bims-imicid 2023-08-13 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023‒08‒13
25 papers selected by
Dylan Ryan
University of Cambridge

Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells.
Asparagine restriction enhances CD8+ T cell metabolic fitness and antitumoral functionality through an NRF2-dependent stress response.
Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts.
Metabolic rewiring tunes dermal macrophages in staphylococcal skin infection.
The Dual Role of ACOD1 in Inflammation.
A cellular overview of immunometabolism in systemic lupus erythematosus.
Cellular metabolism hijacked by viruses for immunoevasion: potential antiviral targets.
Unveiling the veil of lactate in tumor-associated macrophages: a successful strategy for immunometabolic therapy.
Immunometabolism at the Heart of Cardiovascular Disease.
Surveying the Metabolic and Dysfunctional Profiles of T Cells and NK Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
The TNFα/TNFR2 axis mediates natural killer cell proliferation by promoting aerobic glycolysis.
Glutaminolysis and peripheral CD4+ T cell differentiation: from mechanism to intervention strategy.
A metabolite from commensal Candida albicans enhances the bactericidal activity of macrophages and protects against sepsis.
Apoptotic bodies inhibit inflammation by PDL1-PD1-mediated macrophage metabolic reprogramming.
T-cell dysfunction by pseudohypoxia and autocrine purinergic signaling in chronic lymphocytic leukemia.
Elevated glucose metabolism driving pro-inflammatory response in B cells contributes to the progression of type 1 diabetes.
mTOR-Mediated Immunometabolic Reprogramming Nanomodulators Enable Sensitive Switching of Energy Deprivation-Induced Microglial Polarization for Alzheimer's Disease Management.
Pseudomonas aeruginosa hijacks the murine nitric oxide metabolic pathway to evade killing by neutrophils in the lung.
Impact of Lipid Metabolism on Macrophage Polarization: Implications for Inflammation and Tumor Immunity.
TGF-β uncouples glycolysis and inflammation in macrophages and controls survival during sepsis.
Acute exercise modulates the inflammatory response in adipose tissue in both lean and obese mice.
Dimethyl itaconate selectively targets inflammatory and metabolic pathways in chronic lymphocytic leukemia.
Selenomethionine against titanium particle-induced osteolysis by regulating the ROS-dependent NLRP3 inflammasome activation via the β-catenin signaling pathway.
Glycogen synthase kinase 3 controls T-cell exhaustion by regulating NFAT activation.
Metabolites and Immune Response in Tumor Microenvironments.

Nature. 2023 Aug 09.

Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells.

Liliana M Sanmarco, Joseph M Rone, Carolina M Polonio, Gonzalo Fernandez Lahore, Federico Giovannoni, Kylynne Ferrara, Cristina Gutierrez-Vazquez, Ning Li, Anna Sokolovska, Agustin Plasencia, Camilo Faust Akl, Payal Nanda, Evelin S Heck, Zhaorong Li, Hong-Gyun Lee, Chun-Cheih Chao, Claudia M Rejano-Gordillo, Pedro H Fonseca-Castro, Tomer Illouz, Mathias Linnerbauer, Jessica E Kenison, Rocky M Barilla, Daniel Farrenkopf, Nikolas A Stevens, Gavin Piester, Elizabeth N Chung, Lucas Dailey, Vijay K Kuchroo, David Hava, Michael A Wheeler, Clary Clish, Roni Nowarski, Eduardo Balsa, Jose M Lora, Francisco J Quintana.

Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells1,2. Genetic variants that are associated with the function of DCs have been linked to autoimmune disorders3,4, and DCs are therefore attractive therapeutic targets for such diseases. However, developing DC-targeted therapies for autoimmunity requires identification of the mechanisms that regulate DC function. Here, using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies, we identify a regulatory loop of negative feedback that operates in DCs to limit immunopathology. Specifically, we find that lactate, produced by activated DCs and other immune cells, boosts the expression of NDUFA4L2 through a mechanism mediated by hypoxia-inducible factor 1α (HIF-1α). NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs that are involved in the control of pathogenic autoimmune T cells. We also engineer a probiotic that produces lactate and suppresses T cell autoimmunity through the activation of HIF-1α-NDUFA4L2 signalling in DCs. In summary, we identify an immunometabolic pathway that regulates DC function, and develop a synthetic probiotic for its therapeutic activation.

DOI: https://doi.org/10.1038/s41586-023-06409-6
Nat Metab. 2023 Aug 07.

Asparagine restriction enhances CD8+ T cell metabolic fitness and antitumoral functionality through an NRF2-dependent stress response.

J N Rashida Gnanaprakasam, Bhavana Kushwaha, Lingling Liu, Xuyong Chen, Siwen Kang, Tingting Wang, Teresa A Cassel, Christopher M Adams, Richard M Higashi, David A Scott, Gang Xin, Zihai Li, Jun Yang, Andrew N Lane, Teresa W-M Fan, Ji Zhang, Ruoning Wang.

Robust and effective T cell immune surveillance and cancer immunotherapy require proper allocation of metabolic resources to sustain energetically costly processes, including growth and cytokine production. Here, we show that asparagine (Asn) restriction on CD8+ T cells exerted opposing effects during activation (early phase) and differentiation (late phase) following T cell activation. Asn restriction suppressed activation and cell cycle entry in the early phase while rapidly engaging the nuclear factor erythroid 2-related factor 2 (NRF2)-dependent stress response, conferring robust proliferation and effector function on CD8+ T cells during differentiation. Mechanistically, NRF2 activation in CD8+ T cells conferred by Asn restriction rewired the metabolic program by reducing the overall glucose and glutamine consumption but increasing intracellular nucleotides to promote proliferation. Accordingly, Asn restriction or NRF2 activation potentiated the T cell-mediated antitumoral response in preclinical animal models, suggesting that Asn restriction is a promising and clinically relevant strategy to enhance cancer immunotherapy. Our study revealed Asn as a critical metabolic node in directing the stress signaling to shape T cell metabolic fitness and effector functions.

DOI: https://doi.org/10.1038/s42255-023-00856-1
Sci Transl Med. 2023 08 09. 15(708): eabq1533

Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts.

Joseph W Guarnieri, Joseph M Dybas, Hossein Fazelinia, Man S Kim, Justin Frere, Yuanchao Zhang, Yentli Soto Albrecht, Deborah G Murdock, Alessia Angelin, Larry N Singh, Scott L Weiss, Sonja M Best, Marie T Lott, Shiping Zhang, Henry Cope, Victoria Zaksas, Amanda Saravia-Butler, Cem Meydan, Jonathan Foox, Christopher Mozsary, Yaron Bram, Yared Kidane, Waldemar Priebe, Mark R Emmett, Robert Meller, Sam Demharter, Valdemar Stentoft-Hansen, Marco Salvatore, Diego Galeano, Francisco J Enguita, Peter Grabham, Nidia S Trovao, Urminder Singh, Jeffrey Haltom, Mark T Heise, Nathaniel J Moorman, Victoria K Baxter, Emily A Madden, Sharon A Taft-Benz, Elizabeth J Anderson, Wes A Sanders, Rebekah J Dickmander, Stephen B Baylin, Eve Syrkin Wurtele, Pedro M Moraes-Vieira, Deanne Taylor, Christopher E Mason, Jonathan C Schisler, Robert E Schwartz, Afshin Beheshti, Douglas C Wallace.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins bind to host mitochondrial proteins, likely inhibiting oxidative phosphorylation (OXPHOS) and stimulating glycolysis. We analyzed mitochondrial gene expression in nasopharyngeal and autopsy tissues from patients with coronavirus disease 2019 (COVID-19). In nasopharyngeal samples with declining viral titers, the virus blocked the transcription of a subset of nuclear DNA (nDNA)-encoded mitochondrial OXPHOS genes, induced the expression of microRNA 2392, activated HIF-1α to induce glycolysis, and activated host immune defenses including the integrated stress response. In autopsy tissues from patients with COVID-19, SARS-CoV-2 was no longer present, and mitochondrial gene transcription had recovered in the lungs. However, nDNA mitochondrial gene expression remained suppressed in autopsy tissue from the heart and, to a lesser extent, kidney, and liver, whereas mitochondrial DNA transcription was induced and host-immune defense pathways were activated. During early SARS-CoV-2 infection of hamsters with peak lung viral load, mitochondrial gene expression in the lung was minimally perturbed but was down-regulated in the cerebellum and up-regulated in the striatum even though no SARS-CoV-2 was detected in the brain. During the mid-phase SARS-CoV-2 infection of mice, mitochondrial gene expression was starting to recover in mouse lungs. These data suggest that when the viral titer first peaks, there is a systemic host response followed by viral suppression of mitochondrial gene transcription and induction of glycolysis leading to the deployment of antiviral immune defenses. Even when the virus was cleared and lung mitochondrial function had recovered, mitochondrial function in the heart, kidney, liver, and lymph nodes remained impaired, potentially leading to severe COVID-19 pathology.

DOI: https://doi.org/10.1126/scitranslmed.abq1533
Sci Immunol. 2023 Aug 18. 8(86): eadg3517

Metabolic rewiring tunes dermal macrophages in staphylococcal skin infection.

Aaron James Forde, Julia Kolter, Pascale Zwicky, Sebastian Baasch, Florens Lohrmann, Marleen Eckert, Vitka Gres, Simon Lagies, Oliver Gorka, Angelika S Rambold, Joerg M Buescher, Bernd Kammerer, Nico Lachmann, Marco Prinz, Olaf Groß, Edward J Pearce, Burkhard Becher, Philipp Henneke.

The skin needs to balance tolerance of colonizing microflora with rapid detection of potential pathogens. Flexible response mechanisms would seem most suitable to accommodate the dynamic challenges of effective antimicrobial defense and restoration of tissue homeostasis. Here, we dissected macrophage-intrinsic mechanisms and microenvironmental cues that tune macrophage signaling in localized skin infection with the colonizing and opportunistic pathogen Staphylococcus aureus. Early in skin infection, the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by γδ T cells and hypoxic conditions within the dermal microenvironment diverted macrophages away from a homeostatic M-CSF- and hypoxia-inducible factor 1α (HIF-1α)-dependent program. This allowed macrophages to be metabolically rewired for maximal inflammatory activity, which requires expression of Irg1 and generation of itaconate, but not HIF-1α. This multifactorial macrophage rewiring program was required for both the timely clearance of bacteria and for the provision of local immune memory. These findings indicate that immunometabolic conditioning allows dermal macrophages to cycle between antimicrobial activity and protection against secondary infections.

DOI: https://doi.org/10.1126/sciimmunol.adg3517
J Immunol. 2023 08 15. 211(4): 518-526

The Dual Role of ACOD1 in Inflammation.

Runliu Wu, Jiao Liu, Daolin Tang, Rui Kang.

Immunometabolism is an interdisciplinary field that focuses on the relationship between metabolic pathways and immune responses. Dysregulated immunometabolism contributes to many pathological settings, such as cytokine storm or immune tolerance. Aconitate decarboxylase 1 (ACOD1, also known as immunoresponsive gene 1), the mitochondrial enzyme responsible for catalyzing itaconate production, was originally identified as a bacterial LPS-inducible gene involved in innate immunity in mouse macrophages. We now know that the upregulation of ACOD1 expression in immune or nonimmune cells plays a context-dependent role in metabolic reprogramming, signal transduction, inflammasome regulation, and protein modification. The emerging function of ACOD1 in inflammation and infection is a double-edged sword. In this review, we discuss how ACOD1 regulates anti-inflammatory or proinflammatory responses in an itaconate-dependent or -independent manner. Further understanding of ACOD1 expression and function may pave the way for the development of precision therapies for inflammatory diseases.

DOI: https://doi.org/10.4049/jimmunol.2300101
Oxf Open Immunol. 2023 ;4(1): iqad005

A cellular overview of immunometabolism in systemic lupus erythematosus.

Antonios Psarras, Alexander Clarke.

  Systemic lupus erythematosus (SLE) is a complex autoimmune disease, characterized by a breakdown of immune tolerance and the development of autoantibodies against nucleic self-antigens. Immunometabolism is a rapidly expanding scientific field investigating the metabolic programming of cells of the immune system. During the normal immune response, extensive reprogramming of cellular metabolism occurs, both to generate adenosine triphosphate and facilitate protein synthesis, and also to manage cellular stress. Major pathways upregulated include glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle and the pentose phosphate pathway, among others. Metabolic reprogramming also occurs to aid resolution of inflammation. Immune cells of both patients with SLE and lupus-prone mice are characterized by metabolic abnormalities resulting in an altered functional and inflammatory state. Recent studies have described how metabolic reprogramming occurs in many cell populations in SLE, particularly CD4+ T cells, e.g. favouring a glycolytic profile by overactivation of the mechanistic target of rapamycin pathway. These advances have led to an increased understanding of the metabolic changes affecting the inflammatory profile of T and B cells, monocytes, dendritic cells and neutrophils, and how they contribute to autoimmunity and SLE pathogenesis. In the current review, we aim to summarize recent advances in the field of immunometabolism involved in SLE and how these could potentially lead to new therapeutic strategies in the future.

Keywords:  B cells; T cells; autoimmunity; immunometabolism; systemic lupus erythematosus

DOI:  https://doi.org/10.1093/oxfimm/iqad005
Front Immunol. 2023 ;14 1228811

Cellular metabolism hijacked by viruses for immunoevasion: potential antiviral targets.

Jiaqi Li, Yanjin Wang, Hao Deng, Su Li, Hua-Ji Qiu.

  Cellular metabolism plays a central role in the regulation of both innate and adaptive immunity. Immune cells utilize metabolic pathways to modulate the cellular differentiation or death. The intricate interplay between metabolism and immune response is critical for maintaining homeostasis and effective antiviral activities. In recent years, immunometabolism induced by viral infections has been extensively investigated, and accumulating evidence has indicated that cellular metabolism can be hijacked to facilitate viral replication. Generally, virus-induced changes in cellular metabolism lead to the reprogramming of metabolites and metabolic enzymes in different pathways (glucose, lipid, and amino acid metabolism). Metabolic reprogramming affects the function of immune cells, regulates the expression of immune molecules and determines cell fate. Therefore, it is important to explore the effector molecules with immunomodulatory properties, including metabolites, metabolic enzymes, and other immunometabolism-related molecules as the antivirals. This review summarizes the relevant advances in the field of metabolic reprogramming induced by viral infections, providing novel insights for the development of antivirals.

Keywords:  adaptive immunity; immunoevasion; immunometabolism; innate immunity; metabolic reprogramming

DOI:  https://doi.org/10.3389/fimmu.2023.1228811
Front Immunol. 2023 ;14 1208870

Unveiling the veil of lactate in tumor-associated macrophages: a successful strategy for immunometabolic therapy.

Hongxia Tao, Xuansheng Zhong, Anqi Zeng, Linjiang Song.

  Lactate, traditionally regarded as a metabolic waste product at the terminal of the glycolysis process, has recently been found to have multifaceted functional roles in metabolism and beyond. A metabolic reprogramming phenomenon commonly seen in tumor cells, known as the "Warburg effect," sees high levels of aerobic glycolysis result in an excessive production of lactate. This lactate serves as a substrate that sustains not only the survival of cancer cells but also immune cells. However, it also inhibits the function of tumor-associated macrophages (TAMs), a group of innate immune cells ubiquitously present in solid tumors, thereby facilitating the immune evasion of malignant tumor cells. Characterized by their high plasticity, TAMs are generally divided into the pro-inflammatory M1 phenotype and the pro-tumour M2 phenotype. Through a process of 'education' by lactate, TAMs tend to adopt an immunosuppressive phenotype and collaborate with tumor cells to promote angiogenesis. Additionally, there is growing evidence linking metabolic reprogramming with epigenetic modifications, suggesting the participation of histone modification in diverse cellular events within the tumor microenvironment (TME). In this review, we delve into recent discoveries concerning lactate metabolism in tumors, with a particular focus on the impact of lactate on the function of TAMs. We aim to consolidate the molecular mechanisms underlying lactate-induced TAM polarization and angiogenesis and explore the lactate-mediated crosstalk between TAMs and tumor cells. Finally, we also touch upon the latest progress in immunometabolic therapies and drug delivery strategies targeting glycolysis and lactate production, offering new perspectives for future therapeutic approaches.

Keywords:  TAMs; immune escape; immunometabolism; lactate; targeted drug delivery

DOI:  https://doi.org/10.3389/fimmu.2023.1208870
JACC Basic Transl Sci. 2023 Jul;8(7): 884-904

Immunometabolism at the Heart of Cardiovascular Disease.

Matthew DeBerge, Rajesh Chaudhary, Samantha Schroth, Edward B Thorp.

  Immune cell function among the myocardium, now more than ever, is appreciated to regulate cardiac function and pathophysiology. This is the case for both innate immunity, which includes neutrophils, monocytes, dendritic cells, and macrophages, as well as adaptive immunity, which includes T cells and B cells. This function is fueled by cell-intrinsic shifts in metabolism, such as glycolysis and oxidative phosphorylation, as well as metabolite availability, which originates from the surrounding extracellular milieu and varies during ischemia and metabolic syndrome. Immune cell crosstalk with cardiac parenchymal cells, such as cardiomyocytes and fibroblasts, is also regulated by complex cellular metabolic circuits. Although our understanding of immunometabolism has advanced rapidly over the past decade, in part through valuable insights made in cultured cells, there remains much to learn about contributions of in vivo immunometabolism and directly within the myocardium. Insight into such fundamental cell and molecular mechanisms holds potential to inform interventions that shift the balance of immunometabolism from maladaptive to cardioprotective and potentially even regenerative. Herein, we review our current working understanding of immunometabolism, specifically in the settings of sterile ischemic cardiac injury or cardiometabolic disease, both of which contribute to the onset of heart failure. We also discuss current gaps in knowledge in this context and therapeutic implications.

Keywords:  heart failure; immunometabolism; myocardial infarction

DOI:  https://doi.org/10.1016/j.jacbts.2022.12.010
Int J Mol Sci. 2023 Jul 26. pii: 11937. [Epub ahead of print]24(15):

Surveying the Metabolic and Dysfunctional Profiles of T Cells and NK Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Jessica Maya.

  Millions globally suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The inflammatory symptoms, illness onset, recorded outbreak events, and physiological variations provide strong indications that ME/CFS, at least sometimes, has an infectious origin, possibly resulting in a chronic unidentified viral infection. Meanwhile, studies exposing generalized metabolic disruptions in ME/CFS have stimulated interest in isolated immune cells with an altered metabolic state. As the metabolism dictates the cellular function, dissecting the biomechanics of dysfunctional immune cells in ME/CFS can uncover states such as exhaustion, senescence, or anergy, providing insights into the consequences of these phenotypes in this disease. Despite the similarities that are seen metabolically between ME/CFS and other chronic viral infections that result in an exhausted immune cell state, immune cell exhaustion has not yet been verified in ME/CFS. This review explores the evidence for immunometabolic dysfunction in ME/CFS T cell and natural killer (NK) cell populations, comparing ME/CFS metabolic and functional features to dysfunctional immune cell states, and positing whether anergy, exhaustion, or senescence could be occurring in distinct immune cell populations in ME/CFS, which is consistent with the hypothesis that ME/CFS is a chronic viral disease. This comprehensive review of the ME/CFS immunometabolic literature identifies CD8+ T cell exhaustion as a probable contender, underscores the need for further investigation into the dysfunctional state of CD4+ T cells and NK cells, and explores the functional implications of molecular findings in these immune-cell types. Comprehending the cause and impact of ME/CFS immune cell dysfunction is critical to understanding the physiological mechanisms of ME/CFS, and developing effective treatments to alleviate the burden of this disabling condition.

Keywords:  NK cells; T cell exhaustion; T cells; chronic fatigue syndrome; immune cell dysfunction; immunometabolism; myalgic encephalomyelitis

DOI:  https://doi.org/10.3390/ijms241511937
Cell Mol Immunol. 2023 Aug 09.

The TNFα/TNFR2 axis mediates natural killer cell proliferation by promoting aerobic glycolysis.

Abrar Ul Haq Khan, Alaa Kassim Ali, Bryan Marr, Donghyeon Jo, Simin Ahmadvand, Claire Fong-McMaster, Saeedah Musaed Almutairi, Lisheng Wang, Subash Sad, Mary-Ellen Harper, Seung-Hwan Lee.

  Natural killer (NK) cells are predominant innate lymphocytes that initiate the early immune response during infection. NK cells undergo a metabolic switch to fuel augmented proliferation and activation following infection. Tumor necrosis factor-alpha (TNFα) is a well-known inflammatory cytokine that enhances NK cell function; however, the mechanism underlying NK cell proliferation in response to TNFα is not well established. Here, we demonstrated that upon infection/inflammation, NK cells upregulate the expression of TNF receptor 2 (TNFR2), which is associated with increased proliferation, metabolic activity, and effector function. Notably, IL-18 can induce TNFR2 expression in NK cells, augmenting their sensitivity toward TNFα. Mechanistically, TNFα-TNFR2 signaling upregulates the expression of CD25 (IL-2Rα) and nutrient transporters in NK cells, leading to a metabolic switch toward aerobic glycolysis. Transcriptomic analysis revealed significantly reduced expression levels of genes involved in cellular metabolism and proliferation in NK cells from TNFR2 KO mice. Accordingly, our data affirmed that genetic ablation of TNFR2 curtails CD25 upregulation and TNFα-induced glycolysis, leading to impaired NK cell proliferation and antiviral function during MCMV infection in vivo. Collectively, our results delineate the crucial role of the TNFα-TNFR2 axis in NK cell proliferation, glycolysis, and effector function.

Keywords:  Glycolysis; Murine cytomegalovirus; Natural killer cells; Proliferation; TNFR2; TNFα

DOI:  https://doi.org/10.1038/s41423-023-01071-4
Front Immunol. 2023 ;14 1221530

Glutaminolysis and peripheral CD4+ T cell differentiation: from mechanism to intervention strategy.

Tong Liu, Shaohua Ren, Chenglu Sun, Pengyu Zhao, Hao Wang.

  To maintain the body's regular immune system, CD4+ T cell homeostasis is crucial, particularly T helper (Th1, Th17) cells and T regulatory (Treg) cells. Abnormally differentiated peripheral CD4+ T cells are responsible for the occurrence and development of numerous diseases, including autoimmune diseases, transplantation rejection, and irritability. Searching for an effective interventional approach to control this abnormal differentiation is therefore especially important. As immunometabolism progressed, the inherent metabolic factors underlying the immune cell differentiation have gradually come to light. Mounting number of studies have revealed that glutaminolysis plays an indelible role in the differentiation of CD4+ T cells. Besides, alterations in the glutaminolysis can also lead to changes in the fate of peripheral CD4+ T cells. All of this indicate that the glutaminolysis pathway has excellent potential for interventional regulation of CD4+ T cells differentiation. Here, we summarized the process by which glutaminolysis regulates the fate of CD4+ T cells during differentiation and further investigated how to reshape abnormal CD4+ T cell differentiation by targeting glutaminolysis.

Keywords:  CD4 + T cells; T cell differentiation; glutaminolysis; immunometabolism; intervention strategy

DOI:  https://doi.org/10.3389/fimmu.2023.1221530
Cell Mol Immunol. 2023 Aug 09.

A metabolite from commensal Candida albicans enhances the bactericidal activity of macrophages and protects against sepsis.

Peng Gu, Ruofan Liu, Qin Yang, Li Xie, Rongjuan Wei, Jiaxin Li, Fengyi Mei, Tao Chen, Zhenhua Zeng, Yan He, Hongwei Zhou, Hongjuan Peng, Kutty Selva Nandakumar, Huikuan Chu, Yong Jiang, Wei Gong, Ye Chen, Bernd Schnabl, Peng Chen.

  The gut microbiome is recognized as a key modulator of sepsis development. However, the contribution of the gut mycobiome to sepsis development is still not fully understood. Here, we demonstrated that the level of Candida albicans was markedly decreased in patients with bacterial sepsis, and the supernatant of Candida albicans culture significantly decreased the bacterial load and improved sepsis symptoms in both cecum ligation and puncture (CLP)-challenged mice and Escherichia coli-challenged pigs. Integrative metabolomics and the genetic engineering of fungi revealed that Candida albicans-derived phenylpyruvate (PPA) enhanced the bactericidal activity of macrophages and reduced organ damage during sepsis. Mechanistically, PPA directly binds to sirtuin 2 (SIRT2) and increases reactive oxygen species (ROS) production for eventual bacterial clearance. Importantly, PPA enhanced the bacterial clearance capacity of macrophages in sepsis patients and was inversely correlated with the severity of sepsis in patients. Our findings highlight the crucial contribution of commensal fungi to bacterial disease modulation and expand our understanding of the host-mycobiome interaction during sepsis development.

Keywords:  Bacterial clearance; Candida albicans; Macrophage; Phenylpyruvate; Sepsis

DOI:  https://doi.org/10.1038/s41423-023-01070-5
Cell Prolif. 2023 Aug 08. e13531

Apoptotic bodies inhibit inflammation by PDL1-PD1-mediated macrophage metabolic reprogramming.

Tao Jiang, Yanmin Xia, Wenzhe Wang, Jinbo Zhao, Wenhao Liu, Shiyu Liu, Songtao Shi, Bei Li, Xiaoning He, Yan Jin.

Apoptosis triggers immunoregulation to prevent and suppress inflammation and autoimmunity. However, the mechanism by which apoptotic cells modulate immune responses remains largely elusive. In the context of allogeneic mesenchymal stem cells (MSCs) transplantation, long-term immunoregulation is observed in the host despite the short survive of the injected MSCs. In this study, utilizing a mouse model of acute lung injury (ALI), we demonstrate that apoptotic bodies (ABs) released by transplanted human umbilical cord MSCs (UC-MSCs) convert the macrophages from a pro-inflammatory to an anti-inflammatory state, thereby ameliorating the disease. Mechanistically, we identify the expression of programmed cell death 1 ligand 1 (PDL1) on the membrane of UC-MSCs-derived ABs, which interacts with programmed cell death protein 1 (PD1) on host macrophages. This interaction leads to the reprogramming of macrophage metabolism, shifting from glycolysis to mitochondrial oxidative phosphorylation via the Erk-dependent pathway in ALI. Importantly, we have reproduced the PDL1-PD1 effects of ABs on metabolic switch using alveolar macrophages from patients with ALI, suggesting the potential clinical implications of developing therapeutic strategies for the patients.

DOI: https://doi.org/10.1111/cpr.13531
Blood Adv. 2023 Aug 08. pii: bloodadvances.2023010305. [Epub ahead of print]

T-cell dysfunction by pseudohypoxia and autocrine purinergic signaling in chronic lymphocytic leukemia.

Chiara Montironi, Chaja Feige Jacobs, Gaspard Cretenet, Fleur S Peters, Bauke V Schomakers, Michel van Weeghel, Arnon P Kater, Helga Simon-Molas, Eric Eldering.

Acquired T-cell dysfunction is common in chronic B-cell malignancies. Given the strong connection between T-cell metabolism and function, we investigated metabolic alterations as the basis for T-cell dysfunction induced by malignant cells. Using B-cell malignant cell lines and human PBMCs, we first established a model which recapitulates major aspects of cancer-induced T-cell dysfunction. Cell lines derived from chronic lymphocytic leukemia (PGA-1, CII, Mec-1), but not from other B-cell malignancies, altered T-cell metabolome by generating a pseudohypoxic state. T cells were retained in aerobic glycolysis and were not able to switch to OXPHOS. Moreover, T cells produced immunosuppressive adenosine that negatively affected function by dampening activation, which could be restored by blocking of adenosine receptors. Subsequently, we uncovered a similar hypoxic-like signature in autologous T cells from primary CLL samples. Pseudohypoxia was reversible upon depletion of CLL cells ex vivo and, importantly, after in vivo reduction of the leukemic burden with combination therapy (Venetoclax and Obinutuzumab), restoring T-cell function. In conclusion, we uncover a pseudohypoxic program connected with T cell dysfunction in CLL. Modulation of hypoxia and the purinergic pathway might contribute to therapeutic restoration of T-cell function.

DOI: https://doi.org/10.1182/bloodadvances.2023010305
Clin Immunol. 2023 Aug 08. pii: S1521-6616(23)00492-8. [Epub ahead of print] 109729

Elevated glucose metabolism driving pro-inflammatory response in B cells contributes to the progression of type 1 diabetes.

Zeying Li, Mingjiu Zhao, Jingyue Li, Wenjun Luo, Juan Huang, Gan Huang, Zhiguo Xie, Yang Xiao, Jiaqi Huang, Xia Li, Bin Zhao, Zhiguang Zhou.

  Type 1 diabetes (T1D) is an autoimmune disease characterized by the immune system's failure to maintain self-tolerance, resulting in the autoimmune destruction of pancreatic beta cells. Although T1D has conventionally been viewed as a T-cell-dominant disease, recent research has emphasized the contribution of B cells in the onset of the disease. However, the mechanism underlying aberrant B cell responses remains unknown. B cell metabolism is a crucial prerequisite for B cell function and the development of adaptive immune responses. Here, we investigated the metabolic features of B cells, first in a cross-sectional cohort and subsequently in non-obese diabetic (NOD) mice, and revealed that there is an increased frequency of high-glucose-avidity (2-NBDGhigh) B cell population that may contribute to T1D progression. Further characterization of the metabolic, transcriptional and functional phenotype of B cells in NOD mice found that elevated glucose avidity is associated with a greater capacity for co-stimulation, proliferation and inflammatory cytokine production. Mechanistically, elevated Myc signaling orchestrated the glucose metabolism and the pro-inflammatory response of B cells in T1D. In vitro experiments demonstrated that pharmacological inhibition of glucose metabolism using metformin and 2-DG reduced pro-inflammatory cytokine production and B cell proliferation. Moreover, the combination of these inhibitors successfully delayed insulitis development, onset of diabetes, and improved high blood glucose levels in streptozotocin (STZ)-induced diabetic mice model. Taken together, our work has uncovered these high-glucose-avidity B cells as novel adjuvant diagnostic and therapeutic targets for T1D.

Keywords:  Autoimmunity; B cells; Glucose metabolism; LADA; Metabolic inhibitors; Type 1 diabetes

DOI:  https://doi.org/10.1016/j.clim.2023.109729
ACS Nano. 2023 Aug 11.

mTOR-Mediated Immunometabolic Reprogramming Nanomodulators Enable Sensitive Switching of Energy Deprivation-Induced Microglial Polarization for Alzheimer's Disease Management.

Fan Yang, Dongju Zhao, Meng Cheng, Yining Liu, Ziyao Chen, Jin Chang, Yan Dou.

  Metabolic reprogramming that senses brain homeostasis imbalances is necessary to drive detrimental microglial polarization, and specific targeting of this process contributes to the flexible control of pathological inflammatory responses in Alzheimer's disease (AD), displaying distinctive therapeutic benefits. Herein, glutathione-functionalized gold nanocages loaded with the immunosuppressant fingolimod hydrochloride are developed as brain-targeted and microglia-located immunometabolic reprogramming nanomodulators (GAF NPs) for AD management. By virtue of glutathione-mediated transport properties, this nanomodulator can cross the blood-brain barrier and localize to microglia in AD lesions. Through blocking Akt/mTOR/HIF-1α signaling pathways, GAF NPs not only promote the dominated metabolic shift from glycolysis to oxidative phosphorylation under immune activation but also inhibit transporter-mediated glucose overconsumption by microglia. Correlation analysis based on real-time bioenergetic assessment and 18F-labeled fluorodeoxyglucose (FDG) PET reveals that brain glucose utilization and metabolism restored by GAF NP treatment can serve as a sensitive and effective indicator for microglial M1 to M2 polarization switching, ultimately alleviating neuroinflammation and its derived neurodegeneration as well as ameliorating cognitive decline in AD mice. This work highlights a potential nanomedicine aimed at modifying mTOR-mediated immunometabolic reprogramming to halt energy deprivation-induced AD progression.

Keywords:  18F-FDG PET; Akt/mTOR/HIF-1α signaling; Alzheimer’s disease; Immunometabolic reprogramming; brain energy metabolism; microglial polarization; nanomedicine

DOI:  https://doi.org/10.1021/acsnano.3c03232
Cell Rep. 2023 Aug 09. pii: S2211-1247(23)00984-1. [Epub ahead of print]42(8): 112973

Pseudomonas aeruginosa hijacks the murine nitric oxide metabolic pathway to evade killing by neutrophils in the lung.

Yoshinari Nakatsuka, Masanori Matsumoto, Naohiro Inohara, Gabriel Núñez.

  Neutrophils play a critical role in the eradication of Pseudomonas aeruginosa, a major pathogen causing lung infection. However, the mechanisms used by the pathogen to evade neutrophil-mediated killing remain poorly understood. Using a high-density transposon screen, we find that P. aeruginosa colonization in the lung is promoted by pathogen nitrite reductase nirD. nirD is required for ammonia production from nitrite, a metabolite derived from nitrogen oxide (NO) generated by inducible NO synthetase (iNOS) in phagocytes. P. aeruginosa deficient in nirD exhibit reduced survival in wild-type neutrophils but not in iNOS-deficient neutrophils. Mechanistically, nirD enhances P. aeruginosa survival in neutrophils by inhibiting the localization of the pathogen in late phagosomes. P. aeruginosa deficient in nirD show impaired lung colonization after infection in wild-type mice but not in mice with selective iNos deficiency in neutrophils. Thus, P. aeruginosa uses neutrophil iNOS-mediated NO production to limit neutrophil pathogen killing and to promote its colonization in the lung.

Keywords:  CP: Immunology; CP: Microbiology; Pseudomonas aeruginosa; ammonium; iNos; immune evasion; lung infection; neutrophils; nirD; nitric oxide; nitrite reductase

DOI:  https://doi.org/10.1016/j.celrep.2023.112973
Int J Mol Sci. 2023 Jul 27. pii: 12032. [Epub ahead of print]24(15):

Impact of Lipid Metabolism on Macrophage Polarization: Implications for Inflammation and Tumor Immunity.

Evros Vassiliou, Renalison Farias-Pereira.

  Macrophage polarization is influenced by lipids, which also exert significant control over macrophage functions. Lipids and their metabolites are players in intricate signaling pathways that modulate macrophages' responses to pathogens, phagocytosis, ferroptosis, and inflammation. This review focuses on lipid metabolism and macrophage functions and addresses potential molecular targets for the treatment of macrophage-related diseases. While lipogenesis is crucial for lipid accumulation and phagocytosis in M1 macrophages, M2 macrophages likely rely on fatty acid β-oxidation to utilize fatty acids as their primary energy source. Cholesterol metabolism, regulated by factors such as SREBPs, PPARs, and LXRs, is associated with the cholesterol efflux capacity and the formation of foam cells (M2-like macrophages). Foam cells, which are targets for atherosclerosis, are associated with an increase in inflammatory cytokines. Lipolysis and fatty acid uptake markers, such as CD36, also contribute to the production of cytokines. Enhancing the immune system through the inhibition of lipid-metabolism-related factors can potentially serve as a targeted approach against tumor cells. Cyclooxygenase inhibitors, which block the conversion of arachidonic acid into various inflammatory mediators, influence macrophage polarization and have generated attention in cancer research.

Keywords:  cancer; inflammation; lipid; macrophage; metabolism; polarization

DOI:  https://doi.org/10.3390/ijms241512032
Sci Signal. 2023 08 08. 16(797): eade0385

TGF-β uncouples glycolysis and inflammation in macrophages and controls survival during sepsis.

Thierry Gauthier, Chen Yao, Tyrone Dowdy, Wenwen Jin, Yun-Ji Lim, Liliana C Patiño, Na Liu, Shannon I Ohlemacher, Andrew Bynum, Rida Kazmi, Carole A Bewley, Mladen Mitrovic, Daniel Martin, Robert J Morell, Michael Eckhaus, Mioara Larion, Roxane Tussiwand, John J O'Shea, WanJun Chen.

Changes in metabolism of macrophages are required to sustain macrophage activation in response to different stimuli. We showed that the cytokine TGF-β (transforming growth factor-β) regulates glycolysis in macrophages independently of inflammatory cytokine production and affects survival in mouse models of sepsis. During macrophage activation, TGF-β increased the expression and activity of the glycolytic enzyme PFKL (phosphofructokinase-1 liver type) and promoted glycolysis but suppressed the production of proinflammatory cytokines. The increase in glycolysis was mediated by an mTOR-c-MYC-dependent pathway, whereas the inhibition of cytokine production was due to activation of the transcriptional coactivator SMAD3 and suppression of the activity of the proinflammatory transcription factors AP-1, NF-κB, and STAT1. In mice with LPS-induced endotoxemia and experimentally induced sepsis, the TGF-β-induced enhancement in macrophage glycolysis led to decreased survival, which was associated with increased blood coagulation. Analysis of septic patient cohorts revealed that the expression of PFKL, TGFBRI (which encodes a TGF-β receptor), and F13A1 (which encodes a coagulation factor) in myeloid cells positively correlated with COVID-19 disease. Thus, these results suggest that TGF-β is a critical regulator of macrophage metabolism and could be a therapeutic target in patients with sepsis.

DOI: https://doi.org/10.1126/scisignal.ade0385
Nutrition. 2023 May 30. pii: S0899-9007(23)00121-1. [Epub ahead of print]115 112092

Acute exercise modulates the inflammatory response in adipose tissue in both lean and obese mice.

Débora Romualdo Lacerda, Albená Nunes-Silva, Ana Letícia Malheiros Silveira, Kátia Anunciação Costa, Débora Fernandes Rodrigues, Michele Macedo Moraes, Vanessa Pinho, Gustavo Batista Menezes, Mauro Martins Teixeira, Samuel Penna Wanner, Danusa Dias Soares, Adaliene Versiani Matos Ferreira.

  OBJECTIVES: Acute physical exercise acts as a metabolic stressor, promoting activation of the immune system, and this response could be relevant in the adipose tissue remodeling process. In addition, some cytokines have important functions in lipolysis. Because chronic exercise improves obesity-related metabolic and inflammatory dysfunction, herein we investigated the effect of acute exercise on the inflammatory responses in the adipose tissues of lean and obese mice.METHODS: Lean mice were fed a standard chow diet, whereas obese mice were fed a high-refined carbohydrate diet for 8 wk. Both groups were subjected to 60 min of moderate-intensity exercise.
RESULTS: In the epididymal adipose tissue of lean mice, exercise enhanced interleukin (IL)-6 and tumor necrosis factor-α levels, which correlated positively with increased serum free fatty acid concentrations. In vivo confocal imaging of epididymal adipose tissue vessels revealed higher recruitment of neutrophils after exercise. Also, the number of leukocytes expressing CD11b+F480- was elevated 6 h after exercise. Similarly, the chemokine (C-X-C motif) ligand 1 level increased at 6 h and remained high until 24 h after exercise. Myeloperoxidase activity was increased at 6, 12, and 24 h after exercise. Surprisingly, however, no changes were observed in epididymal adipose tissue from obese mice, considering proinflammatory cytokines (IL-6 and tumor necrosis factor-α). On the other hand, IL-13, IL-4, and IL-10 levels were higher in obese mice after exercise.
CONCLUSIONS: These data suggest that acute exercise promotes an inflammatory response in the adipose tissue of lean mice that is observed as part of its role in adipose tissue remodeling. In contrast, acute exercise promotes an antiinflammatory response in adipose tissue from obese mice, likely as an important tool for restoring homeostasis.

Keywords:  Cytokines; Exercise; High-refined carbohydrate diet; Inflammation; Obesity

DOI:  https://doi.org/10.1016/j.nut.2023.112092
Eur J Immunol. 2023 Aug 10. e2350418

Dimethyl itaconate selectively targets inflammatory and metabolic pathways in chronic lymphocytic leukemia.

Ilenia Sana, Maria Elena Mantione, Miriam Meloni, Michela Riba, Pamela Ranghetti, Lydia Scarfò, Paolo Ghia, Marta Muzio.

  Chronic Lymphocytic Leukemia (CLL) co-evolves with its own microenvironment where inflammatory stimuli including Toll Like Receptors (TLR) signaling can protect CLL cells from spontaneous and drug induced apoptosis by upregulating IκBζ, an atypical co-transcription factor. To dissect IκBζ-centered signaling pathways, we performed a gene expression profile of primary leukemic cells expressing either high or low levels of IκBζ after stimulation, highlighting that IκBζ is not only an inflammatory gene but it may control metabolic rewiring of malignant cells thus pointing to a novel potential opportunity for therapy. We exploited the capacity of the Dimethyl Itaconate (DI), an anti-inflammatory electrophilic synthetic derivative of the metabolite Itaconate, to target IκBζ. CLL cells, murine leukemic splenocytes, and leukocytes from healthy donors were treated in vitro with DI that abolished metabolic activation and reduced cell viability of leukemic cells only, even in the presence of robust TLR pre-stimulation. RNA sequencing highlighted that in addition to the expected electrophilic stress signature observed after DI treatment, novel pathways emerged including the downregulation of distinct MHC class II complex genes. In conclusion, DI not only abrogated the pro-inflammatory effects of TLR stimulation but also targeted a specific metabolic vulnerability in CLL cells. This article is protected by copyright. All rights reserved.

Keywords:  B cells; Dimethyl Itaconate; Inflammation; Toll like receptors; chronic lymphocytic leukemia

DOI:  https://doi.org/10.1002/eji.202350418
Front Immunol. 2023 ;14 1171150

Selenomethionine against titanium particle-induced osteolysis by regulating the ROS-dependent NLRP3 inflammasome activation via the β-catenin signaling pathway.

Ruixuan Yu, Yongjian Yuan, Zhicheng Liu, Long Liu, Zhaoning Xu, Yunpeng Zhao, Chunwang Jia, Pengfei Zhang, Hang Li, Yuhao Liu, Yi Wang, Weiwei Li, Lin Nie, Xuecheng Sun, Yuhua Li, Ben Liu, Haichun Liu.

  Wear debris-induced osteolysis, especially titanium (Ti) particles-induced osteolysis, is the most common cause of arthroplasty failure with no effective therapy. Previous studies have suggested that inflammation and impaired osteogenesis are associated with Ti particles -induced osteolysis. Selenium (Se) is an essential trace element in the human body, which forms selenomethionine (Se-Met) in nature, and selenoproteins has strong anti-inflammatory and antioxidant stress effects. In this study, the effects of Se-Met on Ti particles-induced osteolysis were observed and the potential mechanism was explored. We found that exogenous Se-Met relieved osteolysis induced by Ti particles in two animal models and MC3T3-E1 cells. We found that the addition of Se-Met effectively inhibited Ti particle-induced inflammation by regulating reactive oxygen species-dependent (ROS-dependent) NOD-like receptor protein 3 (NLRP3) inflammasome activation. These therapeutic effects were abrogated in MC3T3-E1 cells that had received a β-catenin antagonist, suggesting that Se-Met alleviates inflammatory osteolysis via the β-catenin signaling pathway. Collectively, these findings indicated that Se-Met may serve as a potential therapeutic agent for treating Ti particle-induced osteolysis.

Keywords:  NLRP3; inflammatory osteolysis; selenomethionine; titanium particle-induced osteolysis; β-catenin

DOI:  https://doi.org/10.3389/fimmu.2023.1171150
Cell Mol Immunol. 2023 Aug 09.

Glycogen synthase kinase 3 controls T-cell exhaustion by regulating NFAT activation.

Yubing Fu, Jinjia Wang, Chenfeng Liu, Kunyu Liao, Xianjun Gao, Ronghan Tang, Binbin Fan, Yazhen Hong, Nengming Xiao, Changchun Xiao, Wen-Hsien Liu.

  Cellular immunity mediated by CD8+ T cells plays an indispensable role in bacterial and viral clearance and cancers. However, persistent antigen stimulation of CD8+ T cells leads to an exhausted or dysfunctional cellular state characterized by the loss of effector function and high expression of inhibitory receptors during chronic viral infection and in tumors. Numerous studies have shown that glycogen synthase kinase 3 (GSK3) controls the function and development of immune cells, but whether GSK3 affects CD8+ T cells is not clearly elucidated. Here, we demonstrate that mice with deletion of Gsk3α and Gsk3β in activated CD8+ T cells (DKO) exhibited decreased CTL differentiation and effector function during acute and chronic viral infection. In addition, DKO mice failed to control tumor growth due to the upregulated expression of inhibitory receptors and augmented T-cell exhaustion in tumor-infiltrating CD8+ T cells. Strikingly, anti-PD-1 immunotherapy substantially restored tumor rejection in DKO mice. Mechanistically, GSK3 regulates T-cell exhaustion by suppressing TCR-induced nuclear import of NFAT, thereby in turn dampening NFAT-mediated exhaustion-related gene expression, including TOX/TOX2 and PD-1. Thus, we uncovered the molecular mechanisms underlying GSK3 regulation of CTL differentiation and T-cell exhaustion in anti-tumor immune responses.

Keywords:  Anti-tumor immunity; GSK3; Inhibitory receptors; T-cell exhaustion; Viral infection

DOI:  https://doi.org/10.1038/s41423-023-01075-0
Cancers (Basel). 2023 Jul 31. pii: 3898. [Epub ahead of print]15(15):

Metabolites and Immune Response in Tumor Microenvironments.

Salvatore Cortellino, Valter D Longo.

  The remodeled cancer cell metabolism affects the tumor microenvironment and promotes an immunosuppressive state by changing the levels of macro- and micronutrients and by releasing hormones and cytokines that recruit immunosuppressive immune cells. Novel dietary interventions such as amino acid restriction and periodic fasting mimicking diets can prevent or dampen the formation of an immunosuppressive microenvironment by acting systemically on the release of hormones and growth factors, inhibiting the release of proinflammatory cytokines, and remodeling the tumor vasculature and extracellular matrix. Here, we discuss the latest research on the effects of these therapeutic interventions on immunometabolism and tumor immune response and future scenarios pertaining to how dietary interventions could contribute to cancer therapy.

Keywords:  diets; immune system; metabolism

DOI:  https://doi.org/10.3390/cancers15153898