bims-imicid 2023-12-10 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023–12–10
27 papers selected by
Dylan Ryan, University of Cambridge

De novo NAD+ synthesis contributes to CD8+ T cell metabolic fitness and antitumor function.
Fructose sweetens the adipocyte-T cell alliance against tumors.
Metabolite itaconate in host immunoregulation and defense.
Metabolic flux reprogramming in Mycobacterium tuberculosis-infected human macrophages.
Immunometabolism of dendritic cells in health and disease.
HIF-1α promotes virus replication and cytokine storm in H1N1 virus-induced severe pneumonia through cellular metabolic reprogramming.
Macrophage LMO7 deficiency facilitates inflammatory injury via metabolic-epigenetic reprogramming.
Dual-specificity phosphatase 5-mediated fatty acid oxidation promotes Mycobacterium bovis BCG -induced inflammatory responses.
The influence of maternal high fat diet during lactation on offspring hematopoietic priming.
Host-derived oxidized phospholipids initiate effector-triggered immunity fostering lethality upon microbial encounter.
Proteomic analysis reveals changes in the proteome of human THP-1 macrophages infected with Paracoccidioides brasiliensis.
Mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via mTORC2/HK1-mediated metabolic rewiring.
Mitochondrial metabolic flexibility is critical for CD8+ T cell antitumor immunity.
Metabolic alterations unravel the maternofetal immune responses with disease severity in pregnant women infected with SARS-CoV-2.
Counteracting tryptophan metabolism alterations as a new therapeutic strategy for rheumatoid arthritis.
IL-15-dependent immune crosstalk between natural killer cells and dendritic cells in HIV-1 elite controllers.
USP16 is an ISG15 cross-reactive deubiquitinase that targets pro-ISG15 and ISGylated proteins involved in metabolism.
Fibrinogen-like protein 2 promotes tumor immune suppression by regulating cholesterol metabolism in myeloid-derived suppressor cells.
The mitochondrial fission protein DRP1 influences memory CD8+ T cell formation and function.
Similarities and divergences in the metabolism of immune cells in cancer and helminthic infections.
Targeting YAP1-regulated Glycolysis in Fibroblast-Like Synoviocytes Impairs Macrophage Infiltration to Ameliorate Diabetic Osteoarthritis Progression.
Hepatocyte CHRNA4 mediates the MASH-promotive effects of immune cell-produced acetylcholine and smoking exposure in mice and humans.
Oral magnesium prevents acetaminophen-induced acute liver injury by modulating microbial metabolism.
ω-3 polyunsaturated fatty acid alleviates systemic lupus erythematosus by suppressing autoimmunity in a murine model.
Systemic lupus erythematosus patients have unique changes in serum metabolic profiles across age associated with cardiometabolic risk.
Central obesity is detrimental to anti-inflammatory, phenotype, and exhaustion markers in mononuclear cells - A cross-sectional study.
The dysregulation of immune cells induced by uric acid: mechanisms of inflammation associated with hyperuricemia and its complications.

Cell Rep. 2023 Dec 01. pii: S2211-1247(23)01530-9. [Epub ahead of print]42(12): 113518

De novo NAD+ synthesis contributes to CD8+ T cell metabolic fitness and antitumor function.

Jie Wan, Cheng Cheng, Jiajia Hu, Haiyan Huang, Qiaoqiao Han, Zuliang Jie, Qiang Zou, Jian-Hong Shi, Xiaoyan Yu.

  The dysfunction and clonal constriction of tumor-infiltrating CD8+ T cells are accompanied by alterations in cellular metabolism; however, how the cell-intrinsic metabolic pathway specifies intratumoral CD8+ T cell features remains elusive. Here, we show that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD+) via the kynurenine pathway (KP) contributes to the maintenance of intratumoral CD8+ T cell metabolic and functional fitness. De novo NAD+ synthesis is involved in CD8+ T cell metabolism and antitumor function. KP-derived NAD+ promotes PTEN deacetylation, thereby facilitating PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, impaired cell-autonomous NAD+ synthesis limits CD8+ T cell responses in human colorectal cancer samples. Our results reveal that KP-derived NAD+ regulates the CD8+ T cell metabolic and functional state by restricting PTEN activity and suggest that modulation of de novo NAD+ synthesis could restore CD8+ T cell metabolic fitness and antitumor function.

Keywords:  CP: Cancer; CP: Metabolism

DOI:  https://doi.org/10.1016/j.celrep.2023.113518
Cell Metab. 2023 Dec 05. pii: S1550-4131(23)00415-1. [Epub ahead of print]35(12): 2093-2094

Fructose sweetens the adipocyte-T cell alliance against tumors.

Peipei Zhou, Hongbo Chi.

Dietary fructose is implicated in tumorigenesis, but whether dietary fructose regulates antitumor immunity remains elusive. In this issue of Cell Metabolism, Zhang et al. show that dietary fructose promotes adipocyte-derived leptin production, which attenuates terminal exhaustion programming and boosts the effector function of CD8+ T cells for improved tumor control.

DOI: https://doi.org/10.1016/j.cmet.2023.11.004
Cell Mol Biol Lett. 2023 Dec 02. 28(1): 100

Metabolite itaconate in host immunoregulation and defense.

Wenchang Yang, Yaxin Wang, Kaixiong Tao, Ruidong Li.

  Metabolic states greatly influence functioning and differentiation of immune cells. Regulating the metabolism of immune cells can effectively modulate the host immune response. Itaconate, an intermediate metabolite derived from the tricarboxylic acid (TCA) cycle of immune cells, is produced through the decarboxylation of cis-aconitate by cis-aconitate decarboxylase in the mitochondria. The gene encoding cis-aconitate decarboxylase is known as immune response gene 1 (IRG1). In response to external proinflammatory stimulation, macrophages exhibit high IRG1 expression. IRG1/itaconate inhibits succinate dehydrogenase activity, thus influencing the metabolic status of macrophages. Therefore, itaconate serves as a link between macrophage metabolism, oxidative stress, and immune response, ultimately regulating macrophage function. Studies have demonstrated that itaconate acts on various signaling pathways, including Keap1-nuclear factor E2-related factor 2-ARE pathways, ATF3-IκBζ axis, and the stimulator of interferon genes (STING) pathway to exert antiinflammatory and antioxidant effects. Furthermore, several studies have reported that itaconate affects cancer occurrence and development through diverse signaling pathways. In this paper, we provide a comprehensive review of the role IRG1/itaconate and its derivatives in the regulation of macrophage metabolism and functions. By furthering our understanding of itaconate, we intend to shed light on its potential for treating inflammatory diseases and offer new insights in this field.

Keywords:  Defense; Immunometabolism; Itaconate; Itaconate derivative

DOI:  https://doi.org/10.1186/s11658-023-00503-3
Front Microbiol. 2023 ;14 1289987

Metabolic flux reprogramming in Mycobacterium tuberculosis-infected human macrophages.

Khushboo Borah Slater, Luana Moraes, Ye Xu, Daniel Kim.

  Metabolic fluxes are at the heart of metabolism and growth in any living system. During tuberculosis (TB) infection, the pathogenic Mycobacterium tuberculosis (Mtb) adapts its nutritional behaviour and metabolic fluxes to survive in human macrophages and cause infection. The infected host cells also undergo metabolic changes. However, our knowledge of the infected host metabolism and identification of the reprogrammed metabolic flux nodes remains limited. In this study, we applied systems-based 13C-metabolic flux analysis (MFA) to measure intracellular carbon metabolic fluxes in Mtb-infected human THP-1 macrophages. We provide a flux map for infected macrophages that quantified significantly increased fluxes through glycolytic fluxes towards pyruvate synthesis and reduced pentose phosphate pathway fluxes when compared to uninfected macrophages. The tri carboxylic acid (TCA) cycle fluxes were relatively low, and amino acid fluxes were reprogrammed upon Mtb infection. The knowledge of host metabolic flux profiles derived from our work expands on how the host cell adapts its carbon metabolism in response to Mtb infection and highlights important nodes that may provide targets for developing new therapeutics to improve TB treatment.

Keywords:  Mycobacterium tuberculosis; fluxomics; human macrophages; immunometabolism; tuberculosis

DOI:  https://doi.org/10.3389/fmicb.2023.1289987
Adv Immunol. 2023 ;pii: S0065-2776(23)00032-9. [Epub ahead of print]160 83-116

Immunometabolism of dendritic cells in health and disease.

Chuansheng Guo, Hongbo Chi.

Dendritic cells (DCs) are crucial mediators that bridge the innate and adaptive immune responses. Cellular rewiring of metabolism is an emerging regulator of the activation, migration, and functional specialization of DC subsets in specific microenvironments and immunological conditions. DCs undergo metabolic adaptation to exert immunogenic or tolerogenic effects in different contexts. Also, beyond their intracellular metabolic and signaling roles, metabolites and nutrients mediate the intercellular crosstalk between DCs and other cell types, and such crosstalk orchestrates DC function and immune responses. Here, we provide a comprehensive review of the metabolic regulation of DC biology in various contexts and summarize the current understanding of such regulation in directing immune homeostasis and inflammation, specifically with respect to infections, autoimmunity, tolerance, cancer, metabolic diseases, and crosstalk with gut microbes. Understanding context-specific metabolic alterations in DCs may identify mechanisms for physiological and pathological functions of DCs and yield potential opportunities for therapeutic targeting of DC metabolism in many diseases.

DOI: https://doi.org/10.1016/bs.ai.2023.10.002
Virol Sin. 2023 Nov 30. pii: S1995-820X(23)00142-6. [Epub ahead of print]

HIF-1α promotes virus replication and cytokine storm in H1N1 virus-induced severe pneumonia through cellular metabolic reprogramming.

Xiaoxiao Meng, Yong Zhu, Wenyu Yang, Jiaxiang Zhang, Wei Jin, Rui Tian, Zhengfeng Yang, Ruilan Wang.

  The mortality of patients with severe pneumonia caused by H1N1 infection is closely related to viral replication and cytokine storm. However, the specific mechanisms triggering virus replication and cytokine storm are still not fully elucidated. Here, we identified HIF-1α as one of the major host molecules that facilitates H1N1 virus replication followed by cytokine storm in alveolar epithelial cells. Specifically, HIF-1α protein expression is upregulated after H1N1 infection. Deficiency of HIF-1α attenuates pulmonary injury, viral replication and cytokine storm in vivo. In addition, viral replication and cytokine storm were inhibited after HIF-1α knockdown in vitro. Mechanistically, the invasion of H1N1 virus into alveolar epithelial cells leads to a shift in glucose metabolism to glycolysis, with rapid production of ATP and lactate. Inhibition of glycolysis significantly suppresses viral replication and inflammatory responses. Further analysis revealed that H1N1-induced HIF-1α can promote the expression of hexokinase 2 (HK2), the key enzyme of glycolysis, and then not only provide energy for the rapid replication of H1N1 virus but also produce lactate, which reduces the accumulation of the MAVS/RIG-I complex and inhibits IFN-α/β production. In conclusion, this study demonstrated that the upregulation of HIF-1α by H1N1 infection augments viral replication and cytokine storm by cellular metabolic reprogramming toward glycolysis mainly through upregulation of HK2, providing a theoretical basis for finding potential targets for the treatment of severe pneumonia caused by H1N1 infection.

Keywords:  Glycolysis; H1N1; Hypoxia inducible factor-1α; Severe pneumonia; Virus replication

DOI:  https://doi.org/10.1016/j.virs.2023.11.010
Acta Pharm Sin B. 2023 Dec;13(12): 4785-4800

Macrophage LMO7 deficiency facilitates inflammatory injury via metabolic-epigenetic reprogramming.

Shixin Duan, Xinyi Lou, Shiyi Chen, Hongchao Jiang, Dongxin Chen, Rui Yin, Mengkai Li, Yuseng Gou, Wenjuan Zhao, Lei Sun, Feng Qian.

  Inflammatory bowel disease (IBD) is a formidable disease due to its complex pathogenesis. Macrophages, as a major immune cell population in IBD, are crucial for gut homeostasis. However, it is still unveiled how macrophages modulate IBD. Here, we found that LIM domain only 7 (LMO7) was downregulated in pro-inflammatory macrophages, and that LMO7 directly degraded 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) through K48-mediated ubiquitination in macrophages. As an enzyme that regulates glycolysis, PFKFB3 degradation led to the glycolytic process inhibition in macrophages, which in turn inhibited macrophage activation and ultimately attenuated murine colitis. Moreover, we demonstrated that PFKFB3 was required for histone demethylase Jumonji domain-containing protein 3 (JMJD3) expression, thereby inhibiting the protein level of trimethylation of histone H3 on lysine 27 (H3K27me3). Overall, our results indicated the LMO7/PFKFB3/JMJD3 axis is essential for modulating macrophage function and IBD pathogenesis. Targeting LMO7 or macrophage metabolism could potentially be an effective strategy for treating inflammatory diseases.

Keywords:  Inflammatory bowel disease; JMJD3; LMO7; Macrophage; PFKFB3; Ubiquitination

DOI:  https://doi.org/10.1016/j.apsb.2023.09.012
Exp Cell Res. 2023 Dec 02. pii: S0014-4827(23)00420-2. [Epub ahead of print] 113869

Dual-specificity phosphatase 5-mediated fatty acid oxidation promotes Mycobacterium bovis BCG -induced inflammatory responses.

Jia Luo, Zengjian Tian, Fuyang Song, Chao Ren, Wenmiao Liu.

  Mycobacterium tuberculosis (Mtb) reprograms FAs metabolism of macrophages during infection and affects inflammatory reaction eventually, however, the mechanism remains poorly understood. Here we show that Mycobacterium bovis (BCG) induces DUSP5 expression through TLR2-MAPKs signaling pathway and promotes fatty acid oxidation (FAO). Silencing DUSP5 by adeno-associated virus vector (AAV) ameliorates lung injury and DUSP5 knockdown reduces the expression of IL-1β, IL-6 and inactivated NF-κB signaling in BCG-infected macrophages. Of note, DUSP5 specific siRNA increases the content of free fatty acids (FFAs) and triglyceride (TG), but represses the expression of FAO associated enzymes such as CPT1A and PPARα, suggesting DUSP5 mediated FAO during BCG infection. Moreover, Inhibiting FAO by pharmacological manner suppresses IL-1β, IL-6, TNF-α expression and relieves lung damage. Taken together, our data indicates DUSP5 mediates FAO reprogramming and promotes inflammatory response to BCG infection.

Keywords:  BCG; Dual specificity phosphatase 5; Fatty acid oxidation; Inflammation; Macrophage

DOI:  https://doi.org/10.1016/j.yexcr.2023.113869
Endocrinology. 2023 Dec 04. pii: bqad182. [Epub ahead of print]

The influence of maternal high fat diet during lactation on offspring hematopoietic priming.

Katherine Kim, Mita Varghese, Haijing Sun, Simin Abrishami, Emily Bowers, Dave Bridges, Jennifer L Meijer, Kanakadurga Singer, Brigid Gregg.

  Obesity and metabolic diseases are rising in women of reproductive age, increasing offspring metabolic risk. Maternal nutritional interventions during lactation present an opportunity to modify offspring outcomes. We previously demonstrated in mice that adult male offspring have metabolic impairments and increased adipose tissue macrophages (ATM) when dams are fed high fat diet (HFD) during the postnatal lactation window (HFD PN). We sought to understand the effect of HFD during lactation on early life inflammation. HFD PN offspringwere evaluated at postnatal day 16-19 for tissue weight and gene expression. Profiling of adipose tissue and bone marrow immune cells was conducted through lipidomics, in vitro myeloid colony forming unit assays, and flow cytometry. HFD PN mice had more visceral gonadal white adipose tissue (GWAT) and subcutaneous fat. Adipose tissue RNA sequencing demonstrated enrichment of inflammation, chemotaxis, and fatty acid metabolism and concordant changes in GWAT lipidomics. Bone marrow (BM) of both HFD PN male and female offspring had increased monocytes (CD45+Ly6G-CD11b+CD115+) and B-cells (CD45+Ly6G-CD11b-CD19+). Similarly, serum from HFD PN offspring enhanced in vitro BM myeloid colonies in a toll-like receptor 4-dependent manner. We identified that male HFD PN offspring had increased GWAT pro-inflammatory CD11c+ ATMs (CD45+CD64+). Maternal exposure to HFD alters milk lipids enhancing adiposity and myeloid inflammation even in early life. Future studies are needed to understand the mechanisms driving this pro-inflammatory state of both BM and ATMs, the causes of the sexually dimorphic phenotypes and the feasibility of intervening in this window to improve metabolic health.

Keywords:  Obesity; and sex-differences; macrophage; metabolism; monocyte

DOI:  https://doi.org/10.1210/endocr/bqad182
bioRxiv. 2023 Nov 21. pii: 2023.11.21.568047. [Epub ahead of print]

Host-derived oxidized phospholipids initiate effector-triggered immunity fostering lethality upon microbial encounter.

Marco Di Gioia, Valentina Poli, Piao J Tan, Roberto Spreafico, Anne Chu, Alex G Cuenca, Philip Lsm Gordts, Laura Pandolfi, Federica Meloni, Joseph L Witztum, Janet Chou, James R Springstead, Ivan Zanoni.

Macrophages detect invading microorganisms via pattern recognition receptors that recognize pathogen-associated molecular patterns, or via sensing the activity of virulence factors that initiates effector-triggered immunity (ETI). Tissue damage that follows pathogen encounter leads to the release of host-derived factors that participate to inflammation. How these self -derived molecules are sensed by macrophages and their impact on immunity remain poorly understood. Here we demonstrate that, in mice and humans, host-derived oxidized phospholipids (oxPLs) are formed upon microbial encounter. oxPL blockade restricts inflammation and prevents the death of the host, without affecting pathogen burden. Mechanistically, oxPLs bind and inhibit AKT, a master regulator of immunity and metabolism. AKT inhibition potentiates the methionine cycle, and epigenetically dampens Il10 , a pluripotent anti-inflammatory cytokine. Overall, we found that host-derived inflammatory cues act as " self " virulence factors that initiate ETI and that their activity can be targeted to protect the host against excessive inflammation upon microbial encounter.

DOI: https://doi.org/10.1101/2023.11.21.568047
Front Cell Infect Microbiol. 2023 ;13 1275954

Proteomic analysis reveals changes in the proteome of human THP-1 macrophages infected with Paracoccidioides brasiliensis.

Ana Marina Barroso de Figueiredo, Dayane Moraes, Alexandre Melo Bailão, Olivia Basso Rocha, Lana Ohara Souza Silva, Fátima Ribeiro-Dias, Célia Maria de Almeida Soares.

  Paracoccidioides spp. is the etiologic agent of Paracoccidioidomycosis (PCM), a systemic disease with wide distribution in Latin America. Macrophages are very important cells during the response to infection by P. brasiliensis. In this study, we performed a proteomic analysis to evaluate the consequences of P. brasiliensis yeast cells on the human THP-1 macrophage proteome. We have identified 443 and 2247 upregulated or downregulated proteins, respectively, in macrophages co-cultured with yeast cells of P. brasiliensis in comparison to control macrophages unexposed to the fungus. Proteomic analysis revealed that interaction with P. brasiliensis caused metabolic changes in macrophages that drastically affected energy production pathways. In addition, these macrophages presented regulated many factors related to epigenetic modifications and gene transcription as well as a decrease of many proteins associated to the immune system activity. This is the first human macrophage proteome derived from interactions with P. brasiliensis, which contributes to elucidating the changes that occur during the host response to this fungus. Furthermore, it highlights proteins that may be targets for the development of new therapeutic approaches to PCM.

Keywords:  Paracoccidioides brasiliensis; immunometabolism; macrophages; metabolic reprogramming; proteomic analysis

DOI:  https://doi.org/10.3389/fcimb.2023.1275954
J Biol Chem. 2023 Nov 30. pii: S0021-9258(23)02546-2. [Epub ahead of print] 105518

Mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via mTORC2/HK1-mediated metabolic rewiring.

Xiaofei Peng, Yuting Zhou, Baoying Zhang, Xiaotong Liang, Jingyu Feng, Yuejun Huang, Shufeng Weng, Ying Xu, Haibo Su.

  Bacillus Calmette-Guérin (BCG) vaccination induces a type of immune memory known as "trained immunity", characterized by the immunometabolic and epigenetic changes in innate immune cells. However, the molecular mechanism underlying the strategies for inducing and/or boosting trained immunity in alveolar macrophages remains unknown. Here, we found that mucosal vaccination with the recombinant strain rBCGPPE27 significantly augmented the trained immune response in mice, facilitating a superior protective response against Mycobacterium tuberculosis and non-related bacterial reinfection in mice when compared to BCG. Mucosal immunization with rBCGPPE27 enhanced innate cytokine production by alveolar macrophages associated with promoted glycolytic metabolism, typical of trained immunity. Deficiency of the mammalian target of rapamycin complex 2 and hexokinase 1 abolished the immunometabolic and epigenetic rewiring in mouse alveolar macrophages after mucosal rBCGPPE27 vaccination. Most noteworthy, utilizing rBCGPPE27's higher-up trained effects: The single mucosal immunization with rBCGPPE27-adjuvanted coronavirus disease (CoV-2) vaccine raised the rapid development of virus-specific immunoglobulin G antibodies, boosted pseudovirus neutralizing antibodies, and augmented T helper type 1-biased cytokine release by vaccine-specific T cells, compared to BCG/CoV-2 vaccine. These findings revealed that mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via reprogramming mTORC2- and HK-1-mediated aerobic glycolysis, providing new vaccine strategies for improving tuberculosis (TB) or coronavirus variant vaccinations, and targeting innate immunity via mucosal surfaces.

Keywords:  Bacille Calmette-Guerin; Trained immunity; glycolysis; innate immune memory; mucosal vaccination

DOI:  https://doi.org/10.1016/j.jbc.2023.105518
Sci Adv. 2023 Dec 08. 9(49): eadf9522

Mitochondrial metabolic flexibility is critical for CD8+ T cell antitumor immunity.

Chao Chen, Hong Zheng, Edwin M Horwitz, Satomi Ando, Koichi Araki, Peng Zhao, Zhiguo Li, Mandy L Ford, Rafi Ahmed, Cheng-Kui Qu.

Mitochondria use different substrates for energy production and intermediatory metabolism according to the availability of nutrients and oxygen levels. The role of mitochondrial metabolic flexibility for CD8+ T cell immune response is poorly understood. Here, we report that the deletion or pharmacological inhibition of protein tyrosine phosphatase, mitochondrial 1 (PTPMT1) significantly decreased CD8+ effector T cell development and clonal expansion. In addition, PTPMT1 deletion impaired stem-like CD8+ T cell maintenance and accelerated CD8+ T cell exhaustion/dysfunction, leading to aggravated tumor growth. Mechanistically, the loss of PTPMT1 critically altered mitochondrial fuel selection-the utilization of pyruvate, a major mitochondrial substrate derived from glucose-was inhibited, whereas fatty acid utilization was enhanced. Persistent mitochondrial substrate shift and metabolic inflexibility induced oxidative stress, DNA damage, and apoptosis in PTPMT1 knockout cells. Collectively, this study reveals an important role of PTPMT1 in facilitating mitochondrial utilization of carbohydrates and that mitochondrial flexibility in energy source selection is critical for CD8+ T cell antitumor immunity.

DOI: https://doi.org/10.1126/sciadv.adf9522
J Med Virol. 2023 Dec;95(12): e29257

Metabolic alterations unravel the maternofetal immune responses with disease severity in pregnant women infected with SARS-CoV-2.

Sandhya Hora, Prabhjyoti Pahwa, Hamda Siddiqui, Anoushka Saxena, Minal Kashyap, Jayesh K Sevak, Ravinder Singh, Maryam Javed, Pushpa Yadav, Pratibha Kale, Gayatri Ramakrishna, Meenu Bajpai, Asmita Rathore, Jaswinder S Maras, Shakun Tyagi, Shiv K Sarin, Nirupama Trehanpati.

  Pregnancy being an immune compromised state, coronavirus disease of 2019 (COVID-19) disease poses high risk of premature delivery and threat to fetus. Plasma metabolome regulates immune cellular responses, therefore we aimed to analyze the change in plasma secretome, metabolome, and immune cells with disease severity in COVID-19 positive pregnant females and their cord blood. COVID-19 reverse transcriptase-polymerase chain reaction positive pregnant females (n = 112) with asymptomatic (Asy) (n = 82), mild (n = 21), or moderate (n = 9) disease, healthy pregnant (n = 18), COVID-19 positive nonpregnant females (n = 7) were included. Eighty-two cord blood from COVID-19 positive and seven healthy cord blood were also analyzed. Mother's peripheral blood and cord blood were analyzed for untargeted metabolome profiling and cytokines by using high-resolution mass spectrometry and cytokine bead array. Immune scan was performed only in mothers' blood by flow cytometry. In Asy severe acute respiratory syndrome coronavirus 2 infection, the amino acid metabolic pathways such as glycine, serine, l-lactate, and threonine metabolism were upregulated with downregulation of riboflavin and tyrosine metabolism. However, with mild-to-moderate disease, the pyruvate and nicotinamide adenine dinucleotide (NAD+ ) metabolism were mostly altered. Cord blood mimicked the mother's metabolomic profiles by showing altered valine, leucine, isoleucine, glycine, serine, threonine in Asy and NAD+ , riboflavin metabolism in mild and moderate. Additionally, with disease severity tumor necrosis factor-α, interferon (IFN)-α, IFN-γ, interleukin (IL)-6 cytokine storm, IL-9 was raised in both mothers and neonates. Pyruvate, NAD metabolism and increase in IL-9 and IFN-γ had an impact on nonclassical monocytes, exhausted T and B cells. Our results demonstrated that immune-metabolic interplay in mother and fetus is influenced with increase in IL-9 and IFN-γ regulated pyruvate, lactate tricarboxylic acid, and riboflavin metabolism with context to disease severity.

Keywords:  B cells; COVID-19; NAD+; T cells; cytokines; metabolomics; monocytes; placenta; pregnancy

DOI:  https://doi.org/10.1002/jmv.29257
Ann Rheum Dis. 2023 Nov 24. pii: ard-2023-224014. [Epub ahead of print]

Counteracting tryptophan metabolism alterations as a new therapeutic strategy for rheumatoid arthritis.

David Moulin, Marie Millard, Mahdia Taïeb, Chloé Michaudel, Anne Aucouturier, Antoine Lefèvre, Luis G Bermúdez-Humarán, Philippe Langella, Youssouf Sereme, Kristell Wanherdrick, Preeti Gautam, Xavier Mariette, Philippe Dieudé, Jacques-Eric Gottenberg, Jean-Yves Jouzeau, David Skurnik, Patrick Emond, Denis Mulleman, Jérémie Sellam, Harry Sokol.

   OBJECTIVES: Alterations in tryptophan (Trp) metabolism have been reported in inflammatory diseases, including rheumatoid arthritis (RA). However, understanding whether these alterations participate in RA development and can be considered putative therapeutic targets remains undetermined.In this study, we combined quantitative Trp metabolomics in the serum from patients with RA and corrective administration of a recombinant enzyme in experimental arthritis to address this question.
METHODS: Targeted quantitative Trp metabolomics was performed on the serum from 574 previously untreated patients with RA from the ESPOIR (Etude et Suivi des POlyarthrites Indifférenciées Récentes) cohort and 98 healthy subjects. A validation cohort involved 69 established patients with RA. Dosages were also done on the serum of collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) mice and controls. A proof-of-concept study evaluating the therapeutic potency of targeting the kynurenine pathway was performed in the CAIA model.
RESULTS: Differential analysis revealed dramatic changes in Trp metabolite levels in patients with RA compared with healthy controls. Decreased levels of kynurenic (KYNA) and xanthurenic (XANA) acids and indole derivatives, as well as an increased level of quinolinic acid (QUIN), were found in the serum of patients with RA. They correlated positively with disease severity (assessed by both circulating biomarkers and disease activity scores) and negatively with quality-of-life scores. Similar profiles of kynurenine pathway metabolites were observed in the CAIA and CIA models. From a mechanistic perspective, we demonstrated that QUIN favours human fibroblast-like synoviocyte proliferation and affected their cellular metabolism, through inducing both mitochondrial respiration and glycolysis. Finally, systemic administration of the recombinant enzyme aminoadipate aminotransferase, responsible for the generation of XANA and KYNA, was protective in the CAIA model.
CONCLUSIONS: Altogether, our preclinical and clinical data indicate that alterations in the Trp metabolism play an active role in the pathogenesis of RA and could be considered as a new therapeutic avenue.

Keywords:  antirheumatic agents; inflammation; rheumatoid arthritis

DOI:  https://doi.org/10.1136/ard-2023-224014
Cell Rep. 2023 Dec 02. pii: S2211-1247(23)01542-5. [Epub ahead of print]42(12): 113530

IL-15-dependent immune crosstalk between natural killer cells and dendritic cells in HIV-1 elite controllers.

Ciputra Adijaya Hartana, Melanie Lancien, Ce Gao, Yelizaveta Rassadkina, Mathias Lichterfeld, Xu G Yu.

  As the principal effector cell population of the innate immune system, natural killer (NK) cells may make critical contributions to natural, immune-mediated control of HIV-1 replication. Using genome-wide assessments of activating and inhibitory chromatin features, we demonstrate here that cytotoxic NK (cNK) cells from elite controllers (ECs) display elevated activating histone modifications at the interleukin 2 (IL-2)/IL-15 receptor β chain and the BCL2 gene loci. These histone changes translate into increased responsiveness of cNK cells to paracrine IL-15 secretion, which coincides with higher levels of IL-15 transcription by myeloid dendritic cells in ECs. The distinct immune crosstalk between these innate immune cell populations results in improved IL-15-dependent cNK cell survival and cytotoxicity, paired with a metabolic profile biased toward IL-15-mediated glycolytic activities. Together, these results suggest that cNK cells from ECs display a programmed IL-15 response signature and support the emerging role of innate immune pathways in natural, drug-free control of HIV-1.

Keywords:  CP: Immunology; HIV infection; IL-15; NK cells; chromatin modifications; cytotoxicity; elite controllers; metabolism; trained innate immunity

DOI:  https://doi.org/10.1016/j.celrep.2023.113530
Proc Natl Acad Sci U S A. 2023 Dec 12. 120(50): e2315163120

USP16 is an ISG15 cross-reactive deubiquitinase that targets pro-ISG15 and ISGylated proteins involved in metabolism.

Jin Gan, Adán Pinto-Fernández, Dennis Flierman, Jimmy J L L Akkermans, Darragh P O'Brien, Helene Greenwood, Hannah Claire Scott, Günter Fritz, Klaus-Peter Knobeloch, Jacques Neefjes, Hans van Dam, Huib Ovaa, Hidde L Ploegh, Benedikt M Kessler, Paul P Geurink, Aysegul Sapmaz.

  Interferon-induced ubiquitin (Ub)-like modifier ISG15 covalently modifies host and viral proteins to restrict viral infections. Its function is counteracted by the canonical deISGylase USP18 or Ub-specific protease 18. Notwithstanding indications for the existence of other ISG15 cross-reactive proteases, these remain to be identified. Here, we identify deubiquitinase USP16 as an ISG15 cross-reactive protease by means of ISG15 activity-based profiling. Recombinant USP16 cleaved pro-ISG15 and ISG15 isopeptide-linked model substrates in vitro, as well as ISGylated substrates from cell lysates. Moreover, interferon-induced stimulation of ISGylation was increased by depletion of USP16. The USP16-dependent ISG15 interactome indicated that the deISGylating function of USP16 may regulate metabolic pathways. Targeted enzymes include malate dehydrogenase, cytoplasmic superoxide dismutase 1, fructose-bisphosphate aldolase A, and cytoplasmic glutamic-oxaloacetic transaminase 1. USP16 may thus contribute to the regulation of a subset of metabolism-related proteins during type-I interferon responses.

Keywords:  ISG15; ISGylation; USP16; activity-based probe; metabolism

DOI:  https://doi.org/10.1073/pnas.2315163120
J Immunother Cancer. 2023 Dec 06. pii: e008081. [Epub ahead of print]11(12):

Fibrinogen-like protein 2 promotes tumor immune suppression by regulating cholesterol metabolism in myeloid-derived suppressor cells.

Lei Wu, Xudong Liu, Juan Lei, Nan Zhang, Huakan Zhao, Jiangang Zhang, Huan Deng, Yongsheng Li.

   BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are crucial mediators of tumor-associated immune suppression. Targeting the accumulation and activation of MDSCs has been recognized as a promising approach to enhance the effectiveness of immunotherapies for different types of cancer.
METHODS: The MC38 and B16 tumor-bearing mouse models were established to investigate the role of Fgl2 during tumor progression. Fgl2 and FcγRIIB-deficient mice, adoptive cell transfer, RNA-sequencing and flow cytometry analysis were used to assess the role of Fgl2 on immunosuppressive activity and differentiation of MDSCs.
RESULTS: Here, we show that fibrinogen-like protein 2 (Fgl2) regulates the differentiation and immunosuppressive functions of MDSCs. The absence of Fgl2 leads to an increase in antitumor CD8+ T-cell responses and a decrease in granulocytic MDSC accumulation. The regulation mechanism involves Fgl2 modulating cholesterol metabolism, which promotes the accumulation of MDSCs and immunosuppression through the production of reactive oxygen species and activation of XBP1 signaling. Inhibition of Fgl2 or cholesterol metabolism in MDSCs reduces their immunosuppressive activity and enhances differentiation. Targeting Fgl2 could potentially enhance the therapeutic efficacy of anti-PD-1 antibody in immunotherapy.
CONCLUSION: These results suggest that Fgl2 plays a role in promoting immune suppression by modulating cholesterol metabolism and targeting Fgl2 combined with PD-1 checkpoint blockade provides a promising therapeutic strategy for antitumor therapy.

Keywords:  Immune Checkpoint Inhibitors; Immunotherapy; Metabolic Networks and Pathways; Tumor Microenvironment

DOI:  https://doi.org/10.1136/jitc-2023-008081
J Leukoc Biol. 2023 Dec 06. pii: qiad155. [Epub ahead of print]

The mitochondrial fission protein DRP1 influences memory CD8+ T cell formation and function.

Marissa G Stevens, Frank M Mason, Timothy N J Bullock.

  Pharmacological methods for promoting mitochondrial elongation suggest that effector T cells can be altered to support a memory T cell-like metabolic state. Such mitochondrial elongation approaches may enhance the development of immunological memory. Therefore, we hypothesized that deletion of the mitochondrial fission protein, DRP1, would lead to mitochondrial elongation and generate a large memory T cell population, an approach that could be exploited to enhance vaccination protocols. We find that, as expected, while deletion of DRP1 from T cells in dLckCre x Drp1flfl does compromise the magnitude and functionality of primary effector CD8+ T cells, a disproportionately large pool of memory CD8+ T cells does form. In contrast to primary effector CD8+ T cells, DRP1-deficient memory dLckCre x Drp1flfl CD8+ T cells mount a secondary response comparable to control memory T cells with respect to kinetics, magnitude, and effector capabilities. Interestingly, the relative propensity to form memory cells in the absence of DRP1 was neither associated with differentiation toward more memory precursor CD8+ T cells nor decreased cellular death of effector T cells. Instead, the tendency to form memory CD8+ T cells in the absence of DRP1 is associated with decreased TCR expression. Remarkably, in a competitive environment with DRP1-replete CD8+ T cells, the absence of DRP1 from CD8+ T cells compromised the generation of primary, memory and secondary responses, indicating that approaches targeting DRP1 need to be carefully tailored.

Keywords:  CD8+ T cell; Cell Death; Cytokine; Differentiation; Memory T cell; Metabolism; Mitochondria; T cell receptor

DOI:  https://doi.org/10.1093/jleuko/qiad155
Front Oncol. 2023 ;13 1251355

Similarities and divergences in the metabolism of immune cells in cancer and helminthic infections.

Diego Esperante, Mónica Itzel Martínez Gutiérrez, Mark E Issa, Alejandro Schcolnik-Cabrera, Fela Mendlovic.

  Energetic and nutritional requirements play a crucial role in shaping the immune cells that infiltrate tumor and parasite infection sites. The dynamic interaction between immune cells and the microenvironment, whether in the context of tumor or helminth infection, is essential for understanding the mechanisms of immunological polarization and developing strategies to manipulate them in order to promote a functional and efficient immune response that could aid in the treatment of these conditions. In this review, we present an overview of the immune response triggered during tumorigenesis and establishment of helminth infections, highlighting the transition to chronicity in both cases. We discuss the energetic demands of immune cells under normal conditions and in the presence of tumors and helminths. Additionally, we compare the metabolic changes that occur in the tumor microenvironment and the infection site, emphasizing the alterations that are induced to redirect the immune response, thereby promoting the survival of cancer cells or helminths. This emerging discipline provides valuable insights into disease pathogenesis. We also provide examples of novel strategies to enhance immune activity by targeting metabolic pathways that shape immune phenotypes, with the aim of achieving positive outcomes in cancer and helminth infections.

Keywords:  Th1 and Th2 response; antitumoral response; helminth infection; immune evasion; immunometabolism

DOI:  https://doi.org/10.3389/fonc.2023.1251355
Adv Sci (Weinh). 2023 Dec 03. e2304617

Targeting YAP1-regulated Glycolysis in Fibroblast-Like Synoviocytes Impairs Macrophage Infiltration to Ameliorate Diabetic Osteoarthritis Progression.

Jie Yang, Shanshan Li, Zhenyan Li, Lutian Yao, Meijing Liu, Kui-Leung Tong, Qiutong Xu, Bo Yu, Rui Peng, Tao Gui, Wang Tang, Yidi Xu, Jiaxu Chen, Jun He, Kewei Zhao, Xiaogang Wang, Xiaoying Wang, Zhengang Zha, Huan-Tian Zhang.

  The interplay between immune cells/macrophages and fibroblast-like synoviocytes (FLSs) plays a pivotal role in initiating synovitis; however, their involvement in metabolic disorders, including diabetic osteoarthritis (DOA), is largely unknown. In this study, single-cell RNA sequencing (scRNA-seq) is employed to investigate the synovial cell composition of DOA. A significant enrichment of activated macrophages within eight distinct synovial cell clusters is found in DOA synovium. Moreover, it is demonstrated that increased glycolysis in FLSs is a key driver for DOA patients' synovial macrophage infiltration and polarization. In addition, the yes-associated protein 1 (YAP1)/thioredoxin-interacting protein (TXNIP) signaling axis is demonstrated to play a crucial role in regulating glucose transporter 1 (GLUT1)-dependent glycolysis in FLSs, thereby controlling the expression of a series of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) which may subsequently fine-tune the infiltration of M1-polarized synovial macrophages in DOA patients and db/db diabetic OA mice. For treatment, M1 macrophage membrane-camouflaged Verteporfin (Vt)-loaded PLGA nanoparticles (MVPs) are developed to ameliorate DOA progression by regulating the YAP1/TXNIP signaling axis, thus suppressing the synovial glycolysis and the infiltration of M1-polarized macrophages. The results provide several novel insights into the pathogenesis of DOA and offer a promising treatment approach for DOA.

Keywords:  YAP1; diabetic osteoarthritis; fibroblast-like synoviocytes; glycolysis; macrophages infiltration

DOI:  https://doi.org/10.1002/advs.202304617
Cell Metab. 2023 Dec 05. pii: S1550-4131(23)00412-6. [Epub ahead of print]35(12): 2231-2249.e7

Hepatocyte CHRNA4 mediates the MASH-promotive effects of immune cell-produced acetylcholine and smoking exposure in mice and humans.

Chuyue Pan, Jun Liu, Yingsheng Gao, Maohui Yang, Haiyang Hu, Chang Liu, Minyi Qian, Hai-Yang Yuan, Song Yang, Ming-Hua Zheng, Lirui Wang.

  Metabolic dysfunction-associated steatohepatitis (MASH) is a leading risk factor for liver cirrhosis and hepatocellular carcinoma. Here, we report that CHRNA4, a subunit of nicotinic acetylcholine receptors (nAChRs), is an accelerator of MASH progression. CHRNA4 also mediates the MASH-promotive effects induced by smoking. Chrna4 was expressed specifically in hepatocytes and exhibited increased levels in mice and patients with MASH. Elevated CHRNA4 levels were positively correlated with MASH severity. We further revealed that during MASH development, acetylcholine released from immune cells or nicotine derived from smoking functioned as an agonist to activate hepatocyte-intrinsic CHRNA4, inducing calcium influx and activation of inflammatory signaling. The communication between immune cells and hepatocytes via the acetylcholine-CHRNA4 axis led to the production of a variety of cytokines, eliciting inflammation in liver and promoting the pathogenesis of MASH. Genetic and pharmacological inhibition of CHRNA4 protected mice from diet-induced MASH. Targeting CHRNA4 might be a promising strategy for MASH therapeutics.

Keywords:  CHRNA4; acetylcholine; inflammation; lobeline; metabolic dysfunction-associated steatohepatitis; nicotine; smoking

DOI:  https://doi.org/10.1016/j.cmet.2023.10.018
Cell Host Microbe. 2023 Dec 01. pii: S1931-3128(23)00456-0. [Epub ahead of print]

Oral magnesium prevents acetaminophen-induced acute liver injury by modulating microbial metabolism.

Dongping Li, Yu Chen, Meijuan Wan, Fengyi Mei, Fangzhao Wang, Peng Gu, Xianglong Zhang, Rongjuan Wei, Yunong Zeng, Hanzhao Zheng, Bangguo Chen, Qingquan Xiong, Tao Xue, Tianshan Guan, Jiayin Guo, Yuanxin Tian, Li-Yan Zeng, Zhanguo Liu, Hang Yuan, Ling Yang, Hongbin Liu, Lei Dai, Yao Yu, Yifeng Qiu, Peng Wu, Sanda Win, Tin Aung Than, Riqing Wei, Bernd Schnabl, Neil Kaplowitz, Yong Jiang, Qiang Ma, Peng Chen.

  Acetaminophen overuse is a common cause of acute liver failure (ALF). During ALF, toxins are metabolized by enzymes such as CYP2E1 and transformed into reactive species, leading to oxidative damage and liver failure. Here, we found that oral magnesium (Mg) alleviated acetaminophen-induced ALF through metabolic changes in gut microbiota that inhibit CYP2E1. The gut microbiota from Mg-supplemented humans prevented acetaminophen-induced ALF in mice. Mg exposure modulated Bifidobacterium metabolism and enriched indole-3-carboxylic acid (I3C) levels. Formate C-acetyltransferase (pflB) was identified as a key Bifidobacterium enzyme involved in I3C generation. Accordingly, a Bifidobacterium pflB knockout showed diminished I3C generation and reduced the beneficial effects of Mg. Conversely, treatment with I3C or an engineered bacteria overexpressing Bifidobacterium pflB protected against ALF. Mechanistically, I3C bound and inactivated CYP2E1, thus suppressing formation of harmful reactive intermediates and diminishing hepatocyte oxidative damage. These findings highlight how interactions between Mg and gut microbiota may help combat ALF.

Keywords:  Bifidobacterium; acute liver failure; gut microbiota; indole-3-carboxylic acid; magnesium

DOI:  https://doi.org/10.1016/j.chom.2023.11.006
Int Immunopharmacol. 2023 Dec 02. pii: S1567-5769(23)01626-0. [Epub ahead of print]126 111299

ω-3 polyunsaturated fatty acid alleviates systemic lupus erythematosus by suppressing autoimmunity in a murine model.

Aolu Liu, Zhuang Li, Jingwen Zeng, Yuerong Peng, Shuai Wang, Xinyun Bi, Zhenggang Zhao, Sujin Zhou, Allan Zijian Zhao, Yunping Mu, Fanghong Li.

  Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune inflammatory disease that damages multiple organs by the production of autoantibodies. Numerous research studies have demonstrated the anti-inflammatory effects of ω-3 polyunsaturated fatty acids (PUFAs). A diet rich in ω-3 PUFAs reduces chronic inflammatory and autoimmune conditions. Herein, we investigated the protective effect of ω-3 PUFAs against autoimmune injury in SLE. In a TMPD-induced mouse model of SLE, supplementation with eicosapentaenoic acid (EPA)-rich (97%) fish oil was found to alleviate systemic autoimmune phenotypes such as ascites, lipogranulomas and serum dsDNA levels. In addition, EPA also significantly improved renal manifestations, reducing proteinuria, glomerulonephritis, and immune complex deposition. Mechanistically, ω-3 PUFAs were shown to modulate the differentiation of B lymphocyte subsets of primary splenic lymphocytes in the spontaneous murine lupus model MRL/MpJ-Faslpr in vitro, specifically that both EPA and DHA suppressed the number of total B cells, B1B2 cells and plasma cells. Concurrently, they were also found to promote the secretion of the anti-inflammatory cytokine IL10, mainly produced by Breg and Treg cells. Thus, nutritional supplementation with ω-3 PUFAs can regulate B cell's differentiation and anti-inflammatory function and strongly prevent autoimmune responses and lupus nephritis. The diets balance between ω-6 and ω-3 PUFAs intake may represent a promising treatment strategy to prevent or delay the onset of SLE.

Keywords:  Autoimmune and lupus nephritis; B lymphocyte differentiation; Inflammatory; Systemic lupus erythematosus; ω-3 polyunsaturated fatty acids

DOI:  https://doi.org/10.1016/j.intimp.2023.111299
Rheumatology (Oxford). 2023 Dec 04. pii: kead646. [Epub ahead of print]

Systemic lupus erythematosus patients have unique changes in serum metabolic profiles across age associated with cardiometabolic risk.

Elizabeth C Jury, Junjie Peng, Alexandra Van Vijfeijken, Lucia Martin Gutierrez, Laurel Woodridge, Chris Wincup, Ines Pineda-Torra, Coziana Ciurtin, George A Robinson.

   OBJECTIVES: Cardiovascular disease through accelerated atherosclerosis is a leading cause of mortality for patients with systemic lupus erythematosus (SLE), likely due to increased chronic inflammation and cardiometabolic defects over age. We investigated age-associated changes in metabolomic profiles of SLE patients and healthy controls (HCs).
METHODS: Serum NMR metabolomic profiles from female SLE patients (n = 164, age = 14-76) and HCs (n = 123, age = 13-72) were assessed across age by linear regression and by age group between patients/HCs (Group-1, age ≤ 25, n = 62/46; Group-2, age = 26-49, n = 50/46; Group-3, age ≥ 50, n = 52/31) using multiple t-tests. The impact of inflammation, disease activity and treatments were assessed, and UK Biobank disease-wide association analysis of metabolites was performed.
RESULTS: Age-specific metabolomic profiles were identified in SLE patients vs HCs, including reduced amino acids (Group-1), increased very-low-density lipoproteins (Group-2), and increased low-density lipoproteins (Group-3). Twenty-five metabolites were significantly altered in all SLE age groups, dominated by decreased atheroprotective high-density lipoprotein (HDL) subsets, HDL-bound apolipoprotein(Apo)A1 and increased glycoprotein acetyls (GlycA). Furthermore, ApoA1 and GlycA were differentially associated with disease activity and serological measures, as well as atherosclerosis incidence and myocardial infarction mortality risk through disease-wide association. Separately, glycolysis pathway metabolites (acetone/citrate/creatinine/glycerol/lactate/pyruvate) uniquely increased with age in SLE, significantly influenced by prednisolone (increased pyruvate/lactate) and hydroxychloroquine (decreased citrate/creatinine) treatment and associated with type-1 and type-2 diabetes by disease-wide association.
CONCLUSIONS: Increasing HDL (ApoA1) levels through therapeutic/nutritional intervention, whilst maintaining low disease activity, in SLE patients from a young age could improve cardiometabolic disease outcomes. Biomarkers from the glycolytic pathway could indicate adverse metabolic effects of current therapies.

Keywords:  SLE; age; atherosclerosis; cardiometabolic; cardiovascular disease; comorbidities; lipids; metabolism; metabolomics

DOI:  https://doi.org/10.1093/rheumatology/kead646
Clin Nutr ESPEN. 2023 Dec;pii: S2405-4577(23)02194-0. [Epub ahead of print]58 397-408

Central obesity is detrimental to anti-inflammatory, phenotype, and exhaustion markers in mononuclear cells - A cross-sectional study.

Tiago Olean-Oliveira, Camila S Padilha, Caique Figueiredo, Gilson Pires Dorneles, Bruna Marmett, Alessandra Peres, Pedro Romão, Alexandre Abílio de Souza Teixeira, José Procópio Jabur Ribeiro, Vanessa Ribeiro Dos Santos, André Olean-Oliveira, Marcos F S Teixeira, Patrícia M Seraphim, Karsten Krüger, José Cesar Rosa-Neto, Fábio Santos Lira.

   OBJECTIVE: To investigate the role of central obesity on immunometabolic response in peripheral blood mononuclear cells (PBMCs) from normal weight and overweight/obese young men.
METHODS: Eighteen individuals were classified as normal weight (NW; n = 9 - age: 25 ± 5 and BMI: 21.4 ± 1.7) and overweight/obese (OW; n = 9 - age: 29 ± 7 and BMI: 29.2 ± 2.7). The body composition was evaluated by dual-energy x-ray absorptiometry (DXA), waist circumference, and visceral and subcutaneous fat depots by ultrasound. Physical activity levels, metabolic parameters, immune phenotypic characterization, cytokine production by lipopolysaccharide (LPS) -stimulated whole blood cells and LPS or phorbol 12-myristate 13-acetate (PMA)-stimulated PBMC, and mitochondrial respiration in PBMCs were evaluated. Expression of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma (PPAR-γ), nuclear factor-kappa B (NF-κB), toll-like receptor 4 (TLR-4), hypoxia-inducible factor-1 alpha (HIF-1α), and adrenergic receptor beta 1 and 2 (AR-β1 and β2) genes were evaluated in cultured PBMC using quantitative real-time polymerase chain reaction (qRT-PCR).
RESULTS: Individuals with overweight/obese (OW) presented higher glucose (P = 0.009) and leptin (P = 0.010) than individuals with normal weight (NW). PBMCs of OW under stimulation with LPS presented a lower production of interleukin-10 (IL-10) (P = 0.011) and macrophage inflammatory protein-1alpha (MIP-1α) (P = 0.048) than NW. Mitochondrial respiration rates were not different between NW and OW subjects. Cultured PBMCs in LPS-stimulated condition indicated higher gene expression of AR-β2 in OW, while PMA-stimulated PBMCs presented lower expression of AMPK (P = 0.002) and higher expression of NF-κB (P=<0.0001) than NW. OW presented higher numbers of CD3+CD4+ T cells (P = 0.009) and higher expression of programmed cell death protein 1 (PD-1) in CD8+ T cells (P = 0.001) than NW.
CONCLUSION: Central obesity promoted reductions in interleukin 10 production response and increase in AR-β2 expressions in mitogen-stimulated PBMCs. Furthermore, central obesity altered the phenotype of PBMCs, also increasing the expression of PD-1 exhaustion markers in young adults.

Keywords:  Body fat; Immune system; Immunometabolism; Physical fitness

DOI:  https://doi.org/10.1016/j.clnesp.2023.10.035
Front Immunol. 2023 ;14 1282890

The dysregulation of immune cells induced by uric acid: mechanisms of inflammation associated with hyperuricemia and its complications.

Delun Li, Siyu Yuan, Yiyao Deng, Xiaowan Wang, Shouhai Wu, Xuesheng Chen, Yimeng Li, Jianting Ouyang, Danyao Lin, Haohao Quan, Xinwen Fu, Chuang Li, Wei Mao.

  Changes in lifestyle induce an increase in patients with hyperuricemia (HUA), leading to gout, gouty arthritis, renal damage, and cardiovascular injury. There is a strong inflammatory response in the process of HUA, while dysregulation of immune cells, including monocytes, macrophages, and T cells, plays a crucial role in the inflammatory response. Recent studies have indicated that urate has a direct impact on immune cell populations, changes in cytokine expression, modifications in chemotaxis and differentiation, and the provocation of immune cells by intrinsic cells to cause the aforementioned conditions. Here we conducted a detailed review of the relationship among uric acid, immune response, and inflammatory status in hyperuricemia and its complications, providing new therapeutic targets and strategies.

Keywords:  MSU; gouty arthritis; immune cell; sUA; serum uric acid; uric acid (UA)

DOI:  https://doi.org/10.3389/fimmu.2023.1282890