Itaconate: A Metabolite Regulates Inflammation Response and Oxidative Stress

Metabolic products can lead to crucial biological function alterations. Itaconate is probably the best example of how a metabolic process can be diverted to generate an immunomodulator effect in macrophages. Through inflammatory stimuli, such as lipopolysaccharide, the immune response gene 1 is activated and promotes the production of itaconate from the tricarboxylic acid cycle by decarboxylating cis-aconitate. Itaconate has been reported to have multiple immunoregulatory and antioxidative effects. In addition, reports have described its antibacterial and protumor effects. The involved mechanism in these effects includes the activation of nuclear factor E2-related factor 2 by alkylation of Kelch-like ECH-associated protein 1, inhibition of aerobic glycolysis by targeting glyceraldehyde-3-phosphate dehydrogenase and fructose-bisphosphate aldolase A, inhibition of succinate dehydrogenase, and blockade of IκBζ translation. All of these discoveries elucidated the transformation of the pro- into anti-inflammatory status in macrophages, which is crucial in innate immunity and set the ground for the emerging therapeutic implications of itaconate. In this review, we point out that itaconate is a novel and pivotal metabolic determinant of the immunoregulatory response in macrophages and highlight studies that have improved our understanding of the connection between the immune response and metabolism. In addition, we shed light on the therapeutic potential of itaconate and its derivatives to treat inflammatory diseases.

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Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8+T cell stemness and antitumor immunity

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1920413117 ◽

2020 ◽

Vol 117 (11) ◽

pp. 6047-6055 ◽

Cited By ~ 10

Author(s):

Dalton Hermans ◽

Sanjivan Gautam ◽

Juan C. García-Cañaveras ◽

Daniel Gromer ◽

Suman Mitra ◽

...

Keyword(s):

Cell Differentiation ◽

Lactate Dehydrogenase ◽

T Cell ◽

Therapeutic Potential ◽

Aerobic Glycolysis ◽

Tricarboxylic Acid Cycle ◽

Lactate Production ◽

Developmental Differences ◽

T Cell Differentiation ◽

Quiescent State

Interleukin (IL)-2 and IL-21 dichotomously shape CD8+T cell differentiation. IL-2 drives terminal differentiation, generating cells that are poorly effective against tumors, whereas IL-21 promotes stem cell memory T cells (TSCM) and antitumor responses. Here we investigated the role of metabolic programming in the developmental differences induced by these cytokines. IL-2 promoted effector-like metabolism and aerobic glycolysis, robustly inducing lactate dehydrogenase (LDH) and lactate production, whereas IL-21 maintained a metabolically quiescent state dependent on oxidative phosphorylation. LDH inhibition rewired IL-2–induced effects, promoting pyruvate entry into the tricarboxylic acid cycle and inhibiting terminal effector and exhaustion programs, including mRNA expression of members of the NR4A family of nuclear receptors, as well asPrdm1andXbp1. While deletion ofLdhaprevented development of cells with antitumor effector function, transient LDH inhibition enhanced the generation of memory cells capable of triggering robust antitumor responses after adoptive transfer. LDH inhibition did not significantly affect IL-21–induced metabolism but caused major transcriptomic changes, including the suppression of IL-21–induced exhaustion markers LAG3, PD1, 2B4, and TIM3. LDH inhibition combined with IL-21 increased the formation of TSCMcells, resulting in more profound antitumor responses and prolonged host survival. These findings indicate a pivotal role for LDH in modulating cytokine-mediated T cell differentiation and underscore the therapeutic potential of transiently inhibiting LDH during adoptive T cell-based immunotherapy, with an unanticipated cooperative antitumor effect of LDH inhibition and IL-21.

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“Galectin-1 Induces Central and Peripheral Cell Death: Implications in T-Cell Physiopathology”

Developmental Immunology ◽

10.1155/2000/36321 ◽

2000 ◽

Vol 7 (2-4) ◽

pp. 117-129 ◽

Cited By ~ 13

Author(s):

C. E. Sotomayor ◽

G. A. Rabinovich

Keyword(s):

Immune Response ◽

Immune System ◽

T Cell ◽

Therapeutic Potential ◽

Inflammatory Diseases ◽

Lymphoid Organs ◽

Peripheral Cell ◽

Contact Exposure ◽

Induced Apoptosis ◽

Complex Scenario

The immune system has a remarkable capacity to maintain a state of equilibrium even as it responds to a diverse array of foreign proteins and despite its contact exposure to self-antigens. Apoptosis is one of the mechanisms aimed at preserving the homeostasis after the completion of an immune response, thus returning the immune system to a basal state and warranting the elimination of autoagressive cells in both central and peripheral lymphoid organs. Targeted deletions in critical genes involved in the apoptotic death machinery together with natural spontaneous mutations have clearly shown the importance of apoptosis in the regulation of the immune response. This complex scenario of stimulatory and inhibitory genes has been enriched with the finding that galectin-1, a 14.5 kDa β-galactoside-binding protein, is able to induce apoptosis of immature cortical thymocytes and mature T cells by cross-linking cell surface glycoconjugates. Galectin-1 is present not only in central and peripheral lymphoid organs, but also at sites of immune privilege. In the present article we will discuss the implications of galectin-1-induced apoptosis in T-cell physiopathology in an attempt to validate its therapeutic potential in autoimmune and inflammatory diseases.

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Cell death–mediated cytokine release and its therapeutic implications

Journal of Experimental Medicine ◽

10.1084/jem.20181892 ◽

2019 ◽

Vol 216 (7) ◽

pp. 1474-1486 ◽

Cited By ~ 16

Author(s):

David E. Place ◽

Thirumala-Devi Kanneganti

Keyword(s):

Immune Response ◽

Cell Death ◽

Inflammatory Diseases ◽

Therapeutic Strategies ◽

Cytokine Release ◽

Therapeutic Implications ◽

The Past ◽

Cell Death Pathways ◽

Regulated Cell Death ◽

Cellular Components

Targeting apoptosis to treat diseases has seen tremendous success over the past decades. More recently, alternative forms of regulated cell death, including pyroptosis and necroptosis, have been described. Understanding the molecular cascades regulating both pyroptosis and necroptosis will yield even more targets to treat diseases. These lytic forms of cell death are distinct from apoptosis due to their characteristic lysis and release of cellular components that promote disease or direct a beneficial immune response. In this review, we focus on how pyroptosis and necroptosis, which release potent immune cytokines such as IL-1 and IL-18, contribute to various diseases. We also consider the important role that the executioners of these cell death pathways, GSDMD and MLKL, play in the progression of inflammatory diseases. Crosstalk between the different cell death pathways likely plays a major role physiologically. New therapeutic strategies targeting these specific molecules hold enormous potential for managing inflammatory diseases.

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Hyperferritinaemia: An Iron Sword of Autoimmunity

Current Pharmaceutical Design ◽

10.2174/1381612825666190709202804 ◽

2019 ◽

Vol 25 (27) ◽

pp. 2909-2918 ◽

Cited By ~ 4

Author(s):

Joanna Giemza-Stokłosa ◽

Md. Asiful Islam ◽

Przemysław J. Kotyla

Keyword(s):

Immune Response ◽

Macrophage Activation ◽

Inflammatory Diseases ◽

Acute Phase Reactant ◽

Catastrophic Antiphospholipid Syndrome ◽

Inflammatory Conditions ◽

Phase Reactant ◽

Signalling Molecule ◽

Cytokine Synthesis

Background:: Ferritin is a molecule that plays many roles being the storage for iron, signalling molecule, and modulator of the immune response. Methods:: Different electronic databases were searched in a non-systematic way to find out the literature of interest. Results:: The level of ferritin rises in many inflammatory conditions including autoimmune disorders. However, in four inflammatory diseases (i.e., adult-onset Still’s diseases, macrophage activation syndrome, catastrophic antiphospholipid syndrome, and sepsis), high levels of ferritin are observed suggesting it as a remarkable biomarker and pathological involvement in these diseases. Acting as an acute phase reactant, ferritin is also involved in the cytokine-associated modulator of the immune response as well as a regulator of cytokine synthesis and release which are responsible for the inflammatory storm. Conclusion:: This review article presents updated information on the role of ferritin in inflammatory and autoimmune diseases with an emphasis on hyperferritinaemic syndrome.

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Therapeutic Potential of Amniotic Fluid Derived Mesenchymal Stem Cells Based on their Differentiation Capacity and Immunomodulatory Properties

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190222201749 ◽

2019 ◽

Vol 14 (4) ◽

pp. 327-336 ◽

Cited By ~ 9

Author(s):

Carl R. Harrell ◽

Marina Gazdic ◽

Crissy Fellabaum ◽

Nemanja Jovicic ◽

Valentin Djonov ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Animal Models ◽

Amniotic Fluid ◽

Therapeutic Potential ◽

Inflammatory Diseases ◽

Therapeutic Effects ◽

Differentiation Potential ◽

Differentiation Capacity ◽

Cell Based Therapy

Background: Amniotic Fluid Derived Mesenchymal Stem Cells (AF-MSCs) are adult, fibroblast- like, self-renewable, multipotent stem cells. During the last decade, the therapeutic potential of AF-MSCs, based on their huge differentiation capacity and immunomodulatory characteristics, has been extensively explored in animal models of degenerative and inflammatory diseases. Objective: In order to describe molecular mechanisms responsible for the therapeutic effects of AFMSCs, we summarized current knowledge about phenotype, differentiation potential and immunosuppressive properties of AF-MSCs. Methods: An extensive literature review was carried out in March 2018 across several databases (MEDLINE, EMBASE, Google Scholar), from 1990 to present. Keywords used in the selection were: “amniotic fluid derived mesenchymal stem cells”, “cell-therapy”, “degenerative diseases”, “inflammatory diseases”, “regeneration”, “immunosuppression”. Studies that emphasized molecular and cellular mechanisms responsible for AF-MSC-based therapy were analyzed in this review. Results: AF-MSCs have huge differentiation and immunosuppressive potential. AF-MSCs are capable of generating cells of mesodermal origin (chondrocytes, osteocytes and adipocytes), neural cells, hepatocytes, alveolar epithelial cells, insulin-producing cells, cardiomyocytes and germ cells. AF-MSCs, in juxtacrine or paracrine manner, regulate proliferation, activation and effector function of immune cells. Due to their huge differentiation capacity and immunosuppressive characteristic, transplantation of AFMSCs showed beneficent effects in animal models of degenerative and inflammatory diseases of nervous, respiratory, urogenital, cardiovascular and gastrointestinal system. Conclusion: Considering the fact that amniotic fluid is obtained through routine prenatal diagnosis, with minimal invasive procedure and without ethical concerns, AF-MSCs represents a valuable source for cell-based therapy of organ-specific or systemic degenerative and inflammatory diseases.

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Protective Effects of Lactoferrin against SARS-CoV-2 Infection In Vitro

Nutrients ◽

10.3390/nu13020328 ◽

2021 ◽

Vol 13 (2) ◽

pp. 328 ◽

Cited By ~ 1

Author(s):

Claudio Salaris ◽

Melania Scarpa ◽

Marina Elli ◽

Alice Bertolini ◽

Simone Guglielmetti ◽

...

Keyword(s):

Immune Response ◽

Epithelial Cells ◽

Intestinal Epithelial Cells ◽

Plaque Assay ◽

Immune Response Gene ◽

Intestinal Epithelial ◽

Antiviral Immune Response ◽

Qrt Pcr ◽

Anti Inflammatory

SARS-CoV-2 is a newly emerging virus that currently lacks curative treatments. Lactoferrin (LF) is a naturally occurring non-toxic glycoprotein with broad-spectrum antiviral, immunomodulatory and anti-inflammatory effects. In this study, we assessed the potential of LF in the prevention of SARS-CoV-2 infection in vitro. Antiviral immune response gene expression was analyzed by qRT-PCR in uninfected Caco-2 intestinal epithelial cells treated with LF. An infection assay for SARS-CoV-2 was performed in Caco-2 cells treated or not with LF. SARS-CoV-2 titer was determined by qRT-PCR, plaque assay and immunostaining. Inflammatory and anti-inflammatory cytokine production was determined by qRT-PCR. LF significantly induced the expression of IFNA1, IFNB1, TLR3, TLR7, IRF3, IRF7 and MAVS genes. Furthermore, LF partially inhibited SARS-CoV-2 infection and replication in Caco-2 intestinal epithelial cells. Our in vitro data support LF as an immune modulator of the antiviral immune response with moderate effects against SARS-CoV-2 infection.

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Skullcapflavone II Suppresses TNF-α/IFN-γ-Induced TARC, MDC, and CTSS Production in HaCaT Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22126428 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6428

Author(s):

Hanon Lee ◽

Dong Hun Lee ◽

Jang-Hee Oh ◽

Jin Ho Chung

Keyword(s):

P38 Mapk ◽

Therapeutic Potential ◽

Inflammatory Diseases ◽

Mapk Signaling ◽

Hacat Cells ◽

Protein Levels ◽

Tnf Α ◽

Ifn Γ ◽

Mapk Signaling Pathways ◽

Pro Inflammatory Cytokines

Skullcapflavone II (SFII), a flavonoid derived from Scutellaria baicalensis, has been reported to have anti-inflammatory properties. However, its therapeutic potential for skin inflammatory diseases and its mechanism are unknown. Therefore, this study aimed to investigate the effect of SFII on TNF-α/IFN-γ-induced atopic dermatitis (AD)-associated cytokines, such as thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC). Co-stimulation with TNF-α/IFN-γ in HaCaT cells is a well-established model for induction of pro-inflammatory cytokines. We treated cells with SFII prior to TNF-α/IFN-γ-stimulation and confirmed that it significantly inhibited TARC and MDC expression at the mRNA and protein levels. Additionally, SFII also inhibited the expression of cathepsin S (CTSS), which is associated with itching in patients with AD. Using specific inhibitors, we demonstrated that STAT1, NF-κB, and p38 MAPK mediate TNF-α/IFN-γ-induced TARC and MDC, as well as CTSS expression. Finally, we confirmed that SFII significantly suppressed TNF-α/IFN-γ-induced phosphorylation of STAT1, NF-κB, and p38 MAPK. Taken together, our study indicates that SFII inhibits TNF-α/IFN-γ-induced TARC, MDC, and CTSS expression by regulating STAT1, NF-κB, and p38 MAPK signaling pathways.

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Curcumin and Freshwater Clam Extracts Alleviate the Progression of Osteoarthritis by Reducing Synovial Inflammation and Allowing Cartilage Regeneration

Processes ◽

10.3390/pr9060931 ◽

2021 ◽

Vol 9 (6) ◽

pp. 931

Author(s):

Chiao-Hsu Ke ◽

Chia-Hui Hsu ◽

Yu-Ling Lin ◽

Wei-Hsiang Huang ◽

Hsin-Pei Weng ◽

...

Keyword(s):

Scoring System ◽

Inflammatory Diseases ◽

Synergistic Effects ◽

Symptomatic Relief ◽

Cartilage Regeneration ◽

Research Society ◽

Infrapatellar Fat Pad ◽

Freshwater Clam ◽

Inflammatory Status ◽

Anti Inflammatory

Osteoarthritis (OA) is a common degenerative disorder and is accompanied by numerous pain symptoms. With increased age, individuals develop a chronic inflammatory status, and pro-inflammatory cytokines as well as mediators contribute to the progression of OA. However, no desirable remedies have been completely able to inhibit OA progression or safely provide effective symptomatic relief. Natural component extracts or dietary-derived compounds are widely used for anti-inflammatory diseases. Curcumin and freshwater clam extract (FCE) have been proven as functional foods that are able to regulate immune systems. This study demonstrated that curcumin and FCE had synergistic effects on alleviating the progression of OA by assuaging inflammation and repairing the cartilage within the joints. After consumption of curcumin and FCE, the severity of synovitis was quantified by the infrapatellar fat pad inflammation scoring system and the Osteoarthritis Research Society International (OARSI) scoring system. Significant improvement and articular cartilage regeneration were noted. Moreover, once the inflammation within the joints was reduced, the animals redistributed their body weight on the OA-induced hindlimb. In summary, curcumin and FCE possess desirable anti-inflammatory and repair functions, suggesting their potential as alternative remedies in the management of OA or other inflammatory diseases.

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Pharmacological Targeting of Heme Oxygenase-1 in Osteoarthritis

Antioxidants ◽

10.3390/antiox10030419 ◽

2021 ◽

Vol 10 (3) ◽

pp. 419

Author(s):

Yohei Sanada ◽

Sho Joseph Ozaki Tan ◽

Nobuo Adachi ◽

Shigeru Miyaki

Keyword(s):

Heme Oxygenase ◽

Redox Homeostasis ◽

Synovial Fibroblasts ◽

Protective Role ◽

Joint Disease ◽

Heme Oxygenase 1 ◽

Transcriptional Level ◽

Related Factor ◽

Mobility Limitations ◽

Therapeutic Implications

Osteoarthritis (OA) is a common aging-associated disease that clinically manifests as joint pain, mobility limitations, and compromised quality of life. Today, OA treatment is limited to pain management and joint arthroplasty at the later stages of disease progression. OA pathogenesis is predominantly mediated by oxidative damage to joint cartilage extracellular matrix and local cells such as chondrocytes, osteoclasts, osteoblasts, and synovial fibroblasts. Under normal conditions, cells prevent the accumulation of reactive oxygen species (ROS) under oxidatively stressful conditions through their adaptive cytoprotective mechanisms. Heme oxygenase-1 (HO-1) is an iron-dependent cytoprotective enzyme that functions as the inducible form of HO. HO-1 and its metabolites carbon monoxide and biliverdin contribute towards the maintenance of redox homeostasis. HO-1 expression is primarily regulated at the transcriptional level through transcriptional factor nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), specificity protein 1 (Sp1), transcriptional repressor BTB-and-CNC homology 1 (Bach1), and epigenetic regulation. Several studies report that HO-1 expression can be regulated using various antioxidative factors and chemical compounds, suggesting therapeutic implications in OA pathogenesis as well as in the wider context of joint disease. Here, we review the protective role of HO-1 in OA with a focus on the regulatory mechanisms that mediate HO-1 activity.

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Endometrial Inflammation at the Time of Insemination and Its Effect on Subsequent Fertility of Dairy Cows

Animals ◽

10.3390/ani11071858 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1858

Author(s):

Karen Wagener ◽

Marc Drillich ◽

Christine Aurich ◽

Christoph Gabler

Keyword(s):

Immune Response ◽

Dairy Cows ◽

Mrna Expression ◽

Reverse Transcription ◽

Artificial Insemination ◽

Cox Regression ◽

Related Factor ◽

Subsequent Fertility ◽

Cxcl8 Mrna ◽

Repeat Breeder

Our objective was to investigate the level of endometrial immune response at artificial insemination (AI) and to relate it to subsequent fertility. From 71 healthy cows, endometrial cytobrush samples were taken at the first AI for cytological and mRNA analyses. Total RNA isolated from the cytobrushes was used for reverse transcription qPCR for selected transcripts. Animals were grouped into pregnant (PREG; n = 32) and non-pregnant (non-PREG; n = 39) cows following their first AI. The mRNA abundance of the neutrophil-related factor CEACAM1 and the chemokine CXCL5 was 1.2- (p = 0.03) and 2.0-fold (p = 0.04) greater in PREG than in non-PREG cows, respectively. Animals were further subdivided according to the number of inseminations until pregnancy (PREG1, n = 32; PREG2-3, n = 19) and in repeat breeder cows (RBC, n = 13). CEACAM1 and CXCL8 mRNA expression was 1.7- (p = 0.01) and 2.3-fold (p = 0.03) greater in PREG1 than in RBC, respectively. Cox regression showed that cows with PMN ≥ 1% had a 1.8-fold increased chance of pregnancy within 150 days postpartum compared with cows with fewer PMNs. We conclude that a certain level of inflammation before the stimulus of AI might be beneficial for subsequent fertility.

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