bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2024‒05‒05
fifteen papers selected by
Dylan Ryan, University of Cambridge
  1. ER-associated degradation adapter Sel1L is required for CD8+ T cell function and memory formation following acute viral infection.
  2. Acetate reprogrammes tumour metabolism and promotes PD-L1 expression and immune evasion by upregulating c-Myc.
  3. Regulatory T cells and bioenergetics of peripheral blood mononuclear cells linked to pediatric obesity.
  4. Oxidative phosphorylation regulates B cell effector cytokines and promotes inflammation in multiple sclerosis.
  5. Glutamine-derived aspartate is required for eIF5A hypusination-mediated translation of HIF-1α to induce the polarization of tumor-associated macrophages.
  6. Immunometabolism of CD8+ T cell differentiation in cancer.
  7. Infection-associated gene regulation of L-tartrate metabolism in Salmonella enterica serovar Typhimurium.
  8. Metabolic reprogramming of tumor-associated macrophages using glutamine antagonist JHU083 drives tumor immunity in myeloid-rich prostate and bladder cancer tumors.
  9. The multifaceted life of macrophages in white adipose tissue: Immune shift couples with metabolic switch.
  10. The role of cholesterol and its oxidation products in tuberculosis pathogenesis.
  11. Eosinophil biology from the standpoint of metabolism: implications for metabolic disorders and asthma.
  12. Itaconate alleviates diet-induced obesity via activation of brown adipocyte thermogenesis.
  13. Hypotensive drugs mitigate the high-sodium diet-induced pro-inflammatory activation of mouse macrophages in vivo.
  14. Lysosomal dysfunction by inactivation of V-ATPase drives innate immune response in C. elegans.
  15. Microglial CMPK2 promotes neuroinflammation and brain injury after ischemic stroke.
  1. Cell Rep. 2024 Apr 29. pii: S2211-1247(24)00484-4. [Epub ahead of print]43(5): 114156
    ER-associated degradation adapter Sel1L is required for CD8+ T cell function and memory formation following acute viral infection.
    Luis O Correa-Medero, Shayna E Jankowski, Hanna S Hong, Nicholas D Armas, Aditi I Vijendra, Mack B Reynolds, Garrett M Fogo, Dominik Awad, Alexander T Dils, Kantaro A Inoki, Reid G Williams, Annabelle M Ye, Nadezhda Svezhova, Francisco Gomez-Rivera, Kathleen L Collins, Mary X O'Riordan, Thomas H Sanderson, Costas A Lyssiotis, Shannon A Carty.
      The maintenance of antigen-specific CD8+ T cells underlies the efficacy of vaccines and immunotherapies. Pathways contributing to CD8+ T cell loss are not completely understood. Uncovering the pathways underlying the limited persistence of CD8+ T cells would be of significant benefit for developing novel strategies of promoting T cell persistence. Here, we demonstrate that murine CD8+ T cells experience endoplasmic reticulum (ER) stress following activation and that the ER-associated degradation (ERAD) adapter Sel1L is induced in activated CD8+ T cells. Sel1L loss limits CD8+ T cell function and memory formation following acute viral infection. Mechanistically, Sel1L is required for optimal bioenergetics and c-Myc expression. Finally, we demonstrate that human CD8+ T cells experience ER stress upon activation and that ER stress is negatively associated with improved T cell functionality in T cell-redirecting therapies. Together, these results demonstrate that ER stress and ERAD are important regulators of T cell function and persistence.
    Keywords:  CD8 T cell; CP: Immunology; ER stress; ERAD; Myc; T cell memory; immunometabolism; protein homeostasis
    DOI:  https://doi.org/10.1016/j.celrep.2024.114156
  2. Nat Metab. 2024 May 03.
    Acetate reprogrammes tumour metabolism and promotes PD-L1 expression and immune evasion by upregulating c-Myc.
    Juhong Wang, Yannan Yang, Fei Shao, Ying Meng, Dong Guo, Jie He, Zhimin Lu.
      Acetate, a precursor of acetyl-CoA, is instrumental in energy production, lipid synthesis and protein acetylation. However, whether acetate reprogrammes tumour metabolism and plays a role in tumour immune evasion remains unclear. Here, we show that acetate is the most abundant short-chain fatty acid in human non-small cell lung cancer tissues, with increased tumour-enriched acetate uptake. Acetate-derived acetyl-CoA induces c-Myc acetylation, which is mediated by the moonlighting function of the metabolic enzyme dihydrolipoamide S-acetyltransferase. Acetylated c-Myc increases its stability and subsequent transcription of the genes encoding programmed death-ligand 1, glycolytic enzymes, monocarboxylate transporter 1 and cell cycle accelerators. Dietary acetate supplementation promotes tumour growth and inhibits CD8+ T cell infiltration, whereas disruption of acetate uptake inhibits immune evasion, which increases the efficacy of anti-PD-1-based therapy. These findings highlight a critical role of acetate promoting tumour growth beyond its metabolic role as a carbon source by reprogramming tumour metabolism and immune evasion, and underscore the potential of controlling acetate metabolism to curb tumour growth and improve the response to immune checkpoint blockade therapy.
    DOI:  https://doi.org/10.1038/s42255-024-01037-4
  3. Immunometabolism (Cobham). 2024 Apr;6(2): e00040
    Regulatory T cells and bioenergetics of peripheral blood mononuclear cells linked to pediatric obesity.
    Shannon Rose, Reid D Landes, Kanan K Vyas, Leanna Delhey, Sarah Blossom.
      Background: Obesity-associated inflammation drives the development of insulin resistance and type 2 diabetes. We sought to identify associations of circulating regulatory T cells (Treg) with the degree of obesity (eg, body mass index Z-score [BMIz]), insulin resistance (homeostatic model of insulin resistance [HOMA-IR]), and glycemic control (HbA1c) in children and adolescents. We further sought to examine associations among bioenergetics of peripheral blood mononuclear cells (PBMCs) and CD4 T cells and BMIz, HOMA-IR, and HbA1c.Methods: A total of 65 children and adolescents between the ages 5 and 17 years were studied. HbA1c and fasting levels of plasma glucose and insulin were measured. We quantified circulating Tregs (CD3+CD4+CD25+CD127-FoxP3+) by flow cytometry, and measured mitochondrial respiration (oxygen consumption rate [OCR]) and glycolysis (extracellular acidification rate [ECAR]) in PBMCs and isolated CD4 T cells by Seahorse extracellular flux analysis.
    Results: Tregs (% CD4) are negatively associated with BMIz but positively associated with HOMA-IR. In PBMCs, OCR/ECAR (a ratio of mitochondrial respiration to glycolysis) is positively associated with BMIz but negatively associated with HbA1c.
    Conclusions: In children, Tregs decrease as body mass index increases; however, the metabolic stress and inflammation associated with insulin resistance may induce a compensatory increase in Tregs. The degree of obesity is also associated with a shift away from glycolysis in PBMCs but as HbA1c declines, metabolism shifts back toward glycolysis. Comprehensive metabolic assessment of the immune system is needed to better understand the implications immune cell metabolic alterations in the progression from a healthy insulin-sensitive state toward glucose intolerance in children.
    Trial registration: This observational study was registered at the ClinicalTrials.gov (NCT03960333, https://clinicaltrials.gov/study/NCT03960333?term=NCT03960333&rank=1).
    Keywords:  adolescents; childhood obesity; glucose intolerance; glycolysis; immunometabolism; inflammation; insulin resistance; mTOR
    DOI:  https://doi.org/10.1097/IN9.0000000000000040
  4. Sci Immunol. 2024 May 03. 9(95): eadk0865
    Oxidative phosphorylation regulates B cell effector cytokines and promotes inflammation in multiple sclerosis.
    Rui Li, Yanting Lei, Ayman Rezk, Diego A Espinoza, Jing Wang, Huiru Feng, Bo Zhang, Isabella P Barcelos, Hang Zhang, Jing Yu, Xinrui Huo, Fangyi Zhu, Changxin Yang, Hao Tang, Amy C Goldstein, Brenda L Banwell, Hakon Hakonarson, Hongwei Xu, Michael Mingueneau, Bo Sun, Hulun Li, Amit Bar-Or.
      Dysregulated B cell cytokine production contributes to pathogenesis of immune-mediated diseases including multiple sclerosis (MS); however, the underlying mechanisms are poorly understood. In this study we investigated how cytokine secretion by pro-inflammatory (GM-CSF-expressing) and anti-inflammatory (IL-10-expressing) B cells is regulated. Pro-inflammatory human B cells required increased oxidative phosphorylation (OXPHOS) compared with anti-inflammatory B cells. OXPHOS reciprocally modulated pro- and anti-inflammatory B cell cytokines through regulation of adenosine triphosphate (ATP) signaling. Partial inhibition of OXPHOS or ATP-signaling including with BTK inhibition resulted in an anti-inflammatory B cell cytokine shift, reversed the B cell cytokine imbalance in patients with MS, and ameliorated neuroinflammation in a myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis mouse model. Our study identifies how pro- and anti-inflammatory cytokines are metabolically regulated in B cells and identifies ATP and its metabolites as a "fourth signal" that shapes B cell responses and is a potential target for restoring the B cell cytokine balance in autoimmune diseases.
    DOI:  https://doi.org/10.1126/sciimmunol.adk0865
  5. Exp Mol Med. 2024 May 01.
    Glutamine-derived aspartate is required for eIF5A hypusination-mediated translation of HIF-1α to induce the polarization of tumor-associated macrophages.
    Dong-Ho Kim, Yoo Na Kang, Jonghwa Jin, Mihyang Park, Daehoon Kim, Ghilsuk Yoon, Jae Won Yun, Jaebon Lee, Soo Young Park, Yu Rim Lee, Jun-Kyu Byun, Yeon-Kyung Choi, Keun-Gyu Park.
      Tumor-associated macrophages (TAMs) are vital contributors to the growth, metastasis, and therapeutic resistance of various cancers, including hepatocellular carcinoma (HCC). However, the exact phenotype of TAMs and the mechanisms underlying their modulation for therapeutic purposes have not been determined. Here, we present compelling evidence that glutamine-derived aspartate in TAMs stimulates spermidine production through the polyamine synthesis pathway, thereby increasing the translation efficiency of HIF-1α via eIF5A hypusination. Consequently, augmented translation of HIF-1α drives TAMs to undergo an increase glycolysis and acquire a metabolic phenotype distinct from that of M2 macrophages. Finally, eIF5A levels in tumor stromal lesions were greater than those in nontumor stromal lesions. Additionally, a higher degree of tumor stromal eIF5A hypusination was significantly associated with a more advanced tumor stage. Taken together, these data highlight the potential of inhibiting hypusinated eIF5A by targeting glutamine metabolism in TAMs, thereby opening a promising avenue for the development of novel therapeutic approaches for HCC.
    DOI:  https://doi.org/10.1038/s12276-024-01214-1
  6. Trends Cancer. 2024 Apr 30. pii: S2405-8033(24)00059-1. [Epub ahead of print]
    Immunometabolism of CD8+ T cell differentiation in cancer.
    Hao Shi, Sidi Chen, Hongbo Chi.
      CD8+ cytotoxic T lymphocytes (CTLs) are central mediators of tumor immunity and immunotherapies. Upon tumor antigen recognition, CTLs differentiate from naive/memory-like toward terminally exhausted populations with more limited function against tumors. Such differentiation is regulated by both immune signals, including T cell receptors (TCRs), co-stimulation, and cytokines, and metabolism-associated processes. These immune signals shape the metabolic landscape via signaling, transcriptional and post-transcriptional mechanisms, while metabolic processes in turn exert spatiotemporal effects to modulate the strength and duration of immune signaling. Here, we review the bidirectional regulation between immune signals and metabolic processes, including nutrient uptake and intracellular metabolic pathways, in shaping CTL differentiation and exhaustion. We also discuss the mechanisms underlying how specific nutrient sources and metabolite-mediated signaling events orchestrate CTL biology. Understanding how metabolic programs and their interplay with immune signals instruct CTL differentiation and exhaustion is crucial to uncover tumor-immune interactions and design novel immunotherapies.
    Keywords:  T cell differentiation; TCR; antitumor function; cytokines; exhaustion; mitochondrial fitness
    DOI:  https://doi.org/10.1016/j.trecan.2024.03.010
  7. mBio. 2024 Apr 29. e0035024
    Infection-associated gene regulation of L-tartrate metabolism in Salmonella enterica serovar Typhimurium.
    Vivian K Rojas, Maria G Winter, Angel G Jimenez, Natasha W Tanner, Stacey L Crockett, Luisella Spiga, David R Hendrixson, Sebastian E Winter.
      Enteric pathogens such as Salmonella enterica serovar Typhimurium experience spatial and temporal changes to the metabolic landscape throughout infection. Host reactive oxygen and nitrogen species non-enzymatically convert monosaccharides to alpha hydroxy acids, including L-tartrate. Salmonella utilizes L-tartrate early during infection to support fumarate respiration, while L-tartrate utilization ceases at later time points due to the increased availability of exogenous electron acceptors such as tetrathionate, nitrate, and oxygen. It remains unknown how Salmonella regulates its gene expression to metabolically adapt to changing nutritional environments. Here, we investigated how the transcriptional regulation for L-tartrate metabolism in Salmonella is influenced by infection-relevant cues. L-tartrate induces the transcription of ttdBAU, genes involved in L-tartrate utilization. L-tartrate metabolism is negatively regulated by two previously uncharacterized transcriptional regulators TtdV (STM3357) and TtdW (STM3358), and both TtdV and TtdW are required for the sensing of L-tartrate. The electron acceptors nitrate, tetrathionate, and oxygen repress ttdBAU transcription via the two-component system ArcAB. Furthermore, the regulation of L-tartrate metabolism is required for optimal fitness in a mouse model of Salmonella-induced colitis. TtdV, TtdW, and ArcAB allow for the integration of two cues, i.e., substrate availability and availability of exogenous electron acceptors, to control L-tartrate metabolism. Our findings provide novel insights into how Salmonella prioritizes the utilization of different electron acceptors for respiration as it experiences transitional nutrient availability throughout infection.IMPORTANCE: Bacterial pathogens must adapt their gene expression profiles to cope with diverse environments encountered during infection. This coordinated process is carried out by the integration of cues that the pathogen senses to fine-tune gene expression in a spatiotemporal manner. Many studies have elucidated the regulatory mechanisms of how Salmonella sense metabolites in the gut to activate or repress its virulence program; however, our understanding of how Salmonella coordinates its gene expression to maximize the utilization of carbon and energy sources found in transitional nutrient niches is not well understood. In this study, we discovered how Salmonella integrates two infection-relevant cues, substrate availability and exogenous electron acceptors, to control L-tartrate metabolism. From our experiments, we propose a model for how L-tartrate metabolism is regulated in response to different metabolic cues in addition to characterizing two previously unknown transcriptional regulators. This study expands our understanding of how microbes combine metabolic cues to enhance fitness during infection.
    Keywords:  Salmonella; gene regulation; metabolism
    DOI:  https://doi.org/10.1128/mbio.00350-24
  8. Cancer Immunol Res. 2024 May 03.
    Metabolic reprogramming of tumor-associated macrophages using glutamine antagonist JHU083 drives tumor immunity in myeloid-rich prostate and bladder cancer tumors.
    Monali Praharaj, Fan Shen, Alex J Lee, Liang Zhao, Thomas R Nirschl, Debebe Theodros, Alok K Singh, Xiaoxu Wang, Kenneth M Adusei, Kara A Lombardo, Raekwon A Williams, Laura A Sena, Elizabeth A Thompson, Ada Tam, Srinivasan Yegnasubramanian, Edward J Pearce, Robert D Leone, Jesse Alt, Rana Rais, Barbara S Slusher, Drew M Pardoll, Jonathan D Powell, Jelani C Zarif.
      Glutamine metabolism in tumor microenvironments critically regulates anti-tumor immunity. Using glutamine-antagonist prodrug JHU083, we report potent tumor growth inhibition in urologic tumors by JHU083-reprogrammed tumor-associated macrophages (TAMs) and tumor-infiltrating monocytes (TIMs). We show JHU083-mediated glutamine antagonism in tumor microenvironments induces TNF, pro-inflammatory, and mTORC1 signaling in intratumoral TAM clusters. JHU083-reprogrammed TAMs also exhibit increased tumor cell phagocytosis and diminished pro-angiogenic capacities. In vivo inhibition of TAM glutamine consumption resulted in increased glycolysis, a broken TCA cycle, and purine metabolism disruption. Although the anti-tumor effect of glutamine antagonism on tumor-infiltrating T cells was moderate, JHU083 promoted a stem cell-like phenotype in CD8+ T cells and decreased Treg abundance. Finally, JHU083 caused a ubiquitous shutdown in glutamine utilizing metabolic pathways in tumor cells, leading to reduced HIF-1alpha, c-MYC phosphorylation, and induction of tumor cell apoptosis, all key anti-tumor features.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-1105
  9. Immunol Rev. 2024 Apr 29.
    The multifaceted life of macrophages in white adipose tissue: Immune shift couples with metabolic switch.
    Qun Wang, Sean M Hartig, Christie M Ballantyne, Huaizhu Wu.
      White adipose tissue (WAT) is a vital endocrine organ that regulates energy balance and metabolic homeostasis. In addition to fat cells, WAT harbors macrophages with distinct phenotypes that play crucial roles in immunity and metabolism. Nutrient demands cause macrophages to accumulate in WAT niches, where they remodel the microenvironment and produce beneficial or detrimental effects on systemic metabolism. Given the abundance of macrophages in WAT, this review summarizes the heterogeneity of WAT macrophages in physiological and pathological conditions, including their alterations in quantity, phenotypes, characteristics, and functions during WAT growth and development, as well as healthy or unhealthy expansion. We will discuss the interactions of macrophages with other cell partners in WAT including adipose stem cells, adipocytes, and T cells in the context of various microenvironment niches in lean or obese condition. Finally, we highlight how adipose tissue macrophages merge immunity and metabolic changes to govern energy balance for the organism.
    Keywords:  immunity; macrophage; metabolism; obesity; white adipose tissue
    DOI:  https://doi.org/10.1111/imr.13338
  10. Immunometabolism (Cobham). 2024 Apr;6(2): e00042
    The role of cholesterol and its oxidation products in tuberculosis pathogenesis.
    Andrew T Roth, Jennifer A Philips, Pallavi Chandra.
      Mycobacterium tuberculosis causes tuberculosis (TB), one of the world's most deadly infections. Lipids play an important role in M. tuberculosis pathogenesis. M. tuberculosis grows intracellularly within lipid-laden macrophages and extracellularly within the cholesterol-rich caseum of necrotic granulomas and pulmonary cavities. Evolved from soil saprophytes that are able to metabolize cholesterol from organic matter in the environment, M. tuberculosis inherited an extensive and highly conserved machinery to metabolize cholesterol. M. tuberculosis uses this machinery to degrade host cholesterol; the products of cholesterol degradation are incorporated into central carbon metabolism and used to generate cell envelope lipids, which play important roles in virulence. The host also modifies cholesterol by enzymatically oxidizing it to a variety of derivatives, collectively called oxysterols, which modulate cholesterol homeostasis and the immune response. Recently, we found that M. tuberculosis converts host cholesterol to an oxidized metabolite, cholestenone, that accumulates in the lungs of individuals with TB. M. tuberculosis encodes cholesterol-modifying enzymes, including a hydroxysteroid dehydrogenase, a putative cholesterol oxidase, and numerous cytochrome P450 monooxygenases. Here, we review what is known about cholesterol and its oxidation products in the pathogenesis of TB. We consider the possibility that the biological function of cholesterol metabolism by M. tuberculosis extends beyond a nutritional role.
    Keywords:  3β-hydroxysteroid dehydrogenase; Mycobacterium tuberculosis; TB; cholesterol; cholesterol oxidase; immunometabolism; oxysterols
    DOI:  https://doi.org/10.1097/IN9.0000000000000042
  11. J Leukoc Biol. 2024 May 03. pii: qiae100. [Epub ahead of print]
    Eosinophil biology from the standpoint of metabolism: implications for metabolic disorders and asthma.
    Nana-Fatima Haruna, Sergejs Berdnikovs, Zhenying Nie.
      Eosinophils, recognized for their immune and remodeling functions and participation in allergic inflammation, have recently garnered attention due to their impact on host metabolism, especially in the regulation of adipose tissue. Eosinophils are now known for their role in adipocyte beiging, adipokine secretion, and adipose tissue inflammation. This intricate interaction involves complex immune and metabolic processes, carrying significant implications for systemic metabolic health. Importantly, the interplay between eosinophils and adipocytes is bidirectional, revealing the dynamic nature of the immune-metabolic axis in adipose tissue. While the homeostatic regulatory role of eosinophils in the adipose tissue is appreciated, this relationship in the context of obesity or allergic inflammation is much less understood. Mechanistic details of eosinophil-adipose interactions, especially the direct regulation of adipocytes by eosinophils, are also lacking. Another poorly understood aspect is the metabolism of the eosinophils themselves, encompassing metabolic shifts during eosinophil subset transitions in different tissue microenvironments, along with potential effects of host metabolism on the programming of eosinophil hematopoiesis and the resulting plasticity. This review consolidates recent research in this emerging and fascinating frontier of eosinophil investigation, identifying unexplored areas and presenting innovative perspectives on eosinophil biology in the context of metabolic disorders and associated health conditions, including asthma.
    Keywords:  Adipocytes; Eosinophils; Metabolism; asthma; obesity
    DOI:  https://doi.org/10.1093/jleuko/qiae100
  12. Cell Rep. 2024 Apr 30. pii: S2211-1247(24)00470-4. [Epub ahead of print]43(5): 114142
    Itaconate alleviates diet-induced obesity via activation of brown adipocyte thermogenesis.
    Zihan Yu, Xianju Li, Yanni Quan, Jiawen Chen, Jiarui Liu, Nairen Zheng, Shuwen Liu, Yini Wang, Wanlin Liu, Chen Qiu, Yi Wang, Ruimao Zheng, Jun Qin.
      Despite medical advances, there remains an unmet need for better treatment of obesity. Itaconate, a product of the decarboxylation of the tricarboxylic acid cycle intermediate cis-aconitate, plays a regulatory role in both metabolism and immunity. Here, we show that itaconate, as an endogenous compound, counteracts high-fat-diet (HFD)-induced obesity through leptin-independent mechanisms in three mouse models. Specifically, itaconate reduces weight gain, reverses hyperlipidemia, and improves glucose tolerance in HFD-fed mice. Additionally, itaconate enhances energy expenditure and the thermogenic capacity of brown adipose tissue (BAT). Unbiased proteomic analysis reveals that itaconate upregulates key proteins involved in fatty acid oxidation and represses the expression of lipogenic genes. Itaconate may provoke a major metabolic reprogramming by inducing fatty acid oxidation and suppression of fatty acid synthesis in BAT. These findings highlight itaconate as a potential activator of BAT-mediated thermogenesis and a promising candidate for anti-obesity therapy.
    Keywords:  CP: Metabolism; brown adipocyte; itaconate; obesity; proteomics; thermogenesis
    DOI:  https://doi.org/10.1016/j.celrep.2024.114142
  13. Biomed Pharmacother. 2024 Apr 26. pii: S0753-3322(24)00532-8. [Epub ahead of print]175 116648
    Hypotensive drugs mitigate the high-sodium diet-induced pro-inflammatory activation of mouse macrophages in vivo.
    Martyna Cieślik, Spencer D Strobel, Paweł Bryniarski, Hanna Twardowska, Adam Chmielowski, Michał Rudek, Dominik Felkle, Katarzyna Zięba, Konrad Kaleta, Mateusz Jarczyński, Bernadeta Nowak, Krzysztof Bryniarski, Katarzyna Nazimek.
      Nowadays, there is an increasing emphasis on the need to alleviate the chronic inflammatory response to effectively treat hypertension. However, there are still gaps in our understanding on how to achieve this. Therefore, research on interaction of antihypertensive drugs with the immune system is extremely interesting, since their therapeutic effect could partly result from amelioration of hypertension-related inflammation, in which macrophages seem to play a pivotal role. Thus, current comprehensive studies have investigated the impact of repeatedly administered hypotensive drugs (captopril, olmesartan, propranolol, carvedilol, amlodipine, verapamil) on macrophage functions in the innate and adaptive immunity, as well as if drug-induced effects are affected by a high-sodium diet (HSD), one of the key environmental risk factors of hypertension. Although the assayed medications increased the generation of reactive oxygen and nitrogen intermediates by macrophages from standard fed donors, they reversed HSD-induced enhancing effects on macrophage oxidative burst and secretion of pro-inflammatory cytokines. On the other hand, some drugs increased macrophage phagocytic activity and the expression of surface markers involved in antigen presentation, which translated into enhanced macrophage ability to activate B cells for antibody production. Moreover, the assayed medications augmented macrophage function and the effector phase of contact hypersensitivity reaction, but suppressed the sensitization phase of cell-mediated hypersensitivity under HSD conditions. Our current findings contribute to the recognition of mechanisms, by which excessive sodium intake affects macrophage immune activity in hypertensive individuals, and provide evidence that the assayed medications mitigate most of the HSD-induced adverse effects, suggesting their additional protective therapeutic activity.
    Keywords:  Antihypertensive medications; Excessive sodium intake; High-salt diet; Hypertension; Immunomodulation; Macrophages
    DOI:  https://doi.org/10.1016/j.biopha.2024.116648
  14. Cell Rep. 2024 Apr 26. pii: S2211-1247(24)00466-2. [Epub ahead of print]43(5): 114138
    Lysosomal dysfunction by inactivation of V-ATPase drives innate immune response in C. elegans.
    Xuepiao Pu, Bin Qi.
      Pathogens target vacuolar ATPase (V-ATPase) to inhibit lysosomal acidification or lysosomal fusion, causing lysosomal dysfunction. However, it remains unknown whether cells can detect dysfunctional lysosomes and initiate an immune response. In this study, we discover that dysfunction of lysosomes caused by inactivation of V-ATPase enhances innate immunity against bacterial infections. We find that lysosomal V-ATPase interacts with DVE-1, whose nuclear localization serves as a proxy for the induction of mitochondrial unfolded protein response (UPRmt). The inactivation of V-ATPase promotes the nuclear localization of DVE-1, activating UPRmt and inducing downstream immune response genes. Furthermore, pathogen resistance conferred by inactivation of V-ATPase requires dve-1 and its downstream immune effectors. Interestingly, animals grow slower after vha RNAi, suggesting that the vha-RNAi-induced immune response costs the most energy through activation of DVE-1, which trades off with growth. This study reveals how dysfunctional lysosomes can trigger an immune response, emphasizing the importance of conserving energy during immune defense.
    Keywords:  C. elegans; CP: Immunology; UPR(mt); V-ATPase; immunity; lysosomes; mitochondria; mitochondrial surveillance; pathogen
    DOI:  https://doi.org/10.1016/j.celrep.2024.114138
  15. Cell Rep Med. 2024 May 02. pii: S2666-3791(24)00191-5. [Epub ahead of print] 101522
    Microglial CMPK2 promotes neuroinflammation and brain injury after ischemic stroke.
    Xin Guan, Sitong Zhu, Jinqian Song, Kui Liu, Mei Liu, Luyang Xie, Yifang Wang, Jin Wu, Xiaojun Xu, Tao Pang.
      Neuroinflammation plays a significant role in ischemic injury, which can be promoted by oxidized mitochondrial DNA (Ox-mtDNA). Cytidine/uridine monophosphate kinase 2 (CMPK2) regulates mtDNA replication, but its role in neuroinflammation and ischemic injury remains unknown. Here, we report that CMPK2 expression is upregulated in monocytes/macrophages and microglia post-stroke in humans and mice, respectively. Microglia/macrophage CMPK2 knockdown using the Cre recombination-dependent adeno-associated virus suppresses the inflammatory responses in the brain, reduces infarcts, and improves neurological outcomes in ischemic CX3CR1Cre/ERT2 mice. Mechanistically, CMPK2 knockdown limits newly synthesized mtDNA and Ox-mtDNA formation and subsequently blocks NLRP3 inflammasome activation in microglia/macrophages. Nordihydroguaiaretic acid (NDGA), as a CMPK2 inhibitor, is discovered to reduce neuroinflammation and ischemic injury in mice and prevent the inflammatory responses in primary human monocytes from ischemic patients. Thus, these findings identify CMPK2 as a promising therapeutic target for ischemic stroke and other brain disorders associated with neuroinflammation.
    Keywords:  CMPK2; NLRP3 inflammasome; Ox-mtDNA; human PBMC cells; microglia; stroke
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101522
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