):

Mitochondrial Function ◽

Immune Cells ◽

Immune Cell ◽

Cell Types ◽

Remarkable Effect ◽

Tumor Onset ◽

Age Related ◽

Immune Mediated ◽

Autoimmune Conditions ◽

Near Term

The biguanide metformin is the most commonly used antidiabetic drug. Recent studies show that metformin not only improves chronic inflammation by improving metabolic parameters but also has a direct anti-inflammatory effect. In light of these findings, it is essential to identify the inflammatory pathways targeted by metformin to develop a comprehensive understanding of the mechanisms of action of this drug. Commonly accepted mechanisms of metformin action include AMPK activation and inhibition of mTOR pathways, which are evaluated in multiple diseases. Additionally, metformin's action on mitochondrial function and cellular homeostasis processes such as autophagy, is of particular interest because of the importance of these mechanisms in maintaining cellular health. Both dysregulated mitochondria and failure of the autophagy pathways, the latter of which impair clearance of dysfunctional, damaged, or excess organelles, affect cellular health drastically and can trigger the onset of metabolic and age-related diseases. Immune cells are the fundamental cell types that govern the health of an organism. Thus, dysregulation of autophagy or mitochondrial function in immune cells has a remarkable effect on susceptibility to infections, response to vaccination, tumor onset, and the development of inflammatory and autoimmune conditions. Here we summarize the latest research on metformin's regulation of immune cell mitochondrial function and autophagy as evidence that new clinical trials on metformin with primary outcomes related to the immune system should be considered to treat immune-mediated diseases over the near term.

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