bims-imicid 2024-01-14 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–01–14
27 papers selected by
Dylan Ryan, University of Cambridge

Prostaglandin E2 controls the metabolic adaptation of T cells to the intestinal microenvironment.
Norovirus NS1/2 protein increases glutaminolysis for efficient viral replication.
A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity.
Eomes-dependent mitochondrial regulation promotes survival of pathogenic CD4+ T cells during inflammation.
Pyruvate dehydrogenase kinase regulates macrophage polarization in metabolic and inflammatory diseases.
TGFβ macrophage reprogramming: A new dimension of macrophage plasticity.
Reprogramming Short-Chain Fatty Acid Metabolism Mitigates Tissue Damage for Streptococcus pyogenes Necrotizing Skin Infection.
OxPhos in adipose tissue macrophages regulated by BTK enhances their M2-like phenotype and confers a systemic immunometabolic benefit in obesity.
Oxidized Low-Density Lipoprotein Accumulation in Macrophages Impairs Lipopolysaccharide-Induced Activation of AKT2, ATP Citrate Lyase, Acetyl-Coenzyme A Production, and Inflammatory Gene H3K27 Acetylation.
Targeting cancer and immune cell metabolism with the complex I inhibitors metformin and IACS-010759.
GRIM-19 deficiency promotes macrophage polarization to the M1 phenotype partly through glycolysis in unexplained recurrent spontaneous abortion.
Propionate functions as a feeding-state-dependent regulatory metabolite to counter pro-inflammatory signaling linked to nutrient load and obesity.
Metabolic regulation of tumor-associated macrophage heterogeneity: insights into the tumor microenvironment and immunotherapeutic opportunities.
Ketone bodies as chemical signals for the immune system.
Testosterone regulates thymic remodeling by altering metabolic reprogramming in male rats.
CD3-downregulation identifies T-helper-cells with superior functionality and distinct metabolism in SARS-CoV2-vaccination- and recall-antigen-specific immunity.
Skin microbe-dependent TSLP-ILC2 priming axis in early life is co-opted in allergic inflammation.
Glycolysis Reprogramming in Idiopathic Pulmonary Fibrosis: Unveiling the Mystery of Lactate in the Lung.
Nutritional regulation of microbiota-derived metabolites: Implications for immunity and inflammation.
Advances in Metabolic Regulation of Macrophage Polarization State.
The mitochondrial genome-encoded peptide MOTS-c interacts with Bcl-2 to alleviate nonalcoholic steatohepatitis progression.
Multi-omics analysis reveals GAPDH posttranscriptional regulation of IFN-γ and PHGDH as a metabolic checkpoint of microglia polarization.
Aerobic glycolysis of bronchial epithelial cells rewires Mycoplasma pneumoniae pneumonia and promotes bacterial elimination.
Chronic Stress Blocks the Endometriosis Immune Response by Metabolic Reprogramming.
The serine synthesis pathway drives osteoclast differentiation through epigenetic regulation of NFATc1 expression.
NLRX1 Prevents M2 Macrophage Polarization and Excessive Renal Fibrosis in Chronic Obstructive Nephropathy.
N-linked Fc glycosylation is not required for IgG-B-cell receptor function in a GC-derived B-cell line.

Nat Commun. 2024 Jan 11. 15(1): 451

Prostaglandin E2 controls the metabolic adaptation of T cells to the intestinal microenvironment.

Matteo Villa, David E Sanin, Petya Apostolova, Mauro Corrado, Agnieszka M Kabat, Carmine Cristinzio, Annamaria Regina, Gustavo E Carrizo, Nisha Rana, Michal A Stanczak, Francesc Baixauli, Katarzyna M Grzes, Jovana Cupovic, Francesca Solagna, Alexandra Hackl, Anna-Maria Globig, Fabian Hässler, Daniel J Puleston, Beth Kelly, Nina Cabezas-Wallscheid, Peter Hasselblatt, Bertram Bengsch, Robert Zeiser, Sagar, Joerg M Buescher, Edward J Pearce, Erika L Pearce.

Immune cells must adapt to different environments during the course of an immune response. Here we study the adaptation of CD8+ T cells to the intestinal microenvironment and how this process shapes the establishment of the CD8+ T cell pool. CD8+ T cells progressively remodel their transcriptome and surface phenotype as they enter the gut wall, and downregulate expression of mitochondrial genes. Human and mouse intestinal CD8+ T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We find that the intestinal microenvironment is rich in prostaglandin E2 (PGE2), which drives mitochondrial depolarization in CD8+ T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE2 sensing promotes CD8+ T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell pool. Thus, a PGE2-autophagy-glutathione axis defines the metabolic adaptation of CD8+ T cells to the intestinal microenvironment, to ultimately influence the T cell pool.

DOI: https://doi.org/10.1038/s41467-024-44689-2
bioRxiv. 2023 Dec 19. pii: 2023.12.19.572316. [Epub ahead of print]

Norovirus NS1/2 protein increases glutaminolysis for efficient viral replication.

Adam Hafner, Noah Meurs, Ari Garner, Elaine Azar, Karla D Passalacqua, Deepak Nagrath, Christiane E Wobus.

Viruses are obligate intracellular parasites that rely on host cell metabolism for successful replication. Thus, viruses rewire host cell pathways involved in central carbon metabolism to increase the availability of building blocks for replication. However, the underlying mechanisms of virus-induced alterations to host metabolism are largely unknown. Noroviruses (NoVs) are highly prevalent pathogens that cause sporadic and epidemic viral gastroenteritis. In the present study, we uncovered several strain-specific and shared host cell metabolic requirements of three murine norovirus (MNV) strains, the acute MNV-1 strain and the persistent CR3 and CR6 strains. While all three strains required glycolysis, glutaminolysis, and the pentose phosphate pathway for optimal infection of macrophages, only MNV-1 relied on host oxidative phosphorylation. Furthermore, the first metabolic flux analysis of NoV-infected cells revealed that both glycolysis and glutaminolysis are upregulated during MNV-1 infection of macrophages. Glutamine deprivation affected the MNV lifecycle at the stage of genome replication, resulting in decreased non-structural and structural protein synthesis, viral assembly, and egress. Mechanistic studies further showed that MNV infection and overexpression of the MNV non-structural protein NS1/2 increased the enzymatic activity of the rate-limiting enzyme glutaminase. In conclusion, the inaugural investigation of NoV-induced alterations to host glutaminolysis identified the first viral regulator of glutaminolysis for RNA viruses, which increases our fundamental understanding of virus-induced metabolic alterations.
Author Summary: All viruses critically depend on the host cells they infect to provide the necessary machinery and building blocks for successful replication. Thus, viruses often alter host metabolic pathways to increase the availability of key metabolites they require. Human noroviruses (HNoVs) are a major cause of acute non-bacterial gastroenteritis, leading to significant morbidity and economic burdens. To date, no vaccines or antivirals are available against NoVs, which demonstrates a need to better understand NoV biology, including the role host metabolism plays during infection. Using the murine norovirus (MNV) model, we show that host cell glutaminolysis is upregulated and required for optimal virus infection of macrophages. Additional data point to a model whereby the viral non-structural protein NS1/2 upregulates the enzymatic activity of glutaminase, the rate-limiting enzyme in glutaminolysis. Insights gained through investigating the role host metabolism plays in MNV replication may assist with improving HNoV cultivation methods and development of novel therapies.

DOI: https://doi.org/10.1101/2023.12.19.572316
Mol Cell. 2024 Jan 04. pii: S1097-2765(23)01034-1. [Epub ahead of print]

A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity.

Xu Wang, Sheng-Qiao Fu, Xiao Yuan, Feng Yu, Qian Ji, Hao-Wen Tang, Rong-Kun Li, Shan Huang, Pei-Qi Huang, Wei-Ting Qin, Hao Zuo, Chang Du, Lin-Li Yao, Hui Li, Jun Li, Dong-Xue Li, Yan Yang, Shu-Yu Xiao, Aziguli Tulamaiti, Xue-Feng Wang, Chun-Hua Dai, Xu Zhang, Shu-Heng Jiang, Li-Peng Hu, Xue-Li Zhang, Zhi-Gang Zhang.

  Apart from the canonical serotonin (5-hydroxytryptamine [5-HT])-receptor signaling transduction pattern, 5-HT-involved post-translational serotonylation has recently been noted. Here, we report a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serotonylation system that promotes the glycolytic metabolism and antitumor immune activity of CD8+ T cells. Tissue transglutaminase 2 (TGM2) transfers 5-HT to GAPDH glutamine 262 and catalyzes the serotonylation reaction. Serotonylation supports the cytoplasmic localization of GAPDH, which induces a glycolytic metabolic shift in CD8+ T cells and contributes to antitumor immunity. CD8+ T cells accumulate intracellular 5-HT for serotonylation through both synthesis by tryptophan hydroxylase 1 (TPH1) and uptake from the extracellular compartment via serotonin transporter (SERT). Monoamine oxidase A (MAOA) degrades 5-HT and acts as an intrinsic negative regulator of CD8+ T cells. The adoptive transfer of 5-HT-producing TPH1-overexpressing chimeric antigen receptor T (CAR-T) cells induced a robust antitumor response. Our findings expand the known range of neuroimmune interaction patterns by providing evidence of receptor-independent serotonylation post-translational modification.

Keywords:  5-HT; CD8(+) T cell; GAPDH; glycolysis; post-translational modification; serotonin; serotonylation; tumor immunity

DOI:  https://doi.org/10.1016/j.molcel.2023.12.015
J Exp Med. 2024 Feb 05. pii: e20230449. [Epub ahead of print]221(2):

Eomes-dependent mitochondrial regulation promotes survival of pathogenic CD4+ T cells during inflammation.

Emeline Joulia, Michaël F Michieletto, Arantxa Agesta, Cindy Peillex, Virginie Girault, Anne-Louise Le Dorze, Romain Peroceschi, Florence Bucciarelli, Marion Szelechowski, Adeline Chaubet, Nawad Hakim, Rémi Marrocco, Emeline Lhuillier, Manuel Lebeurrier, Rafael J Argüello, Abdelhadi Saoudi, Hicham El Costa, Veronique Adoue, Thierry Walzer, Jean-Emmanuel Sarry, Anne S Dejean.

The mechanisms whereby Eomes controls tissue accumulation of T cells and strengthens inflammation remain ill-defined. Here, we show that Eomes deletion in antigen-specific CD4+ T cells is sufficient to protect against central nervous system (CNS) inflammation. While Eomes is dispensable for the initial priming of CD4+ T cells, it is required for long-term maintenance of CNS-infiltrating CD4+ T cells. We reveal that the impact of Eomes on effector CD4+ T cell longevity is associated with sustained expression of multiple genes involved in mitochondrial organization and functions. Accordingly, epigenetic studies demonstrate that Eomes supports mitochondrial function by direct binding to either metabolism-associated genes or mitochondrial transcriptional modulators. Besides, the significance of these findings was confirmed in CD4+ T cells from healthy donors and multiple sclerosis patients. Together, our data reveal a new mechanism by which Eomes promotes severity and chronicity of inflammation via the enhancement of CD4+ T cell mitochondrial functions and resistance to stress-induced cell death.

DOI: https://doi.org/10.1084/jem.20230449
Front Immunol. 2023 ;14 1296687

Pyruvate dehydrogenase kinase regulates macrophage polarization in metabolic and inflammatory diseases.

Chenyu Li, Chuanbin Liu, Junfeng Zhang, Yanyu Lu, Bingtong Jiang, Huabao Xiong, Chunxia Li.

  Macrophages are highly heterogeneous and plastic, and have two main polarized phenotypes that are determined by their microenvironment, namely pro- and anti-inflammatory macrophages. Activation of pro-inflammatory macrophages is closely associated with metabolic reprogramming, especially that of aerobic glycolysis. Mitochondrial pyruvate dehydrogenase kinase (PDK) negatively regulates pyruvate dehydrogenase complex activity through reversible phosphorylation and further links glycolysis to the tricarboxylic acid cycle and ATP production. PDK is commonly associated with the metabolism and polarization of macrophages in metabolic and inflammatory diseases. This review examines the relationship between PDK and macrophage metabolism and discusses the mechanisms by which PDK regulates macrophage polarization, migration, and inflammatory cytokine secretion in metabolic and inflammatory diseases. Elucidating the relationships between the metabolism and polarization of macrophages under physiological and pathological conditions, as well as the regulatory pathways involved, may provide valuable insights into the etiology and treatment of macrophage-mediated inflammatory diseases.

Keywords:  inflammation; macrophage; metabolic reprogramming; polarization; pyruvate dehydrogenase kinase

DOI:  https://doi.org/10.3389/fimmu.2023.1296687
J Leukoc Biol. 2024 Jan 10. pii: qiae001. [Epub ahead of print]

TGFβ macrophage reprogramming: A new dimension of macrophage plasticity.

Mary A Oliver, Xenia D Davis, Julia K Bohannon.

  The August 2023 article in Science Signaling, "TGF-β uncouples glycolysis and inflammation in macrophages and controls survival during sepsis, " challenges the traditional M1/M2 macrophage classification by investigating the impact of transforming growth factor β (TGFβ) on macrophage metabolism and function. Despite its conventional anti-inflammatory role, TGFβ-treated macrophages exhibit a distinct phenotype marked by heightened glycolysis, suppressed proinflammatory cytokines, and increased coagulation factor expression. The study identifies phosphofructokinase-liver type (PFKL) as a crucial glycolytic enzyme regulated by TGFβ via the mTOR-c-MYC pathway. Epigenetic changes induced by TGFβ, such as increased Smad3 activation and reduced proinflammatory transcription factor motif enrichment, contribute to the anti-inflammatory profile. The research extends its implications to sepsis, revealing TGFβ's role in exacerbating coagulation and reducing survival in mouse models. This effect involves upregulation of coagulation factor F13A1, dependent on PFKL activity and glycolysis in macrophages. Connections to COVID-19 pathology are drawn, as TGFβ-treated macrophages and SARS-CoV-2 E protein-exposed cells display similar metabolic profiles. Bioinformatic analysis of COVID-19 patient data suggests correlations between myeloid expression of TGFβR1, PFKL, and F13A1 with disease severity. The study challenges M1/M2 classification, emphasizing the complexity of macrophage responses influenced by TGFβ, proposing TGFβ as a potential therapeutic target for conditions like sepsis and COVID-19 where dysregulated coagulation is significant. Overall, the research provides valuable insights into TGFβ-mediated immunometabolic regulation, paving the way for future investigations and potential therapeutic interventions.

Keywords:  TGFβ; immunometabolism; inflammation; macrophage; sepsis

DOI:  https://doi.org/10.1093/jleuko/qiae001
Res Sq. 2023 Dec 23. pii: rs.3.rs-3689163. [Epub ahead of print]

Reprogramming Short-Chain Fatty Acid Metabolism Mitigates Tissue Damage for Streptococcus pyogenes Necrotizing Skin Infection.

Michael Caparon, Wei Xu, Tara Bradstreet, Zongsen Zou, Suzanne Hickerson, Yuan Zhou, Hongwu He, Brian Edelson.

Disease Tolerance (DT) is a host response to infection that limits collateral damage to host tissues while having a neutral effect on pathogen fitness. Previously, we found that the pathogenic lactic acid bacterium Streptococcus pyogenes manipulates DT using its aerobic mixed-acid fermentation (ARMAF) pathway via the enzyme pyruvate dehydrogenase (PDH) to alter expression of the immunosuppressive cytokine IL-10. However, the microbe-derived molecules that mediate communication with the host's DT pathways remain elusive. Here, we show that ARMAF inhibits accumulation of IL-10-producing inflammatory cells including neutrophils and macrophages, leading to delayed bacterial clearance and wound healing. Expression of IL-10 is inhibited through streptococcal production of the short chain fermentation end-products acetate and formate, via manipulation of host acetyl-CoA metabolism, altering non-histone regulatory lysine acetylation. A bacterial-specific PDH inhibitor reduced tissue damage during murine infection, suggesting that reprogramming carbon flow provides a novel therapeutic strategy to mitigate tissue damage during infection.

DOI: https://doi.org/10.21203/rs.3.rs-3689163/v1
Diabetes. 2024 Jan 08. pii: db220275. [Epub ahead of print]

OxPhos in adipose tissue macrophages regulated by BTK enhances their M2-like phenotype and confers a systemic immunometabolic benefit in obesity.

Oxford Acute Myocardial Infarction (OxAMI) Study

Bruton's tyrosine kinase (BTK) is a non-receptor bound kinase involved in pro-inflammatory signalling in activated macrophages, however, its role within adipose tissue macrophages remains unclear. We have demonstrated that BTK signalling regulates macrophage M2-like polarisation state by up-regulating subunits of mitochondrially encoded electron transport chain Complex I (ND4 and NDL4) and Complex IV (mt-CO1, mt-CO2 and mt-CO3) resulting in an enhanced rate of oxidative phosphorylation (OxPhos) in an NF-κB independent manner. Critically, BTK expression is elevated in adipose tissue macrophages from obese individuals with diabetes, while key mitochondrial genes (mtC01, mtC02 and mtC03) are decreased in inflammatory myeloid cells from obese individuals. Inhibition of BTK signalling either globally (Xid mice) or in myeloid cells (LysMCreBTK), or therapeutically (Acalabrutinib) protects HFD-fed mice from developing glycaemic dysregulation by improving signalling through the IRS1/Akt/GSK3β pathway. The beneficial effects of acalabrutinib treatment are lost in macrophage ablated mice. Inhibition of BTK signalling in myeloid cells but not B-cells, induced a phenotypic switch in adipose tissue macrophages from a pro-inflammatory M1-state to a pro-resolution M2-like phenotype, by shifting macrophage metabolism towards OxPhos. This reduces both local and systemic inflammation and protected mice from the immunometabolic consequences of obesity. Therefore, in BTK we have identified a macrophage specific, druggable target that can regulate adipose tissue polarisation and cellular metabolism that can confer systematic benefit in metabolic syndrome.

DOI: https://doi.org/10.2337/db22-0275
Immunohorizons. 2024 Jan 01. 8(1): 57-73

Oxidized Low-Density Lipoprotein Accumulation in Macrophages Impairs Lipopolysaccharide-Induced Activation of AKT2, ATP Citrate Lyase, Acetyl-Coenzyme A Production, and Inflammatory Gene H3K27 Acetylation.

Kenneth K Y Ting, Pei Yu, Mudia Iyayi, Riley Dow, Sharon J Hyduk, Eric Floro, Hisham Ibrahim, Saraf Karim, Chanele K Polenz, Daniel A Winer, Minna Woo, Jonathan Rocheleau, Jenny Jongstra-Bilen, Myron I Cybulsky.

The accumulation of lipid and the formation of macrophage foam cells is a hallmark of atherosclerosis, a chronic inflammatory disease. To better understand the role of macrophage lipid accumulation in inflammation during atherogenesis, we studied early molecular events that follow the accumulation of oxidized low-density lipoprotein (oxLDL) in cultured mouse macrophages. We previously showed that oxLDL accumulation downregulates the inflammatory response in conjunction with downregulation of late-phase glycolysis. In this study, we show that within hours after LPS stimulation, macrophages with accumulated oxLDL maintain early-phase glycolysis but selectively downregulate activation of AKT2, one of three AKT isoforms. The inhibition of AKT2 activation reduced LPS-induced ATP citrate lyase activation, acetyl-CoA production, and acetylation of histone 3 lysine 27 (H3K27ac) in certain inflammatory gene promoters. In contrast to oxLDL, multiple early LPS-induced signaling pathways were inhibited in macrophages with accumulated cholesterol, including TBK1, AKT1, AKT2, MAPK, and NF-κB, and early-phase glycolysis. The selective inhibition of LPS-induced AKT2 activation was dependent on the generation of mitochondrial oxygen radicals during the accumulation of oxLDL in macrophages prior to LPS stimulation. This is consistent with increased oxidative phosphorylation, fatty acid synthesis, and oxidation pathways found by comparative transcriptomic analyses of oxLDL-loaded versus control macrophages. Our study shows a functional connection between oxLDL accumulation, inactivation of AKT2, and the inhibition of certain inflammatory genes through epigenetic changes that occur soon after LPS stimulation, independent of early-phase glycolysis.

DOI: https://doi.org/10.4049/immunohorizons.2300101
Mol Oncol. 2024 Jan 12.

Targeting cancer and immune cell metabolism with the complex I inhibitors metformin and IACS-010759.

Marc Pujalte-Martin, Amine Belaïd, Simon Bost, Michel Kahi, Pascal Peraldi, Matthieu Rouleau, Nathalie M Mazure, Frédéric Bost.

  Metformin and IACS-010759 are two distinct antimetabolic agents. Metformin, an established antidiabetic drug, mildly inhibits mitochondrial complex I, while IACS-010759 is a new potent mitochondrial complex I inhibitor. Mitochondria is pivotal in the energy metabolism of cells by providing adenosine triphosphate through oxidative phosphorylation (OXPHOS). Hence, mitochondrial metabolism and OXPHOS become a vulnerability when targeted in cancer cells. Both drugs have promising antitumoral effects in diverse cancers, supported by preclinical in vitro and in vivo studies. We present evidence of their direct impact on cancer cells and their immunomodulatory effects. In clinical studies, while observational epidemiologic studies on metformin were encouraging, actual trial results were not as expected. However, IACS-01075 exhibited major adverse effects, thereby causing a metabolic shift to glycolysis and elevated lactic acid concentrations. Therefore, the future outlook for these two drugs depends on preventive clinical trials for metformin and investigations into the plausible toxic effects on normal cells for IACS-01075.

Keywords:  IACS-010759; cancer; clinical trial; immunometabolism; metformin; microenvironment

DOI:  https://doi.org/10.1002/1878-0261.13583
Biol Reprod. 2024 Jan 11. pii: ioae005. [Epub ahead of print]

GRIM-19 deficiency promotes macrophage polarization to the M1 phenotype partly through glycolysis in unexplained recurrent spontaneous abortion.

Bingyu Wang, Yang Yang, Jinwen Ye, Xiaojuan Han, Lin Yang, Yufei Huang, Lan Chao.

  The occurrence of unexplained recurrent spontaneous abortion (URSA) is closely related to immune system disorders, however, the underlying mechanisms remain unclear. The purpose of this study was to investigate the expression of GRIM-19 in URSA and the possible pathogenesis of URSA according to macrophage polarization. Here, we showed that GRIM-19 was downregulated in the uterine decidual macrophages of patients with URSA and that GRIM-19 downregulation was accompanied by increased M1 macrophage polarization. Furthermore, the expression levels of glycolytic enzymes were substantially enhanced in the uterine decidual macrophages of URSA patients, and glycolysis in THP-1-derived macrophages was further enhanced by the downregulation of GRIM-19. Additionally, the increase of M1 macrophages resulting from the loss of GRIM-19 was significantly reversed in cells treated with 2-deoxy-D-glucose (2-DG, an inhibitor of glycolysis). To provide more direct evidence, GRIM-19 deficiency was shown to promote macrophage polarization to the M1 phenotype in GRIM-19+/- mouse uteri. Overall, our study provides evidence that GRIM-19 deficiency may play a role in regulating macrophage polarization in URSA, and that glycolysis may participate in this process.

Keywords:  GRIM-19; Macrophage polarization; URSA; glycolysis

DOI:  https://doi.org/10.1093/biolre/ioae005
J Leukoc Biol. 2024 Jan 11. pii: qiae006. [Epub ahead of print]

Propionate functions as a feeding-state-dependent regulatory metabolite to counter pro-inflammatory signaling linked to nutrient load and obesity.

Kim Han, Allison M Meadows, Matthew J Rodman, Anna Chiara Russo, Rahul Sharma, Komudi Singh, Shahin Hassanzadeh, Pradeep K Dagur, Rebecca D Huffstutler, Fynn N Krause, Julian L Griffin, Yvonne Baumer, Tiffany M Powell-Wiley, Michael N Sack.

  Generally, fasting and refeeding confer anti- and pro-inflammatory effects, respectively. In humans, these caloric-load interventions function, in part, via regulation of CD4+ T cell biology. However, mechanisms orchestrating this regulation remain incomplete. We employed integrative bioinformatics of RNA-seq and HPLC-mass spectrometry data to measure serum metabolites and gene expression of peripheral blood mononuclear cells isolated from fasting and refeeding in volunteers to identify nutrient-load metabolite-driven immunoregulation. Propionate, a short chain fatty acid (SCFA), and the SCFA-sensing G-protein coupled receptor (GPCR) 43 (ffar2) were co-ordinately and inversely regulated by fasting and refeeding. Propionate and FFAR agonists decreased IFNγ and IL-17 and significantly blunted HDAC activity in CD4+ T cells. Furthermore, propionate blunted NFκB activity and diminished IL-6 release. In parallel, propionate reduced phosphorylation of canonical TH1 and TH17 regulators, STAT1 and STAT3, respectively. Conversely, knockdown of FFARs significantly attenuated the anti-inflammatory role of propionate. Interestingly, propionate recapitulated the blunting of CD4+ T helper cell activation in primary cells from obese individuals, extending the role of this metabolite to a disease associated with low-grade inflammation. Together, these data identify a nutrient-load responsive SCFA-GPCR linked pathway to regulate CD4+ helper T cell immune responsiveness.

Keywords:  CD4+ T cells; FFAR2; Fasting; IL-6; Metabolite; NFκB; Propionate

DOI:  https://doi.org/10.1093/jleuko/qiae006
Biomark Res. 2024 Jan 07. 12(1): 1

Metabolic regulation of tumor-associated macrophage heterogeneity: insights into the tumor microenvironment and immunotherapeutic opportunities.

Yujing Qian, Yujia Yin, Xiaocui Zheng, Zhaoyuan Liu, Xipeng Wang.

  Tumor-associated macrophages (TAMs) are a heterogeneous population that play diverse functions in tumors. Their identity is determined not only by intrinsic factors, such as origins and transcription factors, but also by external signals from the tumor microenvironment (TME), such as inflammatory signals and metabolic reprogramming. Metabolic reprogramming has rendered TAM to exhibit a spectrum of activities ranging from pro-tumorigenic to anti-tumorigenic, closely associated with tumor progression and clinical prognosis. This review implicates the diversity of TAM phenotypes and functions, how this heterogeneity has been re-evaluated with the advent of single-cell technologies, and the impact of TME metabolic reprogramming on TAMs. We also review current therapies targeting TAM metabolism and offer new insights for TAM-dependent anti-tumor immunotherapy by focusing on the critical role of different metabolic programs in TAMs.

Keywords:  Immunotherapy; Metabolic reprogramming; Single-cell omics; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1186/s40364-023-00549-7
Am J Physiol Cell Physiol. 2024 Jan 08.

Ketone bodies as chemical signals for the immune system.

Michelangelo Bauwelz Gonzatti, Emily Goldberg.

  Ketone bodies are short chain fatty acids produced by the liver during periods of limited glucose availability, such as during fasting or low carbohydrate feeding. Recent studies have highlighted important non-metabolic functions of the most abundant ketone body, β-hydroxybutyrate (BHB). Notably, many of these functions, including limiting certain sources of inflammation, histone deacetylase inhibition, NFκB inhibition, and GPCR stimulation, are particularly important to consider in immune cells. Likewise, dietary manipulations like caloric restriction or ketogenic diet feeding are associated with lowered inflammation, improved health outcomes, and improved host defense against infection, although the underlying mechanisms of the broad benefits of ketosis remain incompletely understood. In this perspective, we contextualize the current state of the field of non-metabolic functions of ketone bodies specifically in the immune system and speculate on the molecular explanations and broader physiological significance.

Keywords:  BHB; immune; inflammation; ketone bodies; metabolism

DOI:  https://doi.org/10.1152/ajpcell.00478.2023
Gen Comp Endocrinol. 2024 Jan 06. pii: S0016-6480(24)00008-X. [Epub ahead of print]348 114448

Testosterone regulates thymic remodeling by altering metabolic reprogramming in male rats.

Dong Li, Huan Yao, Yonghao Ren, Jiameng Shang, Xinfa Han, Xiaohan Cao, Tianzeng Song, Xianyin Zeng.

  The thymus is an energy-consuming organ, and its metabolism changes with atrophy. Testosterone regulates thymus remodeling (atrophy and regeneration). However, the characteristics of the energy metabolism during testosterone-mediated thymic atrophy and regeneration remain unclear. In this study, we demonstrated that testosterone ablation (implemented by immunocastration and surgical castration) induced global metabolic changes in the thymus. Kyoto Encyclopedia of Genes and Genomes pathway enrichment for differential metabolites and metabolite set enrichment analysis for total metabolites revealed that testosterone ablation affected thymic glycolysis, glutamate metabolism, and fatty acid β-oxidation. Testosterone ablation-induced thymic regeneration was accompanied by attenuated glycolysis and glutamate metabolism and changed fatty acid composition and content. Testosterone supplementation in immunocastrated and surgically castrated rats enhanced glutaminolysis, reduced the level of unsaturated fatty acids, enhanced the β-oxidation of unsaturated fatty acids in the mitochondria, boosted the tricarboxylic acid (TCA) cycle, and accelerated thymic atrophy. Overall, these results imply that metabolic reprogramming is directly related to thymic remodeling.

Keywords:  Glutamate; Glycolysis; Lipid metabolism; Testosterone; Thymus; Tricarboxylic acid cycle

DOI:  https://doi.org/10.1016/j.ygcen.2024.114448
JCI Insight. 2024 Jan 11. pii: e166833. [Epub ahead of print]

CD3-downregulation identifies T-helper-cells with superior functionality and distinct metabolism in SARS-CoV2-vaccination- and recall-antigen-specific immunity.

Arne Sattler, Stefanie Gamradt, Vanessa Proß, Linda Marie Laura Thole, An He, Eva Vanessa Schrezenmeier, Katharina Jechow, Stefan M Gold, Soeren Lukassen, Christian Conrad, Katja Kotsch.

  Functional avidity is supposed to critically shape the quality of immune responses, thereby impacting host protection against infectious agents including SARS-CoV2. Here we show that after human SARS-CoV2 vaccination, a large portion of high-avidity spike-specific CD4+ T cells lose CD3 expression after in vitro activation. The CD3- subset is enriched for cytokine positive cells, including elevated per-cell expression levels, and shows increased polyfunctionality. Assessment of key metabolic pathways by flow cytometry revealed that superior functionality is accompanied by a shift towards fatty acid-synthesis at the expense of their oxidation, whereas glucose transport and glycolysis were similarly regulated in SARS-CoV2-specific CD3- and CD3+ subsets. As opposed to their CD3+ counterparts, frequencies of vaccine-specific CD3- T cells positively correlate with both the size of the naïve CD4+ T cell pool and vaccine-specific IgG levels. Moreover, their frequencies negatively correlate with advancing age and are impaired in patients under immunosuppressive therapy. Typical recall-antigen-reactive T cells show a comparable segregation into functionally and metabolically distinct CD3+ and CD3- subsets, but are quantitatively maintained upon ageing, likely due to earlier recruitment in life. In summary, our data identify CD3- T helper cells as correlates of high quality immune responses that are impaired in at-risk populations.

Keywords:  Cellular immune response; Immunology; Organ transplantation; T cells; Vaccines

DOI:  https://doi.org/10.1172/jci.insight.166833
Cell Host Microbe. 2024 Jan 03. pii: S1931-3128(23)00501-2. [Epub ahead of print]

Skin microbe-dependent TSLP-ILC2 priming axis in early life is co-opted in allergic inflammation.

Jimin Cha, Tae-Gyun Kim, Euihyun Bhae, Ho-Jin Gwak, Yeajin Ju, Young Ho Choe, In-Hwan Jang, Youngae Jung, Sungmin Moon, Taehyun Kim, Wuseong Lee, Jung Sun Park, Youn Wook Chung, Siyoung Yang, Yong-Kook Kang, Young-Min Hyun, Geum-Sook Hwang, Won-Jae Lee, Mina Rho, Ji-Hwan Ryu.

  Although early life colonization of commensal microbes contributes to long-lasting immune imprinting in host tissues, little is known regarding the pathophysiological consequences of postnatal microbial tuning of cutaneous immunity. Here, we show that postnatal exposure to specific skin commensal Staphylococcus lentus (S. lentus) promotes the extent of atopic dermatitis (AD)-like inflammation in adults through priming of group 2 innate lymphoid cells (ILC2s). Early postnatal skin is dynamically populated by discrete subset of primed ILC2s driven by microbiota-dependent induction of thymic stromal lymphopoietin (TSLP) in keratinocytes. Specifically, the indole-3-aldehyde-producing tryptophan metabolic pathway, shared across Staphylococcus species, is involved in TSLP-mediated ILC2 priming. Furthermore, we demonstrate a critical contribution of the early postnatal S. lentus-TSLP-ILC2 priming axis in facilitating AD-like inflammation that is not replicated by later microbial exposure. Thus, our findings highlight the fundamental role of time-dependent neonatal microbial-skin crosstalk in shaping the threshold of innate type 2 immunity co-opted in adulthood.

Keywords:  Staphylococcus; allergic skin inflammation; atopic dermatitis; early postnatal life; group 2 innate lymphoid cells; priming; skin microbiota; tryptophan metabolites

DOI:  https://doi.org/10.1016/j.chom.2023.12.006
Int J Mol Sci. 2023 Dec 25. pii: 315. [Epub ahead of print]25(1):

Glycolysis Reprogramming in Idiopathic Pulmonary Fibrosis: Unveiling the Mystery of Lactate in the Lung.

Peishuo Yan, Jingyi Liu, Zhenwei Li, Jiawei Wang, Zhao Zhu, Lan Wang, Guoying Yu.

  Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease characterized by excessive deposition of fibrotic connective tissue in the lungs. Emerging evidence suggests that metabolic alterations, particularly glycolysis reprogramming, play a crucial role in the pathogenesis of IPF. Lactate, once considered a metabolic waste product, is now recognized as a signaling molecule involved in various cellular processes. In the context of IPF, lactate has been shown to promote fibroblast activation, myofibroblast differentiation, and extracellular matrix remodeling. Furthermore, lactate can modulate immune responses and contribute to the pro-inflammatory microenvironment observed in IPF. In addition, lactate has been implicated in the crosstalk between different cell types involved in IPF; it can influence cell-cell communication, cytokine production, and the activation of profibrotic signaling pathways. This review aims to summarize the current research progress on the role of glycolytic reprogramming and lactate in IPF and its potential implications to clarify the role of lactate in IPF and to provide a reference and direction for future research. In conclusion, elucidating the intricate interplay between lactate metabolism and fibrotic processes may lead to the development of innovative therapeutic strategies for IPF.

Keywords:  IPF; glycolysis reprogramming; lactate; metabolism; pathogenesis

DOI:  https://doi.org/10.3390/ijms25010315
Immunity. 2024 Jan 09. pii: S1074-7613(23)00540-X. [Epub ahead of print]57(1): 14-27

Nutritional regulation of microbiota-derived metabolites: Implications for immunity and inflammation.

Mohammad Arifuzzaman, Nicholas Collins, Chun-Jun Guo, David Artis.

Nutrition profoundly shapes immunity and inflammation across the lifespan of mammals, from pre- and post-natal periods to later life. Emerging insights into diet-microbiota interactions indicate that nutrition has a dominant influence on the composition-and metabolic output-of the intestinal microbiota, which in turn has major consequences for host immunity and inflammation. Here, we discuss recent findings that support the concept that dietary effects on microbiota-derived metabolites potently alter immune responses in health and disease. We discuss how specific dietary components and metabolites can be either pro-inflammatory or anti-inflammatory in a context- and tissue-dependent manner during infection, chronic inflammation, and cancer. Together, these studies emphasize the influence of diet-microbiota crosstalk on immune regulation that will have a significant impact on precision nutrition approaches and therapeutic interventions for managing inflammation, infection, and cancer immunotherapy.

DOI: https://doi.org/10.1016/j.immuni.2023.12.009
Immunol Invest. 2024 Jan 11. 1-21

Advances in Metabolic Regulation of Macrophage Polarization State.

Xin Liu, Ruoxuan Xiang, Xue Fang, Guodong Wang, Yuyan Zhou.

  Macrophages are significant immune-related cells that are essential for tissue growth, homeostasis maintenance, pathogen resistance, and damage healing. The studies on the metabolic control of macrophage polarization state in recent years and the influence of polarization status on the development and incidence of associated disorders are expounded upon in this article. Firstly, we reviewed the origin and classification of macrophages, with particular attention paid to how the tricarboxylic acid cycle and the three primary metabolites affect macrophage polarization. The primary metabolic hub that controls macrophage polarization is the tricarboxylic acid cycle. Finally, we reviewed the polarization state of macrophages influences the onset and progression of cancers, inflammatory disorders, and other illnesses.

Keywords:  Inflammatory response; macrophage polarization; metabolism; tricarboxylic acid cycle

DOI:  https://doi.org/10.1080/08820139.2024.2302828
Cell Rep. 2024 Jan 10. pii: S2211-1247(23)01599-1. [Epub ahead of print]43(1): 113587

The mitochondrial genome-encoded peptide MOTS-c interacts with Bcl-2 to alleviate nonalcoholic steatohepatitis progression.

Huanyu Lu, Linni Fan, Wenli Zhang, Guo Chen, An Xiang, Li Wang, Zifan Lu, Yue Zhai.

  Nonalcoholic steatohepatitis (NASH) is a metabolism-associated fatty liver disease with accumulated mitochondrial stress, and targeting mitochondrial function is a potential therapy. The mitochondrial genome-encoded bioactive peptide MOTS-c plays broad physiological roles, but its effectiveness and direct targets in NASH treatment are still unclear. Here, we show that long-term preventive and short-term therapeutic effects of MOTS-c treatments alleviate NASH-diet-induced liver steatosis, cellular apoptosis, inflammation, and fibrosis. Mitochondrial oxidative capacity and metabolites profiling analysis show that MOTS-c significantly reverses NASH-induced mitochondrial metabolic deficiency. Moreover, we identify that MOTS-c directly interacts with the BH3 domain of antiapoptotic B cell lymphoma-2 (Bcl-2), increases Bcl-2 protein stability, and suppresses Bcl-2 ubiquitination. By using a Bcl-2 inhibitor or adeno-associated virus (AAV)-mediated Bcl-2 knockdown, we further confirm that MOTS-c improves NASH-induced mitochondrial dysfunction, inflammation, and fibrosis, which are dependent on Bcl-2 function. Therefore, our findings show that MOTS-c is a potential therapeutic agent to inhibit the progression of NASH.

Keywords:  Bcl-2; CP: Metabolism; CP: Molecular biology; MOTS-c; apoptosis; mitochondrial dysfunction; nonalcoholic steatohepatitis

DOI:  https://doi.org/10.1016/j.celrep.2023.113587
Brain Behav Immun. 2024 Jan 10. pii: S0889-1591(24)00006-0. [Epub ahead of print]

Multi-omics analysis reveals GAPDH posttranscriptional regulation of IFN-γ and PHGDH as a metabolic checkpoint of microglia polarization.

Shangchen Yang, Ziqi Yuan, Zhu Yufei, Liang Chensi, Chen Zhenlei, Jie Zhang, Lige Leng.

  A "switch" in the metabolic pattern of microglia is considered to be required to meet the metabolic demands of cell survival and functions. However, how metabolic switches regulate microglial function remains controversial. We found here that exposure to amyloid-β triggers microglial inflammation accompanied by increasing GAPDH levels. The increase of GAPDH, a glycolysis enzyme, leads to the reduced release of interferon-γ (IFN-γ) from inflammatory microglia. Such alternation is translational and is regulated by the binding of glycolysis enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to IFN-γ mRNA. GAPDH, by engaging/disengaging glycolysis and through influencing IFN-γ expression, regulates microglia functions, including phagocytosis and cytokine production. Phosphoglycerate dehydrogenase (PHGDH), screened from different state microglia by metabolomics combined with METARECON analysis, is a metabolic enzyme adjacent downstream of GAPDH and synthesizes serine on the collateral pathway derived from glycolysis. Polarization of microglial with PHGDH as a metabolic checkpoint can be bidirectionally regulated by adding IL-4 or giving PHGDH inhibitors. Therefore, regulation of metabolic enzymes not only reprograms metabolic patterns, but also manipulates microglia functions. Further study should be performed to explore the mechanism of metabolic checkpoints in human microglia or more in vivo animal experiments, and may expand to the effects of various metabolic substrates or enzyme, such as lipids and amino acids, on the functions of microglia.

Keywords:  GAPDH; IFN-γ; Metabolic checkpoint; Microglia; PHGDH; Polarization

DOI:  https://doi.org/10.1016/j.bbi.2024.01.009
Infect Immun. 2024 Jan 11. e0024823

Aerobic glycolysis of bronchial epithelial cells rewires Mycoplasma pneumoniae pneumonia and promotes bacterial elimination.

Jun He, Feichen Xiu, Yiwen Chen, Yan Yang, Hongwei Liu, Yixuan Xi, Lu Liu, Xinru Li, Yueyue Wu, Haodang Luo, Liesong Chen, Nan Ding, Jun Hu, En Chen, Xiaoxing You.

  The immune response to Mycoplasma pneumoniae infection plays a key role in clinical symptoms. Previous investigations focused on the pro-inflammatory effects of leukocytes and the pivotal role of epithelial cell metabolic status in finely modulating the inflammatory response have been neglected. Herein, we examined how glycolysis in airway epithelial cells is affected by M. pneumoniae infection in an in vitro model. Additionally, we investigated the contribution of ATP to pulmonary inflammation. Metabolic analysis revealed a marked metabolic shift in bronchial epithelial cells during M. pneumoniae infection, characterized by increased glucose uptake, enhanced aerobic glycolysis, and augmented ATP synthesis. Notably, these metabolic alterations are orchestrated by adaptor proteins, MyD88 and TRAM. The resulting synthesized ATP is released into the extracellular milieu via vesicular exocytosis and pannexin protein channels, leading to a substantial increase in extracellular ATP levels. The conditioned medium supernatant from M. pneumoniae-infected epithelial cells enhances the secretion of both interleukin (IL)-1β and IL-18 by peripheral blood mononuclear cells, partially mediated by the P2X7 purine receptor (P2X7R). In vivo experiments confirm that addition of a conditioned medium exacerbates pulmonary inflammation, which can be attenuated by pre-treatment with a P2X7R inhibitor. Collectively, these findings highlight the significance of airway epithelial aerobic glycolysis in enhancing the pulmonary inflammatory response and aiding pathogen clearance.

Keywords:  Mycoplasma pneumoniae; aerobic glycolysis; bronchial epithelial cells; extracellular ATP; peripheral blood mononuclear cells; purine receptor

DOI:  https://doi.org/10.1128/iai.00248-23
Int J Mol Sci. 2023 Dec 19. pii: 29. [Epub ahead of print]25(1):

Chronic Stress Blocks the Endometriosis Immune Response by Metabolic Reprogramming.

Chong Lu, Jing Xu, Ke Li, Jing Wang, Yilin Dai, Yiqing Chen, Ranran Chai, Congjian Xu, Yu Kang.

  Studies have shown that the occurrence and development of endometriosis are closely linked to long-term psychological stress. The specific contribution of chronic stress to the metabolic adaptations in patients with endometriosis is still unknown. Lesions were removed from ten endometriosis patients during an operation, and the participants were divided into two groups using a psychological questionnaire. An mRNA Human Gene Expression Microarray analysis was applied to compare the mRNA expression profiles between the chronic stress group and the control group. In addition, the reliability of the mRNA Human Gene Expression Microarray analysis was verified by using research on metabolites based on both the liquid chromatography (LC-MS/MS) technique and quantitative reverse transcription polymerase chain reaction (RT-PCR). A microarray analysis of significantly up-regulated, differentially expressed genes between the chronic stress and the control groups showed genes that were principally related to metabolism-related processes and immune-related processes, such as the immune response process, negative regulation of T cell proliferation, the leucine metabolic process, and the L-cysteine metabolic process (p < 0.05). LC-MS showed that the differential metabolites were primarily concerned with arginine and proline metabolism, D-glutamine and D-glutamate metabolism, aspartate metabolism, glycine, serine metabolism, and tyrosine metabolism (p < 0.05). The possibility of chronic stress blocks the endometriosis immune response through metabolic reprogramming. Chronic stress reduces the supply of energy substrates such as arginine and serine, down-regulates T immune cell activation, and affects the anti-tumor immune response, thereby promoting the migration and invasion of endometriosis lesions in patients with chronic stress.

Keywords:  chronic stress; endometriosis; immune response; metabolic reprogramming

DOI:  https://doi.org/10.3390/ijms25010029
Nat Metab. 2024 Jan 10.

The serine synthesis pathway drives osteoclast differentiation through epigenetic regulation of NFATc1 expression.

Steve Stegen, Karen Moermans, Ingrid Stockmans, Bernard Thienpont, Geert Carmeliet.

Bone-resorbing osteoclasts are vital for postnatal bone health, as increased differentiation or activity results in skeletal pathologies such as osteoporosis. The metabolism of mature osteoclasts differs from their progenitor cells, but whether the observed metabolic changes are secondary to the altered cell state or actively drive the process of cell differentiation is unknown. Here, we show that transient activation of the serine synthesis pathway (SSP) is essential for osteoclastogenesis, as deletion of the rate-limiting enzyme phosphoglycerate dehydrogenase in osteoclast progenitors impairs their differentiation and results in increased bone mass. In addition, pharmacological phosphoglycerate dehydrogenase inhibition abrogated bone loss in a mouse model of postmenopausal osteoporosis by blocking bone resorption. Mechanistically, SSP-derived α-ketoglutarate is necessary for histone demethylases that remove repressive histone methylation marks at the nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1) gene locus, thereby inducing NFATc1 expression and consequent osteoclast maturation. Taken together, this study reveals a metabolic-epigenetic coupling mechanism that directs osteoclast differentiation and suggests that the SSP can be therapeutically targeted to prevent osteoporotic bone loss.

DOI: https://doi.org/10.1038/s42255-023-00948-y
Cells. 2023 Dec 21. pii: 23. [Epub ahead of print]13(1):

NLRX1 Prevents M2 Macrophage Polarization and Excessive Renal Fibrosis in Chronic Obstructive Nephropathy.

Ye Liu, Lotte Kors, Loes M Butter, Geurt Stokman, Nike Claessen, Coert J Zuurbier, Stephen E Girardin, Jaklien C Leemans, Sandrine Florquin, Alessandra Tammaro.

   BACKGROUND: Chronic kidney disease often leads to kidney dysfunction due to renal fibrosis, regardless of the initial cause of kidney damage. Macrophages are crucial players in the progression of renal fibrosis as they stimulate inflammation, activate fibroblasts, and contribute to extracellular matrix deposition, influenced by their metabolic state. Nucleotide-binding domain and LRR-containing protein X (NLRX1) is an innate immune receptor independent of inflammasomes and is found in mitochondria, and it plays a role in immune responses and cell metabolism. The specific impact of NLRX1 on macrophages and its involvement in renal fibrosis is not fully understood.
METHODS: To explore the specific role of NLRX1 in macrophages, bone-marrow-derived macrophages (BMDMs) extracted from wild-type (WT) and NLRX1 knockout (KO) mice were stimulated with pro-inflammatory and pro-fibrotic factors to induce M1 and M2 polarization in vitro. The expression levels of macrophage polarization markers (Nos2, Mgl1, Arg1, and Mrc1), as well as the secretion of transforming growth factor β (TGFβ), were measured using RT-PCR and ELISA. Seahorse-based bioenergetics analysis was used to assess mitochondrial respiration in naïve and polarized BMDMs obtained from WT and NLRX1 KO mice. In vivo, WT and NLRX1 KO mice were subjected to unilateral ureter obstruction (UUO) surgery to induce renal fibrosis. Kidney injury, macrophage phenotypic profile, and fibrosis markers were assessed using RT-PCR. Histological staining (PASD and Sirius red) was used to quantify kidney injury and fibrosis.
RESULTS: Compared to the WT group, an increased gene expression of M2 markers-including Mgl1 and Mrc1-and enhanced TGFβ secretion were found in naïve BMDMs extracted from NLRX1 KO mice, indicating functional polarization towards the pro-fibrotic M2 subtype. NLRX1 KO naïve macrophages also showed a significantly enhanced oxygen consumption rate compared to WT cells and increased basal respiration and maximal respiration capacities that equal the level of M2-polarized macrophages. In vivo, we found that NLRX1 KO mice presented enhanced M2 polarization markers together with enhanced tubular injury and fibrosis demonstrated by augmented TGFβ levels, fibronectin, and collagen accumulation.
CONCLUSIONS: Our findings highlight the unique role of NLRX1 in regulating the metabolism and function of macrophages, ultimately protecting against excessive renal injury and fibrosis in UUO.

Keywords:  NLRX1; OXPHOS; macrophage polarization; renal fibrosis

DOI:  https://doi.org/10.3390/cells13010023
Nat Commun. 2024 Jan 09. 15(1): 393

N-linked Fc glycosylation is not required for IgG-B-cell receptor function in a GC-derived B-cell line.

Theresa Kissel, Veerle F A M Derksen, Arthur E H Bentlage, Carolien Koeleman, Lise Hafkenscheid, Diane van der Woude, Manfred Wuhrer, Gestur Vidarsson, René E M Toes.

IgG secreted by B cells carry asparagine N(297)-linked glycans in the fragment crystallizable (Fc) region. Changes in Fc glycosylation are related to health or disease and are functionally relevant, as IgG without Fc glycans cannot bind to Fcɣ receptors or complement factors. However, it is currently unknown whether ɣ-heavy chain (ɣHC) glycans also influence the function of membrane-bound IgG-B-cell receptors (BCR) and thus the outcome of the B-cell immune response. Here, we show in a germinal center (GC)-derived human B-cell line that ɣHC glycans do not affect membrane expression of IgG-BCRs. Furthermore, antigen binding or other BCR-facilitated mechanisms appear unaffected, including BCR downmodulation or BCR-mediated signaling. As expected, secreted IgG lacking Fc glycosylation is unable to carry out effector functions. Together, these observations indicate that IgG-Fc glycosylation serves as a mechanism to control the effector functions of antibodies, but does not regulate the activation of IgG-switched B cells, as its absence had no apparent impact on BCR function.

DOI: https://doi.org/10.1038/s41467-023-44468-5