bims-imicid 2024-10-27 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–10–27
23 papers selected by
Dylan Ryan, University of Cambridge

CENCAT enables immunometabolic profiling by measuring protein synthesis via bioorthogonal noncanonical amino acid tagging.
Increased cholesterol synthesis drives neurotoxicity in patient stem cell-derived model of multiple sclerosis.
Transgelin 2 guards T cell lipid metabolism and antitumour function.
Hypoxia sensing in resident cardiac macrophages regulates monocyte fate specification following ischemic heart injury.
Airway macrophage glycolysis controls lung homeostasis and responses to aeroallergen.
Metabolic Dysregulation and Metabolite Imbalances in Acute-on-chronic Liver Failure: Impact on Immune Status.
Kynurenine-AhR reduces T-cell infiltration and induces a delayed T-cell immune response by suppressing the STAT1-CXCL9/CXCL10 axis in tuberculosis.
Sphingosine-1-Phosphate Signalling Inhibition Suppresses Th1-Like Treg Generation by Reversing Mitochondrial Uncoupling.
Butyrate Inhibits the HDAC8/NF-κB Pathway to Enhance Slc26a3 Expression and Improve the Intestinal Epithelial Barrier to Relieve Colitis.
Metabolomic analysis reveals potential role of immunometabolism dysregulation in recurrent pregnancy loss.
Hexokinase 2 expression in apical enterocytes correlates with inflammation severity in patients with inflammatory bowel disease.
Mitochondrial Quality Control Orchestrates the Symphony of B Cells and Plays Critical Roles in B Cell-Related Diseases.
A newly identified protective role of C5aR1 in kidney tubules against toxin-induced acute kidney injury.
A two-front nutrient supply environment fuels small intestinal physiology through differential regulation of nutrient absorption and host defense.
Microbiota-derived short chain fatty acids in pediatric health and diseases: from gut development to neuroprotection.
From fat storage to immune hubs: the emerging role of adipocytes in coordinating the immune response to infection.
ADA2 is a lysosomal deoxyadenosine deaminase acting on DNA involved in regulating TLR9-mediated immune sensing of DNA.
FABP5+ macrophages contribute to lipid metabolism dysregulation in type A aortic dissection.
Differential Regulation of L-Arginine Metabolism through NOS2 and Arginases during Infection with Trypanosoma cruzi.
CD36-mediated arachidonic acid influx from decidual stromal cells increases inflammatory macrophages in miscarriage.
Overnutrition causes insulin resistance and metabolic disorder through increased sympathetic nervous system activity.
CD56 does not contribute to the anti-tumor, tissue homing, and glycolytic capacity of human NK cells.
Calorie restriction modulates mitochondrial dynamics and autophagy in leukocytes of patients with obesity.

Cell Rep Methods. 2024 Oct 21. pii: S2667-2375(24)00266-2. [Epub ahead of print]4(10): 100883

CENCAT enables immunometabolic profiling by measuring protein synthesis via bioorthogonal noncanonical amino acid tagging.

Frank Vrieling, Hendrik J P van der Zande, Britta Naus, Lisa Smeehuijzen, Julia I P van Heck, Bob J Ignacio, Kimberly M Bonger, Jan Van den Bossche, Sander Kersten, Rinke Stienstra.

  Cellular energy metabolism significantly contributes to immune cell function. To further advance immunometabolic research, novel methods to study the metabolism of immune cells in complex samples are required. Here, we introduce CENCAT (cellular energetics through noncanonical amino acid tagging). This technique utilizes click labeling of alkyne-bearing noncanonical amino acids to measure protein synthesis inhibition as a proxy for metabolic activity. CENCAT successfully reproduced known metabolic signatures of lipopolysaccharide (LPS)/interferon (IFN)γ and interleukin (IL)-4 activation in human primary macrophages. Application of CENCAT in peripheral blood mononuclear cells revealed diverse metabolic rewiring upon stimulation with different activators. Finally, CENCAT was used to analyze the cellular metabolism of murine tissue-resident immune cells from various organs. Tissue-specific clustering was observed based on metabolic profiles, likely driven by microenvironmental priming. In conclusion, CENCAT offers valuable insights into immune cell metabolic responses, presenting a powerful platform for studying cellular metabolism in complex samples and tissues in both humans and mice.

Keywords:  CP: Immunology; CP: Metabolism; OXPHOS; SCENITH; energy metabolism; glycolysis; immunometabolism

DOI:  https://doi.org/10.1016/j.crmeth.2024.100883
Cell Stem Cell. 2024 Oct 14. pii: S1934-5909(24)00328-X. [Epub ahead of print]

Increased cholesterol synthesis drives neurotoxicity in patient stem cell-derived model of multiple sclerosis.

Rosana-Bristena Ionescu, Alexandra M Nicaise, Julie A Reisz, Eleanor C Williams, Pranathi Prasad, Cory M Willis, Madalena B C Simões-Abade, Linda Sbarro, Monika Dzieciatkowska, Daniel Stephenson, Marta Suarez Cubero, Sandra Rizzi, Liviu Pirvan, Luca Peruzzotti-Jametti, Valentina Fossati, Frank Edenhofer, Tommaso Leonardi, Christian Frezza, Irina Mohorianu, Angelo D'Alessandro, Stefano Pluchino.

  Senescent neural progenitor cells have been identified in brain lesions of people with progressive multiple sclerosis (PMS). However, their role in disease pathobiology and contribution to the lesion environment remains unclear. By establishing directly induced neural stem/progenitor cell (iNSC) lines from PMS patient fibroblasts, we studied their senescent phenotype in vitro. Senescence was strongly associated with inflammatory signaling, hypermetabolism, and the senescence-associated secretory phenotype (SASP). PMS-derived iNSCs displayed increased glucose-dependent fatty acid and cholesterol synthesis, which resulted in the accumulation of lipid droplets. A 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase (HMGCR)-mediated lipogenic state was found to induce a SASP in PMS iNSCs via cholesterol-dependent transcription factors. SASP from PMS iNSC lines induced neurotoxicity in mature neurons, and treatment with the HMGCR inhibitor simvastatin altered the PMS iNSC SASP, promoting cytoprotective qualities and reducing neurotoxicity. Our findings suggest a disease-associated, cholesterol-related, hypermetabolic phenotype of PMS iNSCs that leads to neurotoxic signaling and is rescuable pharmacologically.

Keywords:  cellular senescence; cholesterol metabolism; disease modeling; lipid droplets; multi-omics; multiple sclerosis; neural stem cells; neuroimmunology; neurotoxicity; senescence-associated secretory phenotype

DOI:  https://doi.org/10.1016/j.stem.2024.09.014
Nature. 2024 Oct 23.

Transgelin 2 guards T cell lipid metabolism and antitumour function.

Sung-Min Hwang, Deepika Awasthi, Jieun Jeong, Tito A Sandoval, Chang-Suk Chae, Yusibeska Ramos, Chen Tan, Matías Marin Falco, Camilla Salvagno, Alexander Emmanuelli, Ian T McBain, Bikash Mishra, Lionel B Ivashkiv, Dmitriy Zamarin, Evelyn Cantillo, Eloise Chapman-Davis, Kevin Holcomb, Diana K Morales, Xiaoqing Yu, Paulo C Rodriguez, Jose R Conejo-Garcia, Martin Kaczocha, Anna Vähärautio, Minkyung Song, Juan R Cubillos-Ruiz.

Mounting effective immunity against pathogens and tumours relies on the successful metabolic programming of T cells by extracellular fatty acids1-3. Fatty-acid-binding protein 5 (FABP5) has a key role in this process by coordinating the efficient import and trafficking of lipids that fuel mitochondrial respiration to sustain the bioenergetic requirements of protective CD8+ T cells4,5. However, the mechanisms that govern this immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer transgelin 2 (TAGLN2) is necessary for optimal fatty acid uptake, mitochondrial respiration and anticancer function in CD8+ T cells. TAGLN2 interacts with FABP5 to facilitate its cell surface localization and function in activated CD8+ T cells. Analyses of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses induced by the tumour microenvironment repress TAGLN2 in infiltrating CD8+ T cells, thereby enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8+ T cells increased their lipid uptake, mitochondrial respiration and cytotoxic capacity. Accordingly, chimeric antigen receptor T cells overexpressing TAGLN2 bypassed the detrimental effects of tumour-induced ER stress and demonstrated therapeutic efficacy in mice with metastatic ovarian cancer. Our study establishes the role of cytoskeletal TAGLN2 in T cell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2-FABP5 axis.

DOI: https://doi.org/10.1038/s41586-024-08071-y
Nat Cardiovasc Res. 2024 Oct 21.

Hypoxia sensing in resident cardiac macrophages regulates monocyte fate specification following ischemic heart injury.

Farid F Kadyrov, Andrew L Koenig, Junedh M Amrute, Hao Dun, Wenjun Li, Carla J Weinheimer, Jessica M Nigro, Attila Kovacs, Andrea L Bredemeyer, Steven Yang, Shibali Das, Vinay R Penna, Alekhya Parvathaneni, Lulu Lai, Niklas Hartmann, Benjamin J Kopecky, Daniel Kreisel, Kory J Lavine.

Myocardial infarction initiates cardiac remodeling and is central to heart failure pathogenesis. Following myocardial ischemia-reperfusion injury, monocytes enter the heart and differentiate into diverse subpopulations of macrophages. Here we show that deletion of Hif1α, a hypoxia response transcription factor, in resident cardiac macrophages led to increased remodeling and overrepresentation of macrophages expressing arginase 1 (Arg1). Arg1+ macrophages displayed an inflammatory gene signature and may represent an intermediate state of monocyte differentiation. Lineage tracing of Arg1+ macrophages revealed a monocyte differentiation trajectory consisting of multiple transcriptionally distinct states. We further showed that deletion of Hif1α in resident cardiac macrophages resulted in arrested progression through this trajectory and accumulation of an inflammatory intermediate state marked by persistent Arg1 expression. Depletion of the Arg1+ trajectory accelerated cardiac remodeling following ischemic injury. Our findings unveil distinct trajectories of monocyte differentiation and identify hypoxia sensing as an important determinant of monocyte differentiation following myocardial infarction.

DOI: https://doi.org/10.1038/s44161-024-00553-6
Mucosal Immunol. 2024 Oct 18. pii: S1933-0219(24)00105-3. [Epub ahead of print]

Airway macrophage glycolysis controls lung homeostasis and responses to aeroallergen.

Gesa J Albers, Christina Michalaki, Patricia P Ogger, Amy F Lloyd, Benjamin Causton, Simone A Walker, Anna Caldwell, John M Halket, Linda V Sinclair, Sarah H Forde, Cormac McCarthy, Timothy S C Hinks, Clare M Lloyd, Adam J Byrne.

The lungs represent a dynamic microenvironment where airway macrophages (AMs) are the major lung-resident macrophages. AMs dictate the balance between tissue homeostasis and immune activation and thus have contradictory functions by maintaining tolerance and tissue homeostasis, as well as initiating strong inflammatory responses. Emerging evidence has highlighted the connection between macrophage function and cellular metabolism. However, the functional importance of these processes in tissue-resident specialized macrophage populations such as those found in the airways, remain poorly elucidated. Here, we reveal that glycolysis is a fundamental pathway in AMs which regulates both lung homeostasis and responses to inhaled allergen. Using macrophage specific targeting in vivo, and multi-omics approaches, we determined that glycolytic activity in AMs is necessary to restrain type 2 (T2) immunity during homeostasis. Exposure to a range of common aeroallergens, including house dust mite (HDM), drove AM-glycolysis and furthermore, AM-specific inhibition of glycolysis altered inflammation in the airways and HDM-driven airway metabolic adaptations in vivo. Additionally, allergen sensitised asthmatics had profound metabolic changes in the airways, compared to non-sensitised asthmatic controls. Finally, we found that allergen driven AM-glycolysis in mice was TLR2 dependent. Thus, our findings demonstrate a direct relationship between glycolysis in AMs, AM-mediated homeostatic processes, and T2 immune responses in the lungs. These data suggest that glycolysis is essential for the plasticity of AMs. Depending on the immunological context, AM-glycolysis is required to exert homeostatic activity but once activated by allergen, AM-glycolysis influences inflammatory responses. Thus, precise modulation of glycolytic activity in AMs is essential for preserving lung homeostasis and regulating airway inflammation.

DOI: https://doi.org/10.1016/j.mucimm.2024.10.002
J Clin Transl Hepatol. 2024 Oct 28. 12(10): 865-877

Metabolic Dysregulation and Metabolite Imbalances in Acute-on-chronic Liver Failure: Impact on Immune Status.

Danmei Zhang, Chunxia Shi, Yukun Wang, Jin Guo, Zuojiong Gong.

  Liver failure encompasses a range of severe clinical syndromes resulting from the deterioration of liver function, triggered by factors both within and outside the liver. While the definition of acute-on-chronic liver failure (ACLF) may vary by region, it is universally recognized for its association with multiorgan failure, a robust inflammatory response, and high short-term mortality rates. Recent advances in metabolomics have provided insights into energy metabolism and metabolite alterations specific to ACLF. Additionally, immunometabolism is increasingly acknowledged as a pivotal mechanism in regulating immune cell functions. Therefore, understanding the energy metabolism pathways involved in ACLF and investigating how metabolite imbalances affect immune cell functionality are crucial for developing effective treatment strategies for ACLF. This review methodically examined the immune and metabolic states of ACLF patients and elucidated how alterations in metabolites impact immune functions, offering novel perspectives for immune regulation and therapeutic management of liver failure.

Keywords:  Acute-on-chronic liver failure; Immunometabolism; Metabolic reprogramming; Metabolism; Metabolomics; Microenvironment

DOI:  https://doi.org/10.14218/JCTH.2024.00203
Cell Mol Immunol. 2024 Oct 22.

Kynurenine-AhR reduces T-cell infiltration and induces a delayed T-cell immune response by suppressing the STAT1-CXCL9/CXCL10 axis in tuberculosis.

Xin Liu, Mengjie Yang, Ping Xu, Mingwei Du, Shanshan Li, Jin Shi, Qiang Li, Jinfeng Yuan, Yu Pang.

  Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a critical global health issue that is complicated by the ability of the pathogen to delay the host's T-cell immune response. This delay in T-cell recruitment to the site of infection is a pivotal survival strategy for Mtb, allowing it to establish a persistent chronic infection. To investigate the underlying mechanisms, this study focused on Mtb's exploitation of host tryptophan metabolism. Mtb upregulates indoleamine 2,3-dioxygenase 1 (IDO1) in inflammatory macrophages, thereby increasing kynurenine (Kyn) production. Kyn then activates the aryl hydrocarbon receptor (AhR), leading to the upregulation of suppressor of cytokine signaling 3 and subsequent inhibition of the JAK-STAT1 signaling pathway. This results in reduced secretion of the chemokines CXCL9 and CXCL10, which are crucial for T-cell recruitment to the lungs. Supported by in vivo mouse models, our findings reveal that disrupting this pathway through AhR knockout significantly enhances T-cell infiltration and activity, thereby undermining Mtb-induced immunosuppression. In contrast, additional Kyn injection obviously inhibited T-cell infiltration and activity. These results highlight potential therapeutic targets of AhR and IDO1, offering new avenues for enhancing the host immune response against tuberculosis and guiding future vaccine development efforts.

Keywords:   Mycobacterium tuberculosis ; Chemokines; IDO1; Immunosuppression; Tryptophan metabolism

DOI:  https://doi.org/10.1038/s41423-024-01230-1
Immunology. 2024 Oct 24.

Sphingosine-1-Phosphate Signalling Inhibition Suppresses Th1-Like Treg Generation by Reversing Mitochondrial Uncoupling.

Rachel Coulombeau, Claudia Selck, Nicolas Giang, Abdulrahman Al-Mohammad, Natalie Ng, Allison K Maher, Rafael Argüello, Antonio Scalfari, James Varley, Richard Nicholas, Margarita Dominguez-Villar.

  Inflammatory environments induce the generation of dysfunctional IFNγ+T-bet+FOXP3+ Th1-like Tregs, which show defective function and are found in autoimmune conditions including multiple sclerosis (MS). The pathways that control the generation of Th1-like Tregs are not well understood. Sphingosine-1-phosphate (S1P) signalling molecules are upregulated in Th1-like Tregs, and in vivo S1P inhibition with Fingolimod (FTY720) inhibits the expression of genes responsible for Treg plasticity in MS patients. However, the underlying mechanisms are unknown. Here we show that S1P signalling inhibition by FTY720 inhibits the generation of Th1-like Tregs and rescues their suppressive function. These effects are mediated by a decrease in mTORC1 signalling and reversal of the mitochondrial uncoupling that Tregs undergo during their reprogramming into Th1-like Tregs in vitro. Finally, these results are validated in in vivo-generated Th1-like Tregs, as Tregs from MS patients treated with FTY720 display decreased Th1-like Treg frequency, increased suppressive function and mitochondrial metabolism rebalance. These results highlight the involvement of mitochondrial uncoupling in Treg reprogramming and identify S1P signalling inhibition as a target to suppress the generation of dysfunctional Th1-like Tregs.

Keywords:  EAE/MS; Treg; autoimmunity

DOI:  https://doi.org/10.1111/imm.13870
J Agric Food Chem. 2024 Oct 23.

Butyrate Inhibits the HDAC8/NF-κB Pathway to Enhance Slc26a3 Expression and Improve the Intestinal Epithelial Barrier to Relieve Colitis.

Kaixin Peng, Siqi Xiao, Suhong Xia, Congxin Li, Hongbing Yu, Qin Yu.

  Dietary fiber is known to promote the production of short-chain fatty acids (SCFAs) by gut bacteria, which can enhance intestinal epithelial barrier function and ameliorate intestinal inflammation in patients with inflammatory bowel disease (IBD). Interestingly, some IBD patients show reduced expression of solute carrier family member 3 (Slc26a3) in intestinal epithelial cells. The objective of this research was to investigate the interaction between SCFAs and Slc26a3 during colitis and assess how this interaction affects intestinal epithelial barrier function. We showed that butyrate alleviated colonic inflammation in a dose-dependent manner in a dextran sulfate sodium salt (DSS)-induced colitis model. Consistent with this, butyrate increased Slc26a3 and tight junction protein levels. In addition, butyrate inhibited histone deacetylase (HDAC) levels and significantly increased the expression of Slc26a3 by the acetylation of histones in Caco-2BBe cells. The utilization of a pan-HDAC inhibitor or inhibitors specific to certain classes of HDACs revealed that butyrate primarily suppressed HDAC8 to blunt the NF-κB pathways and enhance the expression of Slc26a3. Notably, we demonstrated that HDAC8 activation counteracted the beneficial effect of butyrate in DSS-induced colitis. Therefore, we concluded that butyrate improves the expression of Slc26a3 via inhibition of the HDAC8/NF-κB pathway, leading to increased intestinal epithelial barrier function.

Keywords:  DRA; IECs; histone deacetylase; short-chain fatty acids; ulcerative colitis

DOI:  https://doi.org/10.1021/acs.jafc.4c04456
Front Endocrinol (Lausanne). 2024 ;15 1476774

Metabolomic analysis reveals potential role of immunometabolism dysregulation in recurrent pregnancy loss.

Xiaofeng Ye, Chong Ma, Wenqi Guo, Yan Guo, Dong-Dong Li, Sihang Zhou, Qingyu Hu, Yanjun Hong, Zhiyong Xie, Liping Wang.

   Background: Recurrent pregnancy loss (RPL) affects women's reproductive health seriously, with immune dysfunction playing a key role in its cause, yet the exact mechanisms remain elusive. We aim to investigate potential mechanisms and identify biomarkers linked to RPL.
Methods: Immune cytokine testing and metabolomic profiling were conducted on the serum of 34 RPL patients and 30 healthy individuals. The metabolic pathways of the differential metabolites were analyzed, and specific metabolites were validated through targeted profiling. Potential biomarkers were identified, and the relationships between immune cytokines and differential metabolites were explored.
Results: In the RPL group, serum interleukin-6 and interleukin-10 levels were significantly higher, while interleukin-2 and interferon-γ were significantly lower. A total of 296 differential metabolites were detected by untargeted metabolomic profiling between the RPL and control groups, with most linked to amino acid metabolism. Targeted metabolomic profiling of amino acid metabolism revealed upregulation of indole-3-acetic acid, tyrosine, glycine, isoleucine, tryptophan, lysine, aspartic acid, arginine, leucine, threonine, glutamic acid, cystine, and phenylpyruvic acid (PPA) in the RPL group. Moreover, PPA and 5-hydroxy-L-tryptophan showed great potential in predicting RPL in a diagnostic model. Cystine and tyrosine were associated with immune cytokines in correlation analysis.
Conclusion: The study highlights the role of amino acid metabolism in RPL pathogenesis, suggesting that PPA and 5-HTP may be potential predictive indicators, while cystine and tyrosine may potentially regulate immune responses related to RPL. Further investigation into the molecular mechanisms underlying these findings could potentially result in the creation of novel diagnostic and therapeutic approaches for RPL.

Keywords:  amino acid metabolism; biomarkers; immune cytokines; immunometabolism; mechanisms; metabolomics; recurrent pregnancy loss

DOI:  https://doi.org/10.3389/fendo.2024.1476774
BMC Med. 2024 Oct 23. 22(1): 490

Hexokinase 2 expression in apical enterocytes correlates with inflammation severity in patients with inflammatory bowel disease.

Saskia Weber-Stiehl, Jan Taubenheim, Lea Järke, Christoph Röcken, Stefan Schreiber, Konrad Aden, Christoph Kaleta, Philip Rosenstiel, Felix Sommer.

   BACKGROUND: Inflammation is characterized by a metabolic switch promoting glycolysis and lactate production. Hexokinases (HK) catalyze the first reaction of glycolysis and inhibition of epithelial HK2 protected from colitis in mice. HK2 expression has been described as elevated in patients with intestinal inflammation; however, there is conflicting data from few cohorts especially with severely inflamed individuals; thus, systematic studies linking disease activity with HK2 levels are needed.
METHODS: We examined the relationship between HK2 expression and inflammation severity using bulk transcriptome data derived from the mucosa of thoroughly phenotyped inflammatory bowel disease (IBD) patients of two independent cohorts including both subtypes Crohn's disease (CD) and ulcerative colitis (UC). Publicly available single-cell RNA sequencing data were analyzed, and immunofluorescence staining on colonic biopsies of unrelated patients with intestinal inflammation was performed to confirm the RNA-based findings on cellular and protein level.
RESULTS: HK2 expression gradually increased from mild to intermediate inflammation, yet strongly declined at high inflammation scores. Expression of epithelial marker genes also declined at high inflammation scores, whereas that of candidate immune marker genes increased, indicating a cellular remodeling of the mucosa during inflammation with an infiltration of HK2-negative immune cells and a loss of terminal differentiated epithelial cells in the apical epithelium-the main site of HK2 expression. Normalizing for the enterocyte loss clearly identified epithelial HK2 expression as gradually increasing with disease activity and remaining elevated at high inflammation scores. HK2 protein expression was mostly restricted to brush border enterocytes, and these cells along with HK2 levels vanished with increasing disease severity.
CONCLUSIONS: Our findings clearly define dysregulated epithelial HK2 expression as an indicator of disease activity in intestinal inflammation and suggest targeted HK2-inhibition as a potential therapeutic avenue.

Keywords:  HK2; Hexokinase; Human biopsies; Inflammation

DOI:  https://doi.org/10.1186/s12916-024-03710-7
J Immunol Res. 2024 ;2024 5577506

Mitochondrial Quality Control Orchestrates the Symphony of B Cells and Plays Critical Roles in B Cell-Related Diseases.

Wuhao Li, Peiyang Cai, Ye Xu, Weihong Tian, Licong Jing, Qiaoyi Lv, Yangjing Zhao, Hui Wang, Qixiang Shao.

  B cells are essential for humoral immune response due to their ability to secrete antibodies. The development of B cells from the bone marrow to the periphery is tightly regulated by a complex set of immune signals, and each subset of B cells has a unique metabolic profile. Mitochondria, which serve as cellular energy powerhouses, play an essential role in regulating cell survival and immune responses. To maintain metabolic homeostasis, mitochondria dynamically adjust their morphology, distribution, and mass via biogenesis, fusion and fission, translocation, and mitophagy. Despite its extreme importance, the role of mitochondrial quality control (MQC) in B cells has not been thoroughly summarized, unlike in T cells. This article aims to review the mechanism of MQC that shapes B cell fate and functions. In addition, we will discuss the physiological and pathological implications of MQC in B cells, providing new insights into potential therapeutic targets for diseases associated with B cell abnormalities.

Keywords:  B cell; B cell-related diseases; mitochondria; mitochondrial dynamics; mitochondrial quality control

DOI:  https://doi.org/10.1155/2024/5577506
Am J Pathol. 2024 Oct 18. pii: S0002-9440(24)00367-5. [Epub ahead of print]

A newly identified protective role of C5aR1 in kidney tubules against toxin-induced acute kidney injury.

Samuel Mon-Wei Yu, Emily King, Miguel Fribourg, Susan Hartzell, Liam Tsou, Logan Gee, Vivette D D'Agati, Joshua M Thurman, John Cijiang He, Paolo Cravedi.

Acute kidney injury (AKI) remains a major reason for hospitalization with limited therapeutic options. While complement activation is implicated in AKI, the role of C5a receptor 1 (C5aR1) in kidney tubular cells is unclear. We used aristolochic acid nephropathy (AAN) and folic acid nephropathy (FAN) models to establish the role of C5aR1 in kidney tubules during AKI in germline C5ar1-/- mice, myeloid cell-specific, and kidney tubule-specific C5ar1 knockout mice. After aristolochic acid and folic acid injection, C5ar1-/- mice had increased AKI severity and a higher degree of tubular injury. Macrophage depletion in C5ar1-/- mice or myeloid cell-specific C5ar1 deletion did not affect the outcomes of AA-induced AKI. RNA-sequencing data from RTECs showed that C5ar1 deletion was associated with the downregulation of mitochondrial metabolism and ATP production transcriptional pathways. Metabolic studies confirmed reduced mitochondrial membrane potential at baseline and increased mitochondrial oxidative stress after injury in C5ar1-/- RTECs. Moreover, C5ar1-/- RTECs had enhanced glycolysis, glucose uptake, and lactate production upon injury, corroborated by metabolomics analysis of kidneys from AAN mice. Kidney tubule-specific C5ar1 knockout mice recapitulated exacerbated AKI observed in C5ar1-/- mice in AAN and FAN. Our data indicate that C5aR1 signaling in kidney tubules exerts renoprotective effects against toxin-induced AKI by limiting overt glycolysis and maintaining mitochondrial function, revealing a novel link between the complement system and tubular cell metabolism.

DOI: https://doi.org/10.1016/j.ajpath.2024.10.003
Cell. 2024 Oct 19. pii: S0092-8674(24)00903-6. [Epub ahead of print]

A two-front nutrient supply environment fuels small intestinal physiology through differential regulation of nutrient absorption and host defense.

Jian Zhang, Ruonan Tian, Jia Liu, Jie Yuan, Siwen Zhang, Zhexu Chi, Weiwei Yu, Qianzhou Yu, Zhen Wang, Sheng Chen, Mobai Li, Dehang Yang, Tianyi Hu, Qiqi Deng, Xiaoyang Lu, Yidong Yang, Rongbin Zhou, Xue Zhang, Wanlu Liu, Di Wang.

  The small intestine contains a two-front nutrient supply environment created by luminal dietary and microbial metabolites (enteral side) and systemic metabolites from the host (serosal side). Yet, it is unknown how each side contributes differentially to the small intestinal physiology. Here, we generated a comprehensive, high-resolution map of the small intestinal two-front nutrient supply environment. Using in vivo tracing of macronutrients and spatial metabolomics, we visualized the spatiotemporal dynamics and cell-type tropism in nutrient absorption and the region-specific metabolic heterogeneity within the villi. Specifically, glutamine from the enteral side fuels goblet cells to support mucus production, and the serosal side loosens the epithelial barrier by calibrating fungal metabolites. Disorganized feeding patterns, akin to the human lifestyle of skipping breakfast, increase the risk of metabolic diseases by inducing epithelial memory of lipid absorption. This study improves our understanding of how the small intestine is spatiotemporally regulated by its unique nutritional environment.

Keywords:  adaptation; breakfast skipping; in vivo metabolite tracing; metabolic heterogeneity; multi-omics; the small intestine; two-front nutrient supply; zonated function of enterocyte

DOI:  https://doi.org/10.1016/j.cell.2024.08.012
Front Microbiol. 2024 ;15 1456793

Microbiota-derived short chain fatty acids in pediatric health and diseases: from gut development to neuroprotection.

Chou-Yi Hsu, Lusine G Khachatryan, Nada Khairi Younis, Mohammed Ahmed Mustafa, Nabeel Ahmad, Zainab H Athab, Angelina V Polyanskaya, Elena Victorovna Kasanave, Rasoul Mirzaei, Sajad Karampoor.

  The infant gut microbiota undergoes significant changes during early life, which are essential for immune system maturation, nutrient absorption, and metabolic programming. Among the various microbial metabolites, short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, produced through the fermentation of dietary fibers by gut bacteria, have emerged as critical modulators of host-microbiota interactions. SCFAs serve as energy sources for colonic cells and play pivotal roles in regulating immune responses, maintaining gut barrier integrity, and influencing systemic metabolic pathways. Recent research highlights the potential neuroprotective effects of SCFAs in pediatric populations. Disruptions in gut microbiota composition and SCFA production are increasingly associated with a range of pediatric health issues, including obesity, allergic disorders, inflammatory bowel disease (IBD), and neurodevelopmental disorders. This review synthesizes current knowledge on the role of microbiota-derived SCFAs in pediatric health, emphasizing their contributions from gut development to neuroprotection. It also underscores the need for further research to unravel the precise mechanisms by which SCFAs influence pediatric health and to develop targeted interventions that leverage SCFAs for therapeutic benefits.

Keywords:  SCFAs; gut barrier function; inflammatory bowel disease; neuroprotection; probiotics

DOI:  https://doi.org/10.3389/fmicb.2024.1456793
FEBS J. 2024 Oct 20.

From fat storage to immune hubs: the emerging role of adipocytes in coordinating the immune response to infection.

Matthew C Sinton, Shingo Kajimura.

  Adipose tissue is a rich source of diverse cell populations, including immune cells, adipocytes and stromal cells. Interactions between these different cell types are now appreciated to be critical for maintaining tissue structure and function, by governing processes such as adipogenesis, lipolysis and differentiation of white to beige adipocytes. Interactions between these cells also drive inflammation in obesity, leading to an expansion of adipose tissue immune cells, and the secretion of proinflammatory cytokines from immune cells and from adipocytes themselves. However, in evolutionary terms, obesity is a recent phenomenon, raising the question of why adipocytes evolved to express factors that influence the immune response. Studies of various pathogens indicate that adipocytes are highly responsive to infection, altering their metabolic profiles in a way that can be used to release nutrients and fuel the immune response. In the case of infection with the extracellular parasite Trypanosoma brucei, attenuating the ability of adipocytes to sense the cytokine IL-17 results in a loss of control of the local immune response and an increased pathogen load. Intriguingly, comparisons of the adipocyte response to infection suggest that the immune responses of these cells occur in a pathogen-dependent manner, further confirming their complexity. Here, with a focus on murine adipose tissue, we discuss the emerging concept that, in addition to their canonical function, adipocytes are immune signalling hubs that integrate and disseminate signals from the immune system to generate a local environment conducive to pathogen clearance.

Keywords:  adipocytes; adipose tissue immunity; adipose‐immune communication; host–pathogen interactions; immune hubs

DOI:  https://doi.org/10.1111/febs.17302
Cell Rep. 2024 Oct 22. pii: S2211-1247(24)01250-6. [Epub ahead of print]43(11): 114899

ADA2 is a lysosomal deoxyadenosine deaminase acting on DNA involved in regulating TLR9-mediated immune sensing of DNA.

Ole Kristian Greiner-Tollersrud, Máté Krausz, Vincent Boehler, Aikaterini Polyzou, Maximilian Seidl, Ambra Spahiu, Zeinab Abdullah, Katarzyna Andryka-Cegielski, Felix Immunuel Dominick, Katrin Huebscher, Andreas Goschin, Cristian R Smulski, Eirini Trompouki, Regina Link, Hilmar Ebersbach, Honnappa Srinivas, Martine Marchant, Georgios Sogkas, Dieter Staab, Cathrine Vågbø, Danilo Guerini, Sebastian Baasch, Eicke Latz, Gunther Hartmann, Philippe Henneke, Roger Geiger, Xiao P Peng, Bodo Grimbacher, Eva Bartok, Ingrun Alseth, Max Warncke, Michele Proietti.

  Although adenosine deaminase 2 (ADA2) is considered an extracellular ADA, evidence questions the physiological relevance of this activity. Our study reveals that ADA2 localizes within the lysosomes, where it is targeted through modifications of its glycan structures. We show that ADA2 interacts with DNA molecules, altering their sequences by converting deoxyadenosine (dA) to deoxyinosine (dI). We characterize its DNA substrate preferences and provide data suggesting that DNA, rather than free adenosine, is its natural substrate. Finally, we demonstrate that dA-to-dI editing of DNA molecules and ADA2 regulate lysosomal immune sensing of nucleic acids (NAs) by modulating Toll-like receptor 9 (TLR9) activation. Our results describe a mechanism involved in the complex interplay between NA metabolism and immune response, possibly impacting ADA2 deficiency (DADA2) and other diseases involving this pathway, including autoimmune diseases, cancer, or infectious diseases.

Keywords:  ADA2; CP: Immunology; DADA2; DNA editing; TLR9; Toll-like receptors; innate immunity; inosine; nucleic acid immunity; nucleic-acid sensing; type I interferon

DOI:  https://doi.org/10.1016/j.celrep.2024.114899
Int Immunopharmacol. 2024 Oct 23. pii: S1567-5769(24)01960-X. [Epub ahead of print]143(Pt 2): 113438

FABP5+ macrophages contribute to lipid metabolism dysregulation in type A aortic dissection.

Xin Chen, Ruoshi Chen, Yuefeng Wu, Anfeng Yu, Fei Wang, Chenxi Ying, Yifei Yin, Xiaofan Chen, Liang Ma, Yufei Fu.

  Type A aortic dissection (TAAD) is an acute onset disease with a high mortality rate. TAAD is caused by a tear in the aortic intima and subsequent blood infiltration. The most prominent characteristics of TAAD are aortic media degeneration and inflammatory cell infiltration, which disturb the structural integrity and function of nonimmune and immune cells in the aortic wall. However, to date, there is no systematic evaluation of the interactions between nonimmune cells and immune cells and their effects on metabolism in the context of aortic dissection. Here, multiomics, including bulk RNA-seq, single-cell RNA-seq, and lipid metabolomics, was applied to elucidate the comprehensive TAAD lipid metabolism landscape. Normally, monocytes in the stress response state secrete a variety of cytokines. Injured fibroblasts lack the ability to degrade lipids, which is suspected to contribute to a high lipid environment. Macrophages differentiate into fatty acid binding protein 5-positive (FABP5+) macrophages under the stimulation of metabolic substrates. Moreover, the upregulation of Fabp5+ macrophages were retrospectively validated in TAAD model mice and TAAD patients. Finally, Fabp5+ macrophages can generate a wide range of proinflammatory cytokines, which possibly contribute to TAAD pathogenesis.

Keywords:  Aortic dissection; FABP5; Foam cells; Lipid metabolism; Macrophages

DOI:  https://doi.org/10.1016/j.intimp.2024.113438
Pathogens. 2024 Oct 08. pii: 878. [Epub ahead of print]13(10):

Differential Regulation of L-Arginine Metabolism through NOS2 and Arginases during Infection with Trypanosoma cruzi.

Arturo A Wilkins-Rodríguez, Paz María Salazar-Schettino, Rebeca G Manning-Cela, Laila Gutiérrez-Kobeh.

  L-arginine metabolism through arginases and inducible nitric oxide synthase (NOS2) constitutes a fundamental axis for the resolution or progression of Chagas disease. Infection with Trypanosoma cruzi can cause a wide spectrum of disease, ranging from acute forms contained by the host immune response to chronic ones, such as the chronic chagasic cardiomyopathy. Here, we analyzed, in an in vitro model, the ability of two T. cruzi isolates, with different degrees of virulence, to regulate the metabolism of L-arginine through arginase 1 (Arg-1) and NOS2 in macrophages and through arginase 2 (Arg-2) and NOS2 in cardiomyocytes. Stimulation of bone marrow-derived macrophages (BMMΦ), obtained from CD1 mice, with TNF-α + IFN-γ induced their polarization into classically activated macrophages (CAMΦ), which expressed functional NOS2, while stimulation with IL-4 induced their polarization into alternatively activated macrophages (AAMΦ), which expressed functional Arg-1. Interestingly, stimulation of cardiomyocytes, obtained from hearts of CD1 neonatal mice, with TNF-α + IFN-γ or IL-4 also resulted in functional NOS2 and arginase expression, as observed in CAMΦ and AAMΦ, but Arg-2 was the arginase isoform expressed instead of Arg-1. We observed that infection of BMMΦ with the more virulent T. cruzi isolate (QRO) importantly diminished NOS2 expression and nitric oxide (NO) production in CAMΦ, allowing parasite survival, while infection with the less virulent isolate (CI2) did not diminish NOS2 activity and NO production in CAMΦ to a great extent, which resulted in parasite killing. Regarding Arg-1, infection of BMMΦ with the QRO isolate significantly induced Arg-1 expression and activity in AAMΦ, which resulted in a higher parasite load than the one in the unstimulated BMMΦ. Even though infection with CI2 isolate did not increase Arg-1 expression and activity in AAMΦ, the parasite load was higher than the one in the unstimulated BMMΦ but at a lesser magnitude than that observed during infection with the QRO isolate. On the other hand, infection of cardiomyocytes with either QRO or CI2 isolates and further stimulation with TNF-α + IFN-γ inhibited NOS2 expression and NO production, leading to amelioration of infection. Surprisingly, infection of cardiomyocytes with either QRO or CI2 isolates and further stimulation with IL-4 strongly inhibited Arg-2 expression and function, which resulted in parasite loads similar to those observed in unstimulated cardiomyocytes. Our results suggest that T. cruzi isolates that exhibit variable virulence or pathogenicity degrees differentially regulate L-arginine metabolism through Arg-1/2 and NOS2 in macrophages and cardiomyocytes.

Keywords:  L-arginine; NOS2; Trypanosoma cruzi; arginases 1 and 2; cardiomyocytes; macrophages

DOI:  https://doi.org/10.3390/pathogens13100878
Cell Rep. 2024 Oct 19. pii: S2211-1247(24)01232-4. [Epub ahead of print]43(11): 114881

CD36-mediated arachidonic acid influx from decidual stromal cells increases inflammatory macrophages in miscarriage.

Jiajia Chen, Tingxuan Yin, Xianyang Hu, Lingyu Chang, Yifei Sang, Ling Xu, Weijie Zhao, Lu Liu, Chunfang Xu, Yikong Lin, Yue Li, Qingyu Wu, Dajin Li, Yanhong Li, Meirong Du.

  Spontaneous abortion is associated with aberrant lipid metabolism, but the underlying mechanisms remain unclear. Here, we show that lipids are accumulated in decidual stromal cells (DSCs) and macrophages (dMφs) in women with miscarriage and mouse abortion-prone models. Moreover, we show that excessive lipids from DSCs are transferred to dMφs via a CD36-dependent mechanism that induces inflammation in dMφs. In particular, DSC-derived arachidonic acid (AA) is internalized by dMφs via CD36, which activates cyclooxygenase 2-dependent prostaglandin E2 production and interleukin (IL)-1β expression. In mice, AA injection induces miscarriage, whereas conditional knockout of Cd36 in dMφs ameliorates AA-induced embryo loss. Additionally, DSC-derived prolactin (PRL) inhibits CD36-mediated lipid intake in dMφs, and PRL administration reduces embryo loss in pregnant mice treated with CD36+ Mφs. Our findings reveal a critical interplay between DSCs and dMφs in dysregulated lipid metabolism that may contribute to miscarriage, in which PRL may be harnessed as a therapeutic agent.

Keywords:  CP: Developmental biology; CP: Immunology

DOI:  https://doi.org/10.1016/j.celrep.2024.114881
Cell Metab. 2024 Oct 15. pii: S1550-4131(24)00376-0. [Epub ahead of print]

Overnutrition causes insulin resistance and metabolic disorder through increased sympathetic nervous system activity.

Kenichi Sakamoto, Mary A Butera, Chunxue Zhou, Giulia Maurizi, Bandy Chen, Li Ling, Adham Shawkat, Likhitha Patlolla, Kavira Thakker, Victor Calle, Donald A Morgan, Kamal Rahmouni, Gary J Schwartz, Azeddine Tahiri, Christoph Buettner.

  The mechanisms underlying obesity-induced insulin resistance remain incompletely understood, as impaired cellular insulin signaling, traditionally considered the primary driver of insulin resistance, does not always accompany impaired insulin action. Overnutrition rapidly increases plasma norepinephrine (NE), suggesting overactivation of the sympathetic nervous system (SNS). However, the role of the SNS in obesity is controversial, as both increased and decreased SNS activity (SNA) have been reported. Here, we show that reducing catecholamine (CA) release from the SNS protects against overnutrition-induced insulin resistance as well as hyperglucagonemia, adipose tissue dysfunction, and fatty liver disease, as we demonstrate utilizing a mouse model of inducible and peripherally restricted deletion of tyrosine hydroxylase (th; THΔper). A key mechanism through which heightened SNA induces insulin resistance is by triggering adipose tissue lipolysis. Increased SNA emerges as a critical driver in the pathogenesis of overnutrition-induced insulin resistance and metabolic disease independent of cellular insulin signaling.

Keywords:  adipose tissue dysfunction; adipose tissue lipolysis; diabetes; insulin resistance; liver steatosis; metabolic disease; metabolic inflammation; norepinephrine; obesity; sympathetic nervous system

DOI:  https://doi.org/10.1016/j.cmet.2024.09.012
J Leukoc Biol. 2024 Oct 25. pii: qiae227. [Epub ahead of print]

CD56 does not contribute to the anti-tumor, tissue homing, and glycolytic capacity of human NK cells.

Ana L Portillo, Eduardo A Rojas, Misaal Mehboob, Adnan Moinuddin, Elizabeth Balint, Emily Feng, Christopher Silvestri, Fatemeh Vahedi, Tyrah M Ritchie, Alexa J Mansour, Jonathan L Bramson, Ali A Ashkar.

  Natural Killer (NK) cells are critical innate immune cells involved in the clearance of virally infected and malignant cells. Human NK cells are distinguished by their surface expression of CD56 and a lack of CD3. While CD56 expression and cell surface density has long been used as the prototypic marker to characterize primary human NK cell functional subsets, the exact functional role of CD56 in primary human NK cells is still not fully understood. Here we eliminated the expression of CD56 in human ex vivo expanded NK cells (CD56bright) using CRISPR/Cas9 in order to assess the function of CD56 in this highly activated and cytotoxic NK cell population. We show that the expression of CD56 has no effect on NK cell proliferative capacity or expression of various activation and inhibitory markers. Further, CD56 does not contribute to NK cell-mediated cytotoxicity, inflammatory cytokine production, or the ability of NK cells to control tumor engraftment in vivo. We also found that while deletion of CD56 did not impact NK cell glycolytic metabolism it did increase NK cell reliance on oxidative phosphorylation. Lastly, CD56 does not alter expanded NK cell in vivo tissue trafficking. Our results indicate that while CD56 expression could be used to indicate a hyper-functional state of NK cells, it does not directly influence the anti-tumor functions of expanded NK cells.

Keywords:  CD56/NCAM; CRISPR-Cas9; Natural killer cells

DOI:  https://doi.org/10.1093/jleuko/qiae227
Free Radic Biol Med. 2024 Oct 22. pii: S0891-5849(24)00997-3. [Epub ahead of print]

Calorie restriction modulates mitochondrial dynamics and autophagy in leukocytes of patients with obesity.

Zaida Abad-Jiménez, Sandra López-Domènech, María Pelechá, Laura Perea-Galera, Susana Rovira-Llopis, Celia Bañuls, Ana Blas-García, Nadezda Apostolova, Carlos Morillas, Víctor Manuel Víctor, Milagros Rocha.

   BACKGROUND: Although it is established that caloric restriction offers metabolic and clinical benefits, the molecular mechanisms underlying these effects remain unclear. Thus, this study aimed to investigate whether caloric restriction can modulate mitochondrial function and remodelling and stimulate autophagic flux in the PBMCs of patients with obesity.
METHODS: This was an interventional study of 38 obese subjects (BMI > 35 kg/m2) who underwent 6 months of dietary therapy, including a 6-week very-low-calorie diet (VLCD) followed by an 18-week low-calorie diet (LCD). We determined clinical variables, mitochondrial function parameters (by fluorescence imaging of mitochondrial ROS and membrane potential), and protein expression of markers of mitochondrial dynamics (MNF1, MFN2, OPA, DRP1 and FIS1) and autophagy (LC3, Beclin, BCL2 and NBR1) by western blot.
RESULTS: Caloric restriction induced an improvement in metabolic outcomes that was accompanied by an increase in AMPK expression, a decrease of mitochondrial ROS and mitochondrial membrane potential, which was associated with increased markers of mitochondrial dynamics (MFN2, DRP1 and FIS1) and activation of autophagy as evidenced by augmented LC3 II/I, Beclin1 and NBR1, and a decrease in BCL2.
CONCLUSION: These findings shed light on the specific molecular mechanisms by which caloric restriction facilitates metabolic improvements, highlighting the relevance of pathways involving energy homeostasis and cell recovery, including mitochondrial function and dynamics and autophagy.

Keywords:  Obesity; PBMCs; VLCD; autophagy; mitochondrial quality control; oxidative stress

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.295