Macrophages rely on extracellular serine to suppress aberrant cytokine production

AbstractA growing body of evidence indicates that cellular metabolism is involved in immune cell functions, including cytokine production. Serine is a nutritionally non-essential amino acid that can be generated by de novo synthesis and conversion from glycine. Serine contributes to various cellular responses, but the role in inflammatory responses remains poorly understood. Here, we show that macrophages rely on extracellular serine to suppress aberrant cytokine production. Depleting serine from the culture media reduced the cellular serine content in macrophages markedly, suggesting that macrophages depend largely on extracellular serine rather than cellular synthesis. Under serine deprivation, macrophages stimulated with lipopolysaccharide showed aberrant cytokine expression patterns, including a marked reduction of anti-inflammatory interleukin-10 expression and sustained expression of interleukine-6. Transcriptomic and metabolomics analyses revealed that serine deprivation causes mitochondrial dysfunction: reduction in the pyruvate content, the NADH/NAD+ ratio, the oxygen consumption rate, and the mitochondrial production of reactive oxygen species (ROS). We also found the role of mitochondrial ROS in appropriate cytokine production. Thus, our results indicate that cytokine production in macrophages is tightly regulated by the nutritional microenvironment.

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Resolvins as Regulators of the Immune System

The Scientific World JOURNAL ◽

10.1100/tsw.2010.72 ◽

2010 ◽

Vol 10 ◽

pp. 818-831 ◽

Cited By ~ 20

Author(s):

Hiroyuki Seki ◽

Takaharu Sasaki ◽

Tomomi Ueda ◽

Makoto Arita

Keyword(s):

Immune System ◽

Acute Inflammation ◽

Immune Cell ◽

Inflammatory Responses ◽

Bioactive Metabolites ◽

Cell Functions ◽

First Response ◽

Beneficial Impact

Inflammation is the first response of the immune system to infection or injury, but excessive or inappropriate inflammatory responses contribute to a range of acute and chronic human diseases. Clinical assessment of dietary supplementation of ω-3 polyunsaturated fatty acids (i.e., eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) indicate that they have beneficial impact on these diseases, although the mechanisms are poorly understood at the molecular level. In this decade, it has been revealed that EPA and DHA are enzymatically converted to bioactive metabolites in the course of acute inflammation and resolution. These metabolites were shown to regulate immune cell functions and to display potent anti-inflammatory actions bothin vitroandin vivo. Because of their ability to resolve an acute inflammatory response, they are referred to as proresolving mediators, or resolvins. In this review, we provide an overview of the formation and actions of these lipid mediators.

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The Role of Inflammation in Traumatic Brain Injury

Neurotrauma ◽

10.1093/med/9780190279431.003.0019 ◽

2018 ◽

pp. 211-232

Author(s):

Sarah C. Hellewell ◽

Bridgette D. Semple ◽

Jenna M. Ziebell ◽

Nicole Bye ◽

Cristina Morganti-Kossmann

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Glial Cells ◽

Immune Cell ◽

Brain Trauma ◽

Multiple Roles ◽

Cell Functions ◽

Macrophage Populations

Inflammation occurring following brain trauma represents a significant constituent of complex secondary responses that dictate patients’ outcome. Although a few decades have passed since its discovery, new aspects of this intriguing phenomenon are still being uncovered, ranging from the multiple roles of mediators regulating the inception, progression, and resolution of neuroinflammation, to the development of antiinflammatory therapies. This review provides a summary of the vast research on traumatic brain injury inflammation. The authors describe the fundamental aspects of cytokine and immune cell functions, the orchestrated collaboration of chemokines and leukocytes, the phenotypic distinction of macrophage populations, and the contribution of glial cells. Among the beneficial properties of neuroinflammation, they briefly discuss cytokines’ impact on neurogenesis; the chapter concludes by touching on the implications of antiinflammatory therapies.

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Succinate Is an Inflammation-Induced Immunoregulatory Metabolite in Macrophages

Metabolites ◽

10.3390/metabo10090372 ◽

2020 ◽

Vol 10 (9) ◽

pp. 372 ◽

Cited By ~ 2

Author(s):

Karl J. Harber ◽

Kyra E. de Goede ◽

Sanne G. S. Verberk ◽

Elisa Meinster ◽

Helga E. de Vries ◽

...

Keyword(s):

Immune Responses ◽

Immune Cells ◽

Immune Cell ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Cell Phenotype ◽

Independent Manner ◽

Inflammatory Macrophages ◽

Necrosis Factor

Immunometabolism revealed the crucial role of cellular metabolism in controlling immune cell phenotype and functions. Macrophages, key immune cells that support progression of numerous inflammatory diseases, have been well described as undergoing vast metabolic rewiring upon activation. The immunometabolite succinate particularly gained a lot of attention and emerged as a crucial regulator of macrophage responses and inflammation. Succinate was originally described as a metabolite that supports inflammation via distinct routes. Recently, studies have indicated that succinate and its receptor SUCNR1 can suppress immune responses as well. These apparent contradictory effects might be due to specific experimental settings and particularly the use of distinct succinate forms. We therefore compared the phenotypic and functional effects of distinct succinate forms and receptor mouse models that were previously used for studying succinate immunomodulation. Here, we show that succinate can suppress secretion of inflammatory mediators IL-6, tumor necrosis factor (TNF) and nitric oxide (NO), as well as inhibit Il1b mRNA expression of inflammatory macrophages in a SUCNR1-independent manner. We also observed that macrophage SUCNR1 deficiency led to an enhanced inflammatory response without addition of exogenous succinate. While our study does not reveal new mechanistic insights into how succinate elicits different inflammatory responses, it does indicate that the inflammatory effects of succinate and its receptor SUCNR1 in macrophages are clearly context dependent.

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Niacin protects against abdominal aortic aneurysm formation via GPR109A independent mechanisms: role of NAD+/nicotinamide

Cardiovascular Research ◽

10.1093/cvr/cvz303 ◽

2019 ◽

Vol 116 (14) ◽

pp. 2226-2238 ◽

Cited By ~ 5

Author(s):

Tetsuo Horimatsu ◽

Andra L Blomkalns ◽

Mourad Ogbi ◽

Mary Moses ◽

David Kim ◽

...

Keyword(s):

Immune Cells ◽

Inflammatory Cell ◽

Immune Cell ◽

Inflammatory Responses ◽

Aortic Aneurysms ◽

Cell Infiltration ◽

Protective Effects ◽

Abdominal Aortic ◽

G Protein Coupled

Abstract Aims Chronic adventitial and medial infiltration of immune cells play an important role in the pathogenesis of abdominal aortic aneurysms (AAAs). Nicotinic acid (niacin) was shown to inhibit atherosclerosis by activating the anti-inflammatory G protein-coupled receptor GPR109A [also known as hydroxycarboxylic acid receptor 2 (HCA2)] expressed on immune cells, blunting immune activation and adventitial inflammatory cell infiltration. Here, we investigated the role of niacin and GPR109A in regulating AAA formation. Methods and results Mice were supplemented with niacin or nicotinamide, and AAA was induced by angiotensin II (AngII) infusion or calcium chloride (CaCl2) application. Niacin markedly reduced AAA formation in both AngII and CaCl2 models, diminishing adventitial immune cell infiltration, concomitant inflammatory responses, and matrix degradation. Unexpectedly, GPR109A gene deletion did not abrogate the protective effects of niacin against AAA formation, suggesting GPR109A-independent mechanisms. Interestingly, nicotinamide, which does not activate GPR109A, also inhibited AAA formation and phenocopied the effects of niacin. Mechanistically, both niacin and nicotinamide supplementation increased nicotinamide adenine dinucleotide (NAD+) levels and NAD+-dependent Sirt1 activity, which were reduced in AAA tissues. Furthermore, pharmacological inhibition of Sirt1 abrogated the protective effect of nicotinamide against AAA formation. Conclusion Niacin protects against AAA formation independent of GPR109A, most likely by serving as an NAD+ precursor. Supplementation of NAD+ using nicotinamide-related biomolecules may represent an effective and well-tolerated approach to preventing or treating AAA.

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Interleukin-10 Negatively Regulates Local Cytokine and Chemokine Production but Does Not Influence Antibacterial Host Defense during Murine Pneumococcal Meningitis

Infection and Immunity ◽

10.1128/iai.71.4.2276-2279.2003 ◽

2003 ◽

Vol 71 (4) ◽

pp. 2276-2279 ◽

Cited By ~ 20

Author(s):

Petra J. G. Zwijnenburg ◽

Tom van der Poll ◽

Sandrine Florquin ◽

John J. Roord ◽

A. Marceline van Furth

Keyword(s):

Host Defense ◽

Pneumococcal Meningitis ◽

Inflammatory Responses ◽

Interleukin 10 ◽

Wild Type ◽

Chemokine Production ◽

Local Host ◽

Antibacterial Host Defense ◽

Local Cytokine

ABSTRACT To determine the role of endogenous interleukin-10 (IL-10) in local host defense during pneumococcal meningitis, the inflammatory responses of IL-10-gene-deficient and wild-type mice after the induction of meningitis were compared. The absence of IL-10 was associated with higher cytokine and chemokine concentrations and a more pronounced infiltrate, but antibacterial defense or survival was not influenced.

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IL-10 and TNFαGenotypes in SLE

Journal of Biomedicine and Biotechnology ◽

10.1155/2010/838390 ◽

2010 ◽

Vol 2010 ◽

pp. 1-11 ◽

Cited By ~ 30

Author(s):

Patricia López ◽

Carmen Gutiérrez ◽

Ana Suárez

Keyword(s):

Genetic Variants ◽

Cytokine Production ◽

Clinical Phenotype ◽

Lymphocyte Activation ◽

Interleukin 10 ◽

Promoter Regions ◽

Relevant Role ◽

Steady State Levels ◽

Necrosis Factor

The production of two regulators of the inflammatory response, interleukin 10 (IL-10) and tumor necrosis factorα(TNFα), has been found to be deeply deregulated in SLE patients, suggesting that these cytokines may be involved in the pathogenesis of the disease. Genetic polymorphisms at the promoter regions of IL-10 and TNFαgenes have been associated with different constitutive and induced cytokine production. Given that individual steady-state levels of these molecules may deviate an initial immune response towards different forms of lymphocyte activation, functional genetic variants in their promoters could influence the development of SLE. The present review summarizes the information previously reported about the involvement of IL-10 and TNFαgenetic variants on SLE appearance, clinical phenotype, and outcome. We show that, in spite of the heterogeneity of the populations studied, the existing knowledge points towards a relevant role of IL-10 and TNFαgenotypes in SLE.

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DCIS genomic signatures define biology and correlate with clinical outcome: a Human Tumor Atlas Network (HTAN) analysis of TBCRC 038 and RAHBT cohorts

10.1101/2021.06.16.448585 ◽

2021 ◽

Author(s):

Siri H Strand ◽

Belen Rivero-Gutierrez ◽

Kathleen E Houlahan ◽

Jose A Seoane ◽

Lorraine King ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Outcome ◽

Immune Cell ◽

De Novo ◽

Ductal Carcinoma ◽

Early Stage ◽

Expression Patterns ◽

Human Tumor ◽

Multiscale Approach

Ductal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IBC), with variable propensity for progression. We have performed the first multiscale, integrated profiling of DCIS with clinical outcomes by analyzing 677 DCIS samples from 481 patients with 7.1 years median follow-up from the Translational Breast Cancer Research Consortium (TBCRC) 038 study and the Resource of Archival Breast Tissue (RAHBT) cohorts. We made observations on DNA, RNA, and protein expression, and generated a de novo clustering scheme for DCIS that represents a fundamental transcriptomic organization at this early stage of breast neoplasia. Distinct stromal expression patterns and immune cell compositions were identified. We found RNA expression patterns that correlate with later events. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with conventional pathology findings, disease states, and clinical outcome.

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Sexual-dimorphism in human immune system aging

10.1101/755702 ◽

2019 ◽

Author(s):

Eladio J. Márquez ◽

Cheng-han Chung ◽

Radu Marches ◽

Robert J. Rossi ◽

Djamel Nehar-Belaid ◽

...

Keyword(s):

Immune System ◽

Mononuclear Cells ◽

Immune Cell ◽

Rna Seq ◽

Human Immune System ◽

Peripheral Blood Mononuclear ◽

Cell Functions ◽

Age Related ◽

Male Specific

AbstractDifferences in immune function and responses contribute to health- and life-span disparities between sexes. However, the role of sex in immune system aging is not well understood. Here, we characterize peripheral blood mononuclear cells from 172 healthy adults 22-93 years of age using ATAC-seq, RNA-seq, and flow-cytometry. These data reveal a shared epigenomic signature of aging including declining naïve T cell and increasing monocyte/cytotoxic cell functions. These changes were greater in magnitude in men and accompanied by a male-specific genomic decline in B-cell specific loci. Age-related epigenomic changes first spike around late-thirties with similar timing and magnitude between sexes, whereas the second spike is earlier and stronger in men. Unexpectedly, genomic differences between sexes increase after age 65, with men having higher innate and pro-inflammatory activity and lower adaptive activity. Impact of age and sex on immune cell genomes can be visualized at https://immune-aging.jax.org to provide insights into future studies.

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D-Lactate Increases Cytokine Production in Bovine Fibroblast-Like Synoviocytes via MCT1 Uptake and the MAPK, PI3K/Akt, and NFκB Pathways

Animals ◽

10.3390/ani10112105 ◽

2020 ◽

Vol 10 (11) ◽

pp. 2105

Author(s):

Carolina Manosalva ◽

John Quiroga ◽

Stefanie Teuber ◽

Sebastián Cárdenas ◽

María Daniella Carretta ◽

...

Keyword(s):

Cytokine Production ◽

Inflammatory Responses ◽

Monocarboxylate Transporter ◽

Dependent Manner ◽

Monocarboxylate Transporter 1 ◽

Ruminal Acidosis ◽

Excessive Intake ◽

Fermentable Carbohydrates ◽

Fibroblast Like Synoviocytes

Acute ruminal acidosis (ARA) is caused by the excessive intake of highly fermentable carbohydrates, followed by the massive production of D-lactate and the appearance of neutrophilic aseptic polysynovitis. Bovines with ARA develop different lesions, such as ruminitis, polioencephalomalacia (calves), liver abscess and lameness. Lameness in cattle with ARA is closely associated with the presence of laminitis and polysynovitis. However, despite decades of research in bovine lameness as consequence of ruminal acidosis, the aetiology and pathogenesis remain unclear. Fibroblast-like synoviocytes (FLSs) are components of synovial tissue, and under pathological conditions, FLSs increase cytokine production, aggravating inflammatory responses. We hypothesized that D-lactate could induce cytokine production in bovine FLSs. Analysis by qRT-PCR and ELISA revealed that D-lactate, but not L-lactate, increased the expression of IL-6 and IL-8 in a monocarboxylate transporter-1-dependent manner. In addition, we observed that the inhibition of the p38, ERK1/2, PI3K/Akt, and NF-κB pathways reduced the production of IL-8 and IL-6. In conclusion, our results suggest that D-lactate induces an inflammatory response; this study contributes to the literature by revealing a potential key role of D-lactate in the polysynovitis of cattle with ARA.

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Role of Polyamines in Immune Cell Functions

Medical Sciences ◽

10.3390/medsci6010022 ◽

2018 ◽

Vol 6 (1) ◽

pp. 22 ◽

Cited By ~ 14

Author(s):

Rebecca Hesterberg ◽

John Cleveland ◽

Pearlie Epling-Burnette

Keyword(s):

Immune Cell ◽

Cell Functions

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