bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2024‒03‒24
eighteen papers selected by
Dylan Ryan, University of Cambridge
  1. T cell activation contributes to purifying selection against the MELAS-associated m.3243A>G pathogenic variant in blood.
  2. Alterations in metabolic pathways: a bridge between aging and weaker innate immune response.
  3. Unlocking potential: the role of the electron transport chain in immunometabolism.
  4. Physiologic disruption and metabolic reprogramming in infection and sepsis.
  5. Metabolic regulation of the host-fungus interaction: from biological principles to therapeutic opportunities.
  6. Expression of the monocarboxylate transporter MCT1 is required for virus-specific mouse CD8+ T cell memory development.
  7. Serine metabolism is crucial for cGAS-STING signaling and viral defense control in the gut.
  8. Interleukin-10: a novel metabolic inducer of macrophage differentiation and subsequently contributing to improved pregnancy outcomes of mice by orchestrating oxidative phosphorylation metabolism.
  9. Pioglitazone reverses alcohol-induced alterations in alveolar macrophage mitochondrial phenotype.
  10. Targeting metabolism to improve CAR-T cells therapeutic efficacy.
  11. Mitochondrial dysfunction affects hepatic immune and metabolic remodeling in patients with hepatitis B virus-related acute-on-chronic liver failure.
  12. Tricarboxylic acid cycle metabolites: new players in macrophage.
  13. Novel insights into macrophage immunometabolism in nonalcoholic steatohepatitis.
  14. Age-associated accumulation of B cells promotes macrophage inflammation and inhibits lipolysis in adipose tissue during sepsis.
  15. Immunomodulatory and Anti-Inflammatory Effects of Vitamin A and Tryptophan on Monocyte-Derived Dendritic Cells Stimulated with Gliadin in Celiac Disease Patients.
  16. Targeting host deoxycytidine kinase mitigates Staphylococcus aureus abscess formation.
  17. High-fat diet-induced obesity causes intestinal Th17/Treg imbalance that impairs the intestinal barrier and aggravates anxiety-like behavior in mice.
  18. Pretreatment with an antibiotics cocktail enhances the protective effect of probiotics by regulating SCFA metabolism and Th1/Th2/Th17 cell immune responses.
  1. J Inherit Metab Dis. 2024 Mar 18.
    T cell activation contributes to purifying selection against the MELAS-associated m.3243A>G pathogenic variant in blood.
    Melissa A Walker, Shuqiang Li, Kenneth J Livak, Amel Karaa, Catherine J Wu, Vamsi K Mootha.
      T cells have been shown to maintain a lower percentage (heteroplasmy) of the pathogenic m.3243A>G variant (MT-TL1, associated with maternally inherited diabetes and deafness [MIDD] and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes [MELAS]). The mechanism(s) underlying this purifying selection, however, remain unknown. Here we report that purified patient memory CD4+ T cells have lower bulk m.3243A>G heteroplasmy compared to naïve CD4+ T cells. In vitro activation of naïve CD4+ m.3243A>G patient T cells results in lower bulk m.3243A>G heteroplasmy after proliferation. Finally, m.3243A>G patient T cell receptor repertoire sequencing reveals relative oligoclonality compared to controls. These data support a role for T cell activation in peripheral, purifying selection against high m.3243A>G heteroplasmy T cells at the level of the cell, in a likely cell-autonomous fashion.
    Keywords:  MELAS; MIDD; T cell activation; heteroplasmy; mitochondria; mtDNA
    DOI:  https://doi.org/10.1002/jimd.12726
  2. Front Aging. 2024 ;5 1358330
    Alterations in metabolic pathways: a bridge between aging and weaker innate immune response.
    Zahra Saleh, Sara Mirzazadeh, Fatemeh Mirzaei, Kamran Heidarnejad, Seppo Meri, Kurosh Kalantar.
      Aging is a time-dependent progressive physiological process, which results in impaired immune system function. Age-related changes in immune function increase the susceptibility to many diseases such as infections, autoimmune diseases, and cancer. Different metabolic pathways including glycolysis, tricarboxylic acid cycle, amino acid metabolism, pentose phosphate pathway, fatty acid oxidation and fatty acid synthesis regulate the development, differentiation, and response of adaptive and innate immune cells. During aging all these pathways change in the immune cells. In addition to the changes in metabolic pathways, the function and structure of mitochondria also have changed in the immune cells. Thereby, we will review changes in the metabolism of different innate immune cells during the aging process.
    Keywords:  age-related diseases; aging; immunometabolism; innate immunity; metabolic pathways
    DOI:  https://doi.org/10.3389/fragi.2024.1358330
  3. Trends Immunol. 2024 Mar 18. pii: S1471-4906(24)00027-9. [Epub ahead of print]
    Unlocking potential: the role of the electron transport chain in immunometabolism.
    Alessia Zotta, Luke A J O'Neill, Maureen Yin.
      The electron transport chain (ETC) couples electron transfer with proton pumping to generate ATP and it also regulates particular innate and adaptive immune cell function. While NLRP3 inflammasome activation was initially linked to reactive oxygen species (ROS) produced from Complexes I and III, recent research suggests that an intact ETC fueling ATP is needed. Complex II may be responsible for Th1 cell proliferation and in some cases, effector cytokine production. Complex III is required for regulatory T (Treg) cell function, while oxidative phosphorylation (OXPHOS) and Complexes I, IV, and V sustain proliferation and antibody production in B lymphocytes, with OXPHOS also being required for B regulatory (Breg) cell function. Despite challenges, the ETC shows therapeutic targeting potential for immune-related diseases and in immuno-oncology.
    Keywords:  adaptive immunity; electron transport chain; immunometabolism; innate immunity; mitochondria; reactive oxygen species; respiratory complexes
    DOI:  https://doi.org/10.1016/j.it.2024.02.002
  4. Cell Metab. 2024 Mar 13. pii: S1550-4131(24)00058-5. [Epub ahead of print]
    Physiologic disruption and metabolic reprogramming in infection and sepsis.
    Katharina Willmann, Luis F Moita.
      Effective responses against severe systemic infection require coordination between two complementary defense strategies that minimize the negative impact of infection on the host: resistance, aimed at pathogen elimination, and disease tolerance, which limits tissue damage and preserves organ function. Resistance and disease tolerance mostly rely on divergent metabolic programs that may not operate simultaneously in time and space. Due to evolutionary reasons, the host initially prioritizes the elimination of the pathogen, leading to dominant resistance mechanisms at the potential expense of disease tolerance, which can contribute to organ failure. Here, we summarize our current understanding of the role of physiological perturbations resulting from infection in immune response dynamics and the metabolic program requirements associated with resistance and disease tolerance mechanisms. We then discuss how insight into the interplay of these mechanisms could inform future research aimed at improving sepsis outcomes and the potential for therapeutic interventions.
    Keywords:  disease tolerance; immunometabolism; infection; metabolic reprogramming; physiologic disruption; resistance; sepsis; surveillance immunity; therapy
    DOI:  https://doi.org/10.1016/j.cmet.2024.02.013
  5. J Leukoc Biol. 2024 Mar 18. pii: qiae045. [Epub ahead of print]
    Metabolic regulation of the host-fungus interaction: from biological principles to therapeutic opportunities.
    Rita Silva-Gomes, Inês Caldeira, Raquel Fernandes, Cristina Cunha, Agostinho Carvalho.
      Fungal infections present a significant global public health concern, impacting over one billion individuals worldwide and resulting in more than 3 million deaths annually. Despite considerable progress in recent years, the management of fungal infections remains challenging. The limited development of novel diagnostic and therapeutic approaches is largely attributed to our incomplete understanding of the pathogenetic mechanisms involved in these diseases. Recent research has highlighted the pivotal role of cellular metabolism in regulating the interaction between fungi and their hosts. In response to fungal infection, immune cells undergo complex metabolic adjustments to meet the energy demands necessary for an effective immune response. A comprehensive understanding of the metabolic circuits governing antifungal immunity, combined with the integration of individual host traits, holds the potential to inform novel medical interventions for fungal infections. This review explores recent insights into the immunometabolic regulation of host-fungal interactions and the infection outcome and discusses how the metabolic repurposing of immune cell function could be exploited in innovative and personalized therapeutic approaches.
    Keywords:  Fungal infection; Genetic susceptibility; Host-directed therapy; Innate immunity; Metabolism
    DOI:  https://doi.org/10.1093/jleuko/qiae045
  6. Proc Natl Acad Sci U S A. 2024 Mar 26. 121(13): e2306763121
    Expression of the monocarboxylate transporter MCT1 is required for virus-specific mouse CD8+ T cell memory development.
    Stefania D'Aria, Céline Maquet, Shuang Li, Suveera Dhup, Anouk Lepez, Arnaud Kohler, Vincent F Van Hée, Rajesh K Dadhich, Marine Frenière, Fabienne Andris, Ivan Nemazanyy, Pierre Sonveaux, Bénédicte Machiels, Laurent Gillet, Michel Y Braun.
      Lactate-proton symporter monocarboxylate transporter 1 (MCT1) facilitates lactic acid export from T cells. Here, we report that MCT1 is mandatory for the development of virus-specific CD8+ T cell memory. MCT1-deficient T cells were exposed to acute pneumovirus (pneumonia virus of mice, PVM) or persistent γ-herpesvirus (Murid herpesvirus 4, MuHV-4) infection. MCT1 was required for the expansion of virus-specific CD8+ T cells and the control of virus replication in the acute phase of infection. This situation prevented the subsequent development of virus-specific T cell memory, a necessary step in containing virus reactivation during γ-herpesvirus latency. Instead, persistent active infection drove virus-specific CD8+ T cells toward functional exhaustion, a phenotype typically seen in chronic viral infections. Mechanistically, MCT1 deficiency sequentially impaired lactic acid efflux from activated CD8+ T cells, caused an intracellular acidification inhibiting glycolysis, disrupted nucleotide synthesis in the upstream pentose phosphate pathway, and halted cell proliferation which, ultimately, promoted functional CD8+ T cell exhaustion instead of memory development. Taken together, our data demonstrate that MCT1 expression is mandatory for inducing T cell memory and controlling viral infection by CD8+ T cells.
    Keywords:  T cell exhaustion; T cell memory development; lactate transport; monocarboxylate transporters (MCTs); virus latency
    DOI:  https://doi.org/10.1073/pnas.2306763121
  7. iScience. 2024 Mar 15. 27(3): 109173
    Serine metabolism is crucial for cGAS-STING signaling and viral defense control in the gut.
    Björn Becker, Felix Wottawa, Mohamed Bakr, Eric Koncina, Lisa Mayr, Julia Kugler, Guang Yang, Samuel J Windross, Laura Neises, Neha Mishra, Danielle Harris, Florian Tran, Lina Welz, Julian Schwärzler, Zoltán Bánki, Stephanie T Stengel, Go Ito, Christina Krötz, Olivia I Coleman, Christian Jaeger, Dirk Haller, Søren R Paludan, Richard Blumberg, Arthur Kaser, Luka Cicin-Sain, Stefan Schreiber, Timon E Adolph, Elisabeth Letellier, Philip Rosenstiel, Johannes Meiser, Konrad Aden.
      Inflammatory bowel diseases are characterized by the chronic relapsing inflammation of the gastrointestinal tract. While the molecular causality between endoplasmic reticulum (ER) stress and intestinal inflammation is widely accepted, the metabolic consequences of chronic ER stress on the pathophysiology of IBD remain unclear. By using in vitro, in vivo models, and patient datasets, we identified a distinct polarization of the mitochondrial one-carbon metabolism and a fine-tuning of the amino acid uptake in intestinal epithelial cells tailored to support GSH and NADPH metabolism upon ER stress. This metabolic phenotype strongly correlates with IBD severity and therapy response. Mechanistically, we uncover that both chronic ER stress and serine limitation disrupt cGAS-STING signaling, impairing the epithelial response against viral and bacterial infection and fueling experimental enteritis. Consequently, the antioxidant treatment restores STING function and virus control. Collectively, our data highlight the importance of serine metabolism to allow proper cGAS-STING signaling and innate immune responses upon gut inflammation.
    Keywords:  Microbial metabolism; Virology
    DOI:  https://doi.org/10.1016/j.isci.2024.109173
  8. Biol Reprod. 2024 Mar 19. pii: ioae041. [Epub ahead of print]
    Interleukin-10: a novel metabolic inducer of macrophage differentiation and subsequently contributing to improved pregnancy outcomes of mice by orchestrating oxidative phosphorylation metabolism.
    Huan Wang, Liling Wang, Guangshun Gong, Xinxiu Lin, Jing Luo, Chunyan Liu, Gil Mor, Aihua Liao.
      Metabolism regulates the phenotype and function of macrophages. After recruitment to local tissues, monocytes are influenced by the local microenvironment and differentiate into various macrophages depending on different metabolic pathways. However, the metabolic mechanisms underlying decidual macrophage differentiation remain unknown. Interleukin-10 (IL-10) is an important decidual macrophage inducer and promotes oxidative phosphorylation (OXPHOS) of bone marrow-derived macrophages. In this study, we mainly investigate the metabolic changes involved in IL-10 generated macrophages from monocytes using in vitro models. We demonstrate that exposure of monocytes (either peripheral or THP-1) to IL-10 altered the phenotype and function of resultant macrophages that is linked with OXPHOS changes. IL-10 enhanced the mitochondrial complex I and III activity of THP-1 cell-differentiated macrophages and increased the mitochondrial membrane potential, intracellular adenosine triphosphate, and reactive oxygen species levels. OXPHOS blockage with oligomycin changed the cell morphology of IL-10-generated macrophages and the expression levels of cytokines, such as transforming growth factor beta, tumor necrosis factor-alpha, interferon gamma, and IL-10, apart from changes in the expression level of the surface markers CD206, CD209, and CD163. Moreover, in vivo IL-10 administration reduced the lipopolysaccharide (LPS)-induced embryo resorption rate, and this effect was diminished when OXPHOS was inhibited, demonstrating that OXPHOS is important for the improved pregnancy outcomes of IL-10 in LPS-induced abortion-prone mice. Our findings provide deep insights into the roles of IL-10 in macrophage biology and pregnancy maintenance. Nevertheless, the direct evidence that OXPHOS is involved in decidual macrophage differentiation or not needs further investigations.
    Keywords:  THP-1; interleukin-10; macrophage; monocyte; normal pregnancy; oxidative phosphorylation; pregnancy loss
    DOI:  https://doi.org/10.1093/biolre/ioae041
  9. Alcohol Clin Exp Res (Hoboken). 2024 Mar 18.
    Pioglitazone reverses alcohol-induced alterations in alveolar macrophage mitochondrial phenotype.
    Kathryn M Crotty, Shayaan A Kabir, Sarah S Chang, Ashish J Mehta, Samantha M Yeligar.
      BACKGROUND: People with alcohol use disorder (AUD) have an increased risk of developing pneumonia and pulmonary diseases. Alveolar macrophages (AMs) are immune cells of the lower respiratory tract that are necessary for clearance of pathogens. However, alcohol causes AM oxidative stress, mitochondrial damage and dysfunction, and diminished phagocytic capacity, leading to lung injury and immune suppression.METHODS: AMs were isolated by bronchoalveolar lavage from people with AUD and male and female C57BL/6J mice given chronic ethanol (20% w/v, 12 weeks) in drinking water. The peroxisome proliferator-activated receptor γ ligand, pioglitazone, was used to treat human AMs ex vivo (10 μM, 24 h) and mice in vivo by oral gavage (10 mg/kg/day). Levels of AM mitochondrial superoxide and hypoxia-inducible factor-1 alpha (HIF-1α) mRNA, a marker of oxidative stress, were measured by fluorescence microscopy and RT-qPCR, respectively. Mouse AM phagocytic ability was determined by internalized Staphylococcus aureus, and mitochondrial capacity, dependency, and flexibility for glucose, long-chain fatty acid, and glutamine oxidation were measured using an extracellular flux analyzer. In vitro studies used a murine AM cell line, MH-S (±0.08% ethanol, 72 h) to investigate mitochondrial fuel oxidation and ATP-linked respiration.
    RESULTS: Pioglitazone treatment decreased mitochondrial superoxide in AMs from people with AUD and ethanol-fed mice and HIF-1α mRNA in ethanol-fed mouse lungs. Pioglitazone also reversed mouse AM glutamine oxidation and glucose or long-chain fatty acid flexibility to meet basal oxidation needs. In vitro, ethanol decreased the rate of AM mitochondrial and total ATP production, and pioglitazone improved changes in glucose and glutamine oxidation.
    CONCLUSIONS: Pioglitazone reversed chronic alcohol-induced oxidative stress in human AM and mitochondrial substrate oxidation flexibility and superoxide levels in mouse AM. Decreased ethanol-induced AM HIF-1α mRNA with pioglitazone suggests that this pathway may be a focus for metabolic-targeted therapeutics to improve morbidity and mortality in people with AUD.
    Keywords:  alcohol use disorder; immunometabolism; mitochondria; oxidative stress; pulmonary
    DOI:  https://doi.org/10.1111/acer.15300
  10. Chin Med J (Engl). 2024 Mar 19.
    Targeting metabolism to improve CAR-T cells therapeutic efficacy.
    Shasha Liu, Yuyu Zhao, Yaoxin Gao, Feng Li, Yi Zhang.
      ABSTRACT: Chimeric antigen receptor T (CAR-T) cell therapy achieved advanced progress in the treatment of hematological tumors. However, the application of CAR-T cell therapy for solid tumors still faces many challenges. Competition with tumor cells for metabolic resources in an already nutrient-poor tumor microenvironment is a major contributing cause to CAR-T cell therapy's low effectiveness. Abnormal metabolic processes are now acknowledged to shape the tumor microenvironment, which is characterized by increased interstitial fluid pressure, low pH level, hypoxia, accumulation of immunosuppressive metabolites, and mitochondrial dysfunction. These factors are important contributors to restriction of T cell proliferation, cytokine release, and suppression of tumor cell-killing ability. This review provides an overview of how different metabolites regulate T cell activity, analyzes the current dilemmas, and proposes key strategies to reestablish the CAR-T cell therapy's effectiveness through targeting metabolism, with the aim of providing new strategies to surmount the obstacle in the way of solid tumor CAR-T cell treatment.
    DOI:  https://doi.org/10.1097/CM9.0000000000003046
  11. World J Gastroenterol. 2024 Feb 28. 30(8): 881-900
    Mitochondrial dysfunction affects hepatic immune and metabolic remodeling in patients with hepatitis B virus-related acute-on-chronic liver failure.
    Yu Zhang, Xiao-Ling Tian, Jie-Qun Li, Dong-Sheng Wu, Qiang Li, Bin Chen.
      BACKGROUND: Immune dysregulation and metabolic derangement have been recognized as key factors that contribute to the progression of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). However, the mechanisms underlying immune and metabolic derangement in patients with advanced HBV-ACLF are unclear.AIM: To identify the bioenergetic alterations in the liver of patients with HBV-ACLF causing hepatic immune dysregulation and metabolic disorders.
    METHODS: Liver samples were collected from 16 healthy donors (HDs) and 17 advanced HBV-ACLF patients who were eligible for liver transplantation. The mitochondrial ultrastructure, metabolic characteristics, and immune microenvironment of the liver were assessed. More focus was given to organic acid metabolism as well as the function and subpopulations of macrophages in patients with HBV-ACLF.
    RESULTS: Compared with HDs, there was extensive hepatocyte necrosis, immune cell infiltration, and ductular reaction in patients with ACLF. In patients, the liver suffered severe hypoxia, as evidenced by increased expression of hypoxia-inducible factor-1α. Swollen mitochondria and cristae were observed in the liver of patients. The number, length, width, and area of mitochondria were adaptively increased in hepatocytes. Targeted metabolomics analysis revealed that mitochondrial oxidative phosphorylation decreased, while anaerobic glycolysis was enhanced in patients with HBV-ACLF. These findings suggested that, to a greater extent, hepa-tocytes used the extra-mitochondrial glycolytic pathway as an energy source. Patients with HBV-ACLF had elevated levels of chemokine C-C motif ligand 2 in the liver homogenate, which stimulates peripheral monocyte infiltration into the liver. Characterization and functional analysis of macrophage subsets revealed that patients with ACLF had a high abundance of CD68+ HLA-DR+ macrophages and elevated levels of both interleukin-1β and transforming growth factor-β1 in their livers. The abundance of CD206+ CD163+ macrophages and expression of interleukin-10 decreased. The correlation analysis revealed that hepatic organic acid metabolites were closely associated with macrophage-derived cytokines/chemokines.
    CONCLUSION: The results indicated that bioenergetic alteration driven by hypoxia and mitochondrial dysfunction affects hepatic immune and metabolic remodeling, leading to advanced HBV-ACLF. These findings highlight a new therapeutic target for improving the treatment of HBV-ACLF.
    Keywords:  Acute-on-chronic liver failure; Hypoxia-inducible factor-1α; Immune cells; Metabolic phenotype; Mitochondria
    DOI:  https://doi.org/10.3748/wjg.v30.i8.881
  12. Inflamm Res. 2024 Mar 18.
    Tricarboxylic acid cycle metabolites: new players in macrophage.
    Ying Yang, Bing-Bing Cui, Jian Li, Jiao-Jiao Shan, Jun Xu, Cheng-Yong Zhang, Xiao-Tong Wei, Ri-Ran Zhu, Jing-Yi Wang.
      Metabolic remodeling is a key feature of macrophage activation and polarization. Recent studies have demonstrated the role of tricarboxylic acid (TCA) cycle metabolites in the innate immune system. In the current review, we summarize recent advances in the metabolic reprogramming of the TCA cycle during macrophage activation and polarization and address the effects of these metabolites in modulating macrophage function. Deciphering the crosstalk between the TCA cycle and the immune response might provide novel potential targets for the intervention of immune reactions and favor the development of new strategies for the treatment of infection, inflammation, and cancer.
    Keywords:  Citrate; Fumarate; Macrophage; Succinate; Tricarboxylic acid cycle metabolites; α-Ketoglutarate
    DOI:  https://doi.org/10.1007/s00011-024-01853-0
  13. Int Immunopharmacol. 2024 Mar 18. pii: S1567-5769(24)00351-5. [Epub ahead of print]131 111833
    Novel insights into macrophage immunometabolism in nonalcoholic steatohepatitis.
    Yali Yuan, Ye Zhang, Xinyu Lu, Junxiang Li, Muyuan Wang, Wenji Zhang, Mengyu Zheng, Zhongmei Sun, Yunqi Xing, Yitong Li, Yingdi Qu, Yao Jiao, Haixiao Han, Chune Xie, Tangyou Mao.
      Nonalcoholic steatohepatitis (NASH), an inflammatory subtype of nonalcoholic fatty liver disease (NAFLD), is characterized by liver steatosis, inflammation, hepatocellular injury and different degrees of fibrosis, and has been becoming the leading cause of liver-related morbidity and mortality worldwide. Unfortunately, the pathogenesis of NASH has not been completely clarified, and there are no approved therapeutic drugs. Recent accumulated evidences have revealed the involvement of macrophage in the regulation of host liver steatosis, inflammation and fibrosis, and different phenotypes of macrophages have different metabolic characteristics. Therefore, targeted regulation of macrophage immunometabolism may contribute to the treatment and prognosis of NASH. In this review, we summarized the current evidences of the role of macrophage immunometabolism in NASH, especially focused on the related function conversion, as well as the strategies to promote its polarization balance in the liver, and hold promise for macrophage immunometabolism-targeted therapies in the treatment of NASH.
    Keywords:  Immunometabolism; Macrophage; Metabolic characteristics; Nonalcoholic steatohepatitis; Strategies
    DOI:  https://doi.org/10.1016/j.intimp.2024.111833
  14. Cell Rep. 2024 Mar 15. pii: S2211-1247(24)00295-X. [Epub ahead of print]43(3): 113967
    Age-associated accumulation of B cells promotes macrophage inflammation and inhibits lipolysis in adipose tissue during sepsis.
    Anna Carey, Katie Nguyen, Pranathi Kandikonda, Victor Kruglov, Claire Bradley, Korbyn J V Dahlquist, Stephanie Cholensky, Whitney Swanson, Vladimir P Badovinac, Thomas S Griffith, Christina D Camell.
      Non-canonical lipolysis induced by inflammatory cytokines or Toll-like receptor ligands is required for the regulation of inflammation during endotoxemia and sepsis. Canonical lipolysis induced by catecholamines declines during aging due to factors including an expansion of lymphocytes, pro-inflammatory macrophage polarization, and an increase in chronic low-grade inflammation; however, the extent to which the non-canonical pathway of lipolysis is active and impacted by immune cells during aging remains unclear. Therefore, we aimed to define the extent to which immune cells from old mice influence non-canonical lipolysis during sepsis. We identified age-associated impairments of non-canonical lipolysis and an accumulation of dysfunctional B1 B cells in the visceral white adipose tissue (vWAT) of old mice. Lifelong deficiency of B cells results in restored non-canonical lipolysis and reductions in pro-inflammatory macrophage populations. Our study suggests that targeting the B cell-macrophage signaling axis may resolve metabolic dysfunction in aged vWAT and attenuate septic severity in older individuals.
    Keywords:  CP: Immunology; CP: Metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2024.113967
  15. Inflammation. 2024 Mar 16.
    Immunomodulatory and Anti-Inflammatory Effects of Vitamin A and Tryptophan on Monocyte-Derived Dendritic Cells Stimulated with Gliadin in Celiac Disease Patients.
    Fatemeh Asgari, Abdolrahim Nikzamir, Kaveh Baghaei, Siamak Salami, Andrea Masotti, Mohammad Rostami-Nejad.
      Celiac Disease (CeD) is an autoimmune disorder with various symptoms upon gluten exposure. Dendritic cells (DCs) play a crucial role in gliadin-induced inflammation. Vitamin A (retinol; Ret) and its metabolite, retinoic acid (RA), along with tryptophan (Trp) and its metabolite, kynurenic acid (KYNA), are known to influence the immune function of DCs and enhance their tolerogenicity. This research aims to assess the impact of gliadin on DC maturation and the potential of vitamin A and tryptophan to induce immune tolerance in DCs. The monocyte cells obtained from peripheral blood mononuclear cells (PBMCs) of celiac disease patients were differentiated into DCs in the absence or presence of Ret, RA, Trp, KYNA, and then stimulated with peptic and tryptic (PT) digested of gliadin. We used flow cytometry to analyze CD11c, CD14, HLA-DR, CD83, CD86, and CD103 expression. ELISA was carried out to measure TGF-β, IL-10, IL-12, and TNF-α levels. qRT-PCR was used to assess the mRNA expression of retinaldehyde dehydrogenase 2 (RALDH2) and integrin αE (CD103). The mRNA and protein levels of Indoleamine 2, 3-dioxygenase (IDO) was analyzed by qRT-PCR and Western blot assays, respectively. Our findings demonstrate that PT-gliadin enhances the expression of maturation markers, i.e. CD83, CD86 and HLA-DR and promote the secretion of TNF-α and IL-12 in DCs. Interestingly, vitamin A, tryptophan, and their metabolites increase the expression of CD103, while limiting the expression of HLA-DR, CD83, and CD86. They also enhance RALDH2 and IDO expression and promote the secretion of TGF-β and IL-10, while limiting IL-12 and TNF-α secretion. These findings suggest that vitamin A and tryptophan have beneficial effects on PT-gliadin-stimulated DCs, highlighting their potential as therapeutic agents for celiac disease. However, further research is needed to fully understand their underlying mechanisms of action in these cells.
    Keywords:  3-dioxygenase; Celiac disease; Dendritic cells; Immune tolerance.; Indoleamine 2; Tryptophan; Vitamin A
    DOI:  https://doi.org/10.1007/s10753-024-02004-7
  16. Elife. 2024 Mar 21. pii: RP91157. [Epub ahead of print]12
    Targeting host deoxycytidine kinase mitigates Staphylococcus aureus abscess formation.
    Volker Winstel, Evan R Abt, Thuc M Le, Caius G Radu.
      Host-directed therapy (HDT) is an emerging approach to overcome antimicrobial resistance in pathogenic microorganisms. Specifically, HDT targets host-encoded factors required for pathogen replication and survival without interfering with microbial growth or metabolism, thereby eliminating the risk of resistance development. By applying HDT and a drug repurposing approach, we demonstrate that (R)-DI-87, a clinical-stage anticancer drug and potent inhibitor of mammalian deoxycytidine kinase (dCK), mitigates Staphylococcus aureus abscess formation in organ tissues upon invasive bloodstream infection. Mechanistically, (R)-DI-87 shields phagocytes from staphylococcal death-effector deoxyribonucleosides that target dCK and the mammalian purine salvage pathway-apoptosis axis. In this manner, (R)-DI-87-mediated protection of immune cells amplifies macrophage infiltration into deep-seated abscesses, a phenomenon coupled with enhanced pathogen control, ameliorated immunopathology, and reduced disease severity. Thus, pharmaceutical blockade of dCK represents an advanced anti-infective intervention strategy against which staphylococci cannot develop resistance and may help to fight fatal infectious diseases in hospitalized patients.
    Keywords:  Staphylococcus aureus; apoptosis; infectious disease; macrophages; microbiology
    DOI:  https://doi.org/10.7554/eLife.91157
  17. Int Immunopharmacol. 2024 Mar 30. pii: S1567-5769(24)00301-1. [Epub ahead of print]130 111783
    High-fat diet-induced obesity causes intestinal Th17/Treg imbalance that impairs the intestinal barrier and aggravates anxiety-like behavior in mice.
    Yao Cai, Wenlin Deng, Qiuping Yang, Guixian Pan, Zao Liang, Ximei Yang, Sitao Li, Xin Xiao.
      The prevalence of autism spectrum disorders (ASD) has been steadily increasing, and growing evidence suggests a link between high-fat diet (HFD), obesity, and ASD; however, the mechanism underlying this association remains elusive. Herein, BTBR T + tf/J (BTBR) inbred mice (a mouse ASD model) and C57Bl/6J (C57) mice were fed an HFD and normal diet (ND) for 8 weeks (groups: C57 + ND, C57 + HFD, BTBR + ND, and BTBR + HFD). Subsequently, mice underwent behavioral assessments, followed by intestinal tissues harvesting to detect expression of intestinal barrier proteins and inflammatory factors and immune cell numbers, and a correlation analysis. HFD-fed BTBR mice developed obesity, elevated blood sugar, significantly aggravated anxiety-like behaviors, impaired intestinal barrier function, intestinal inflammation with elevated CD4+IL17+ T (Th17) cells and reduced CD4+Foxp3+ T (Treg) cells, exhibiting reduced expression of proteins related to AMPK regulatory pathway (AMPK, p-AMPK, SIRT1). Correlation analysis revealed that the degree of behavioral anxiety, the degree of intestinal barrier damage, the severity of intestinal inflammation, and the degree of immune cell imbalance positively correlated with each other. Accordingly, HFD-induced obesity may cause intestinal Th17/Treg imbalance via the AMPK-SIRT1 pathway, leading to an inflammatory environment in the intestine, impairing intestinal barrier function, and ultimately aggravating anxiety-like behaviors in mice.
    Keywords:  Anxiety; Autism spectrum disorder; High-fat diet; Intestinal barrier; Obesity; Th17/Treg imbalance
    DOI:  https://doi.org/10.1016/j.intimp.2024.111783
  18. BMC Microbiol. 2024 Mar 18. 24(1): 91
    Pretreatment with an antibiotics cocktail enhances the protective effect of probiotics by regulating SCFA metabolism and Th1/Th2/Th17 cell immune responses.
    Jing Xu, Haoming Xu, Xue Guo, Hailan Zhao, Jiaqi Wang, Jianhong Li, Jie He, Hongli Huang, Chen Huang, Chong Zhao, Yingfei Li, Youlian Zhou, Yao Peng, Yuqiang Nie.
      BACKGROUND: Probiotics are a potentially effective therapy for inflammatory bowel disease (IBD); IBD is linked to impaired gut microbiota and intestinal immunity. However, the utilization of an antibiotic cocktail (Abx) prior to the probiotic intervention remains controversial. This study aims to identify the effect of Abx pretreatment from dextran sulfate sodium (DSS)-induced colitis and to evaluate whether Abx pretreatment has an enhanced effect on the protection of Clostridium butyricum Miyairi588 (CBM) from colitis.RESULTS: The inflammation, dysbiosis, and dysfunction of gut microbiota as well as T cell response were both enhanced by Abx pretreatment. Additionally, CBM significantly alleviated the DSS-induced colitis and impaired gut epithelial barrier, and Abx pretreatment could enhance these protective effects. Furthermore, CBM increased the benefit bacteria abundance and short-chain fatty acids (SCFAs) level with Abx pretreatment. CBM intervention after Abx pretreatment regulated the imbalance of cytokines and transcription factors, which corresponded to lower infiltration of Th1 and Th17 cells, and increased Th2 cells.
    CONCLUSIONS: Abx pretreatment reinforced the function of CBM in ameliorating inflammation and barrier damage by increasing beneficial taxa, eliminating pathogens, and inducing a protective Th2 cell response. This study reveals a link between Abx pretreatment, microbiota, and immune response changes in colitis, which provides a reference for the further application of Abx pretreatment before microbiota-based intervention.
    Keywords:   Clostridium butyricum Miyairi588 ; Antibiotic cocktails; Gut microbiota; Short-chain fatty acids; Th1/Th2/Th17 response
    DOI:  https://doi.org/10.1186/s12866-024-03251-2
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