bims-imicid 2022-10-16 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022‒10‒16
forty papers selected by
Dylan Ryan
University of Cambridge

Reprogramming T-Cell Metabolism for Better Anti-Tumor Immunity.
CD8+ T cell metabolic changes in breast cancer.
Metabolic and epigenetic orchestration of (CAR) T cell fate and function.
Macrophage Mitochondrial Biogenesis and Metabolic Reprogramming Induced by Leishmania donovani Require Lipophosphoglycan and Type I Interferon Signaling.
Glutaminolysis and CD4+ T-cell metabolism in autoimmunity: From pathogenesis to therapy prospects.
Metabolic communication in the tumour-immune microenvironment.
Editorial: The emerging role of metabolism and metabolic-related receptors on neutrophil extracellular traps (NET) formation.
Lactate induces metabolic and epigenetic reprogramming of pro-inflammatory Th17 cells.
Proline metabolism reprogramming of trained macrophages induced by early respiratory infection combined with allergen sensitization contributes to development of allergic asthma in childhood of mice.
Lactate-Lactylation Hands between Metabolic Reprogramming and Immunosuppression.
Metabolic homeostasis-regulated nanoparticles for antibody-independent cancer radio-immunotherapy.
Targeting mitochondrial quality control of T cells: Regulating the immune response in HCC.
Role of T Cells in the Pathogenesis of Rheumatoid Arthritis: Focus on Immunometabolism Dysfunctions.
The metabolic plasticity of B cells.
Long noncoding RNA THRIL promotes foam cell formation and inflammation in macrophages.
Rheumatoid arthritis and mitochondrial homeostasis: The crossroads of metabolism and immunity.
The Hippo kinase MST1 negatively regulates the differentiation of follicular helper T cells.
Inhibition of pyruvate dehydrogenase kinase 4 in CD4+ T cells ameliorates intestinal inflammation.
Modeling the effect of environmental cytokines, nutrient conditions and hypoxia on CD4+ T cell differentiation.
Linking nutrient sensing, mitochondrial function, and PRR immune cell signaling in liver disease.
Mannose inhibits Plasmodium parasite growth and cerebral malaria development via regulation of host immune responses.
You are what you eat: How to best fuel your immune system.
Loss of immune regulation in aged T-cells: A metabolic review to show lack of ability to control responses within the self.
Acute cytokine treatment stimulates glucose uptake and glycolysis in human keratinocytes.
Meningeal dendritic cells drive neuropathic pain through elevation of the kynurenine metabolic pathway in mice.
Visualizing inflammation with an M1 macrophage selective probe via GLUT1 as the gating target.
The interferon-inducible protein viperin controls cancer metabolic reprogramming to enhance cancer progression.
T-bet+ B cells exacerbate obesity-related metabolic disease.
HSC derived fatty acid oxidation in steady state and stressed haematopoiesis.
Early effects of LPS-induced neuroinflammation on the rat hippocampal glycolytic pathway.
PARP-inhibition reprograms macrophages toward an anti-tumor phenotype.
High Endogenously Synthesized N-3 Polyunsaturated Fatty Acids in Fat-1 Mice Attenuate High-Fat Diet-Induced Insulin Resistance by Inhibiting NLRP3 Inflammasome Activation via Akt/GSK-3β/TXNIP Pathway.
Resident TH2 cells orchestrate adipose tissue remodeling at a site adjacent to infection.
Sustained Inflammation Induced by LPS Leads to Tolerable Anorexia and Fat Loss via Tlr4 in Mice.
S100A8-mediated metabolic adaptation controls HIV-1 persistence in macrophages in vivo.
Pleiotropic Effects of Vitamin D in Patients with Inflammatory Bowel Diseases.
Obesity Exacerbates Lupus Activity in Fc Gamma Receptor IIb Deficient Lupus Mice Partly through Saturated Fatty Acid-Induced Gut Barrier Defect and Systemic Inflammation.
Dietary D-Lactate Intake Facilitates Inflammatory Resolution by Modulating M1 Macrophage Polarization.
A bacterial phospholipid phosphatase inhibits host pyroptosis by hijacking ubiquitin.
The role of host heme in bacterial infection.

Cells. 2022 Oct 01. pii: 3103. [Epub ahead of print]11(19):

Reprogramming T-Cell Metabolism for Better Anti-Tumor Immunity.

Yu Ping, Chunyi Shen, Bo Huang, Yi Zhang.

  T cells play central roles in the anti-tumor immunity, whose activation and differentiation are profoundly regulated by intrinsic metabolic reprogramming. Emerging evidence has revealed that metabolic processes of T cells are generally altered by tumor cells or tumor released factors, leading to crippled anti-tumor immunity. Therefore, better understanding of T cell metabolic mechanism is crucial in developing the next generation of T cell-based anti-tumor immunotherapeutics. In this review, we discuss how metabolic pathways affect T cells to exert their anti-tumor effects and how to remodel the metabolic programs to improve T cell-mediated anti-tumor immune responses. We emphasize that glycolysis, carboxylic acid cycle, fatty acid oxidation, cholesterol metabolism, amino acid metabolism, and nucleotide metabolism work together to tune tumor-reactive T-cell activation and proliferation.

Keywords:  T cell; T cell metabolism; anti-tumor function; tumor microenvironment

DOI:  https://doi.org/10.3390/cells11193103
Biochim Biophys Acta Mol Basis Dis. 2022 Oct 08. pii: S0925-4439(22)00236-8. [Epub ahead of print] 166565

CD8+ T cell metabolic changes in breast cancer.

Angela Castoldi, Jennifer Lee, Daniel de Siqueira Carvalho, Fabrício O Souto.

  Immunometabolism has advanced our understanding of how the cellular environment and nutrient availability regulates immune cell fate. Not only are metabolic pathways closely tied to cell signaling and differentiation, but can induce different subsets of immune cells to adopt unique metabolic programs, influencing disease progression. Dysregulation of immune cell metabolism plays an essential role in the progression of several diseases including breast cancer (BC). Metabolic reprogramming plays a critical role in regulating T cell functions. CD8+ T cells are an essential cell type within the tumor microenvironment (TME). To induce antitumor responses, CD8+ T cells need to adapt their metabolism to fulfill their energy requirement for effective function. However, different markers and immunologic techniques have made identifying specific CD8+ T cells subtypes in BC a challenge to the field. This review discusses the immunometabolic processes of CD8+ T cell in the TME in the context of BC and highlights the role of CD8+ T cell metabolic changes in tumor progression.

Keywords:  Breast cancer; CD8(+) T cells; Immunometabolism; Tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.bbadis.2022.166565
Cancer Lett. 2022 Oct 07. pii: S0304-3835(22)00435-9. [Epub ahead of print]550 215948

Metabolic and epigenetic orchestration of (CAR) T cell fate and function.

Behnia Akbari, Zahra Hosseini, Pardis Shahabinejad, Saba Ghassemi, Hamid Reza Mirzaei, Roddy S O'Connor.

  Longevity, functionality, and metabolic fitness are key determinants of chimeric antigen receptor (CAR) T cell efficacy. Activated T cells follow an ordered differentiation program which is facilitated by metabolic adaptations. In response to antigen, T cells undergo a highly-regulated shift to glycolysis. Committing to, and engaging in, glycolysis supports T cell expansion and effector function. Inside tumors, heightened tumor cell metabolism and dysregulated perfusion create a competition for nutrients. As local metabolism supports the differentiation of T cells into functionally-competent progeny, nutrient depletion coupled with persisting antigen can trigger T cell exhaustion. Emerging insights into the barriers impeding CAR T cell function in hostile tumor microenvironments (TME) reveal that metabolic intermediates shape the immune response by influencing epigenetic programs and the control of gene expression. In this review, we discuss recent progress connecting cellular metabolism with epigenetic states in CAR T cells. Given that CAR T cell metabolism can be dynamically regulated, we introduce the concepts of "metabolic-based epigenetic altering" and "epigenetic-based metabolism altering" to restore functional competence in CARTs traversing solid TMEs.

Keywords:  CAR T cell; Epigenetics; Immunotherapy; Metabolism; T cell exhaustion

DOI:  https://doi.org/10.1016/j.canlet.2022.215948
mBio. 2022 Oct 12. e0257822

Macrophage Mitochondrial Biogenesis and Metabolic Reprogramming Induced by Leishmania donovani Require Lipophosphoglycan and Type I Interferon Signaling.

Hamlet Acevedo Ospina, Marie-Michèle Guay-Vincent, Albert Descoteaux.

  Pathogen-specific rewiring of host cell metabolism creates the metabolically adapted microenvironment required for pathogen replication. Here, we investigated the mechanisms governing the modulation of macrophage mitochondrial properties by the vacuolar pathogen Leishmania. We report that induction of oxidative phosphorylation and mitochondrial biogenesis by Leishmania donovani requires the virulence glycolipid lipophosphoglycan, which stimulates the expression of key transcriptional regulators and structural genes associated with the electron transport chain. Leishmania-induced mitochondriogenesis also requires a lipophosphoglycan-independent pathway involving type I interferon (IFN) receptor signaling. The observation that pharmacological induction of mitochondrial biogenesis enables an avirulent lipophosphoglycan-defective L. donovani mutant to survive in macrophages supports the notion that mitochondrial biogenesis contributes to the creation of a metabolically adapted environment propitious to the colonization of host cells by the parasite. This study provides novel insight into the complex mechanism by which Leishmania metacyclic promastigotes alter host cell mitochondrial biogenesis and metabolism during the colonization process. IMPORTANCE To colonize host phagocytes, Leishmania metacyclic promastigotes subvert host defense mechanisms and create a specialized intracellular niche adapted to their replication. This is accomplished through the action of virulence factors, including the surface coat glycoconjugate lipophosphoglycan. In addition, Leishmania induces proliferation of host cell mitochondria as well as metabolic reprogramming of macrophages. These metabolic alterations are crucial to the colonization process of macrophages, as they may provide metabolites required for parasite growth. In this study, we describe a new key role for lipophosphoglycan in the stimulation of oxidative phosphorylation and mitochondrial biogenesis. We also demonstrate that host cell pattern recognition receptors Toll-like receptor 4 (TLR4) and endosomal TLRs mediate these Leishmania-induced alterations of host cell mitochondrial biology, which also require type I IFN signaling. These findings provide new insight into how Leishmania creates a metabolically adapted environment favorable to their replication.

Keywords:  IFNAR; Leishmania; lipophosphoglycan; macrophages; mitochondria

DOI:  https://doi.org/10.1128/mbio.02578-22
Front Immunol. 2022 ;13 986847

Glutaminolysis and CD4+ T-cell metabolism in autoimmunity: From pathogenesis to therapy prospects.

Xiaojin Feng, Xue Li, Na Liu, Ningning Hou, Xiaodong Sun, Yongping Liu.

  The recent increase in the pathogenesis of autoimmune diseases revealed the critical role of T cells. Investigation into immunometabolism has drawn attention to metabolic processes other than glycometabolism. In rapidly dividing immune cells, including T lymphocytes, the consumption of glutamine is similar to or higher than that of glucose even though glucose is abundant. In addition to contributing to many processes critical for cellular integrity and function, glutamine, as the most abundant amino acid, was recently regarded as an immunomodulatory nutrient. A better understanding of the biological regulation of glutaminolysis in T cells will provide a new perspective for the treatment of autoimmune diseases. In this review, we summarized the current knowledge of glutamine catabolism in CD4+ T-cell subsets of autoimmunity. We also focused on potential treatments targeting glutaminolysis in patients with autoimmune diseases. Knowledge of immunometabolism is constantly evolving, and glutamine metabolism may be a potential therapeutic target for autoimmune disease therapy.

Keywords:  CD4+ T cells; autoimmune diseases; glutamine; glutaminolysis; immune response

DOI:  https://doi.org/10.3389/fimmu.2022.986847
Nat Cell Biol. 2022 Oct 13.

Metabolic communication in the tumour-immune microenvironment.

Kung-Chi Kao, Stefania Vilbois, Chin-Hsien Tsai, Ping-Chih Ho.

The metabolically hostile tumour microenvironment imposes barriers to tumour-infiltrating immune cells and impedes durable clinical remission following immunotherapy. Metabolic communication between cancer cells and their neighbouring immune cells could determine the amplitude and type of immune responses, highlighting a potential involvement of metabolic crosstalk in immune surveillance and escape. In this Review, we explore tumour-immune metabolic crosstalk and discuss potential nutrient-limiting strategies that favour anti-tumour immune responses.

DOI: https://doi.org/10.1038/s41556-022-01002-x
Front Immunol. 2022 ;13 1028228

Editorial: The emerging role of metabolism and metabolic-related receptors on neutrophil extracellular traps (NET) formation.

Rafael Agustín Burgos, Dirk Werling, Carlos Rodrigo Hermosilla.



Keywords:  NET (neutrophil extracellular traps); cellular reprogramming; immunometabolism; inflammation; innate immunity

DOI:  https://doi.org/10.3389/fimmu.2022.1028228
EMBO Rep. 2022 Oct 10. e54685

Lactate induces metabolic and epigenetic reprogramming of pro-inflammatory Th17 cells.

Aleksandra Lopez Krol, Hannah P Nehring, Felix F Krause, Anne Wempe, Hartmann Raifer, Andrea Nist, Thorsten Stiewe, Wilhelm Bertrams, Bernd Schmeck, Maik Luu, Hanna Leister, Ho-Ryun Chung, Uta-Maria Bauer, Till Adhikary, Alexander Visekruna.

  Increased lactate levels in the tissue microenvironment are a well-known feature of chronic inflammation. However, the role of lactate in regulating T cell function remains controversial. Here, we demonstrate that extracellular lactate predominantly induces deregulation of the Th17-specific gene expression program by modulating the metabolic and epigenetic status of Th17 cells. Following lactate treatment, Th17 cells significantly reduced their IL-17A production and upregulated Foxp3 expression through ROS-driven IL-2 secretion. Moreover, we observed increased levels of genome-wide histone H3K18 lactylation, a recently described marker for active chromatin in macrophages, in lactate-treated Th17 cells. In addition, we show that high lactate concentrations suppress Th17 pathogenicity during intestinal inflammation in mice. These results indicate that lactate is capable of reprogramming pro-inflammatory T cell phenotypes into regulatory T cells.

Keywords:  Th17 cells; Tregs; histone lactylation; immunometabolism; lactate

DOI:  https://doi.org/10.15252/embr.202254685
Front Immunol. 2022 ;13 977235

Proline metabolism reprogramming of trained macrophages induced by early respiratory infection combined with allergen sensitization contributes to development of allergic asthma in childhood of mice.

Hanglin Li, Linyan Ma, Wenjian Li, Boyang Zheng, Junhai Wang, Shunyan Chen, Yang Wang, Fei Ge, Beibei Qin, Xiaoqing Zheng, Yuqing Deng, Ruihong Zeng.

  Background: Infants with respiratory syncytial virus (RSV)-associated bronchiolitis are at increased risk of childhood asthma. Recent studies demonstrated that certain infections induce innate immune memory (also termed trained immunity), especially in macrophages, to respond more strongly to future stimuli with broad specificity, involving in human inflammatory diseases. Metabolic reprogramming increases the capacity of the innate immune cells to respond to a secondary stimulation, is a crucial step for the induction of trained immunity. We hypothesize that specific metabolic reprogramming of lung trained macrophages induced by neonatal respiratory infection is crucial for childhood allergic asthma.Objective: To address the role of metabolic reprogramming in lung trained macrophages induced by respiratory virus infection in allergic asthma.
Methods: Neonatal mice were infected and sensitized by the natural rodent pathogen Pneumonia virus of mice (PVM), a mouse equivalent strain of human RSV, combined with ovalbumin (OVA). Lung CD11b+ macrophages in the memory phase were re-stimulated to investigate trained immunity and metabonomics. Adoptive transfer, metabolic inhibitor and restore experiments were used to explore the role of specific metabolic reprogramming in childhood allergic asthma.
Results: PVM infection combined with OVA sensitization in neonatal mice resulted in non-Th2 (Th1/Th17) type allergic asthma following OVA challenge in childhood of mice. Lung CD11b+ macrophages in the memory phage increased, and showed enhanced inflammatory responses following re-stimulation, suggesting trained macrophages. Adoptive transfer of the trained macrophages mediated the allergic asthma in childhood. The trained macrophages showed metabolic reprogramming after re-stimulation. Notably, proline biosynthesis remarkably increased. Inhibition of proline biosynthesis suppressed the development of the trained macrophages as well as the Th1/Th17 type allergic asthma, while supplement of proline recovered the trained macrophages as well as the allergic asthma.
Conclusion: Proline metabolism reprogramming of trained macrophages induced by early respiratory infection combined with allergen sensitization contributes to development of allergic asthma in childhood. Proline metabolism could be a well target for prevention of allergic asthma in childhood.

Keywords:  allergic asthma; innate immune memory; proline metabolism reprogramming; respiratory virus infection; trained macrophages

DOI:  https://doi.org/10.3389/fimmu.2022.977235
Int J Mol Sci. 2022 Oct 08. pii: 11943. [Epub ahead of print]23(19):

Lactate-Lactylation Hands between Metabolic Reprogramming and Immunosuppression.

Lihua Chen, Lixiang Huang, Yu Gu, Wei Cang, Pengming Sun, Yang Xiang.

  Immune evasion and metabolic reprogramming are two fundamental hallmarks of cancer. Interestingly, lactate closely links them together. However, lactate has long been recognized as a metabolic waste product. Lactate and the acidification of the tumor microenvironment (TME) promote key carcinogenesis processes, including angiogenesis, invasion, metastasis, and immune escape. Notably, histone lysine lactylation (Kla) was identified as a novel post-modification (PTM), providing a new perspective on the mechanism by which lactate functions and providing a promising and potential therapy for tumors target. Further studies have confirmed that protein lactylation is essential for lactate to function; it involves important life activities such as glycolysis-related cell functions and macrophage polarization. This review systematically elucidates the role of lactate as an immunosuppressive molecule from the aspects of lactate metabolism and the effects of histone lysine or non-histone lactylation on immune cells; it provides new ideas for further understanding protein lactylation in elucidating lactate regulation of cell metabolism and immune function. We explored the possibility of targeting potential targets in lactate metabolism for cancer treatment. Finally, it is promising to propose a combined strategy inhibiting the glycolytic pathway and immunotherapy.

Keywords:  immune evasion; immunotherapy; lactate; lactylation; metabolic reprogramming

DOI:  https://doi.org/10.3390/ijms231911943
Adv Mater. 2022 Oct 12. e2207343

Metabolic homeostasis-regulated nanoparticles for antibody-independent cancer radio-immunotherapy.

Wenhao Shen, Teng Liu, Pei Pei, Junmei Li, Sai Yang, Yanxiang Zhang, Hailin Zhou, Lin Hu, Kai Yang.

  The special metabolic traits of cancer cells and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) are promising targets for developing novel cancer therapy strategies, especially the glycolysis and mitochondrial energy metabolism. However, therapies targeting a singular metabolic pathway are always counteracted by the metabolic reprogramming of cancer, resulting in unsatisfactory therapeutic effect. Herein, we employ polyethylene glycol-coated (PEGylated) liposomes as the drug delivery system (DDS) for both mannose and levamisole hydrochloride to simultaneously inhibit glycolysis and restrain mitochondrial energy metabolism and thus inhibit the tumor growth. In combination with radiotherapy, the liposomes could not only modulate the immunosuppressive TME by cellular metabolism regulation to achieve potent therapeutic effect for local tumors, but also suppress the M2 macrophage proliferation triggered by X-ray irradiation and thus enhance the immune response to inhibit metastatic lesions. In brief, we provide a new therapeutic strategy targeting the special metabolic traits of cancer cells and immunosuppressive TAMs to enhance the abscopal effect of radiotherapy for cancer. This article is protected by copyright. All rights reserved.

Keywords:  Abscopal effect; Autophagy; Cell metabolism; Radio-immunotherapy; Tumor-associated macrophages

DOI:  https://doi.org/10.1002/adma.202207343
Front Oncol. 2022 ;12 993437

Targeting mitochondrial quality control of T cells: Regulating the immune response in HCC.

Yixue Xia, Binghong Gao, Xue Zhang.

  Most of the primary hepatocellular carcinoma (HCC) develops from Viral Hepatitis including Hepatitis B virus, Hepatitis C Virus, and Nonalcoholic Steatohepatitis. Herein, T cells play crucial roles combined with chronic inflammation and chronic viral infection. However, T cells are gradually exhausted under chronic antigenic stimulation, which leads to T cell exhaustion in the tumor microenvironment, and the exhaustion is associated with mitochondrial dysfunction in T cells. Meanwhile, mitochondria play a crucial role in altering T cells' metabolism modes to achieve desirable immunological responses, wherein mitochondria maintain quality control (MQC) and promote metabolism regulation in the microenvironment. Although immune checkpoint inhibitors have been widely used in clinical practice, there are some limitations in the therapeutic effect, thus combining immune checkpoint inhibitors with targeting mitochondrial biogenesis may enhance cellular metabolic adaptation and reverse the exhausted state. At present, several studies on mitochondrial quality control in HCC have been reported, however, there are gaps in the regulation of immune cell function by mitochondrial metabolism, particularly the modulating of T cell immune function. Hence, this review summarizes and discusses existing studies on the effects of MQC on T cell populations in liver diseases induced by HCC, it would be clued by mitochondrial quality control events.

Keywords:  T cells exhaustion; hepatocellular carcinoma (HCC); immune cell; metabolism; mitochondria

DOI:  https://doi.org/10.3389/fonc.2022.993437
Inflammation. 2022 Oct 10.

Role of T Cells in the Pathogenesis of Rheumatoid Arthritis: Focus on Immunometabolism Dysfunctions.

Maryam Masoumi, Samira Alesaeidi, Hossein Khorramdelazad, Mousa Behzadi, Rasoul Baharlou, Shahin Alizadeh-Fanalou, Jafar Karami.

  Evidence demonstrated that metabolic-associated T cell abnormalities could be detected in the early stage of RA development. In this context, molecular evaluations have revealed changes in metabolic pathways, leading to the aggressive phenotype of RA T cells. A growing list of genes is downregulated or upregulated in RA T cells, and most of these genes with abnormal expression fall into the category of metabolic pathways. It has been shown that RA T cells shunt glucose towards the pentose phosphate pathway (PPP), which is associated with a high level of nicotinamide adenine dinucleotide phosphate (NADPH) and intermediate molecules. An increased level of NADPH inhibits ATM activation and thereby increases the proliferation capabilities of the RA T cells. Defects in the DNA repair nuclease MRE11A cause failures in repairing mitochondrial DNA, resulting in inhibiting the fatty acid oxidation pathway and further elevated cytoplasmic lipid droplets. Accumulated lipid droplets employ to generate lipid membranes for the cell building program and are also used to form the front-end membrane ruffles that are accomplices with invasive phenotypes of RA T cells. Metabolic pathway involvement in RA pathogenesis expands the pathogenic concept of the disease beyond the common view of autoimmunity triggered by autoantigen recognition. Increased knowledge about metabolic pathways' implications in RA pathogenesis paves the way to understand better the environment/gene interactions and host/microbiota interactions and introduce potential therapeutic approaches. This review summarized emerging data about the roles of T cells in RA pathogenesis with a focus on immunometabolism dysfunctions and how these metabolic alterations can affect the disease process.

Keywords:  Immunometabolism.; RA T cell; Rheumatoid arthritis

DOI:  https://doi.org/10.1007/s10753-022-01751-9
Front Mol Biosci. 2022 ;9 991188

The metabolic plasticity of B cells.

Yurena Vivas-García, Alejo Efeyan.

  The humoral response requires rapid growth, biosynthetic capacity, proliferation and differentiation of B cells. These processes involve profound B-cell phenotypic transitions that are coupled to drastic changes in metabolism so as to meet the extremely different energetic requirements as B cells switch from resting to an activated, highly proliferative state and to plasma or memory cell fates. Thus, B cells execute a multi-step, energetically dynamic process of profound metabolic rewiring from low ATP production to transient and large increments of energy expenditure that depend on high uptake and consumption of glucose and fatty acids. Such metabolic plasticity is under tight transcriptional and post-transcriptional regulation. Alterations in B-cell metabolism driven by genetic mutations or by extrinsic insults impair B-cell functions and differentiation and may underlie the anomalous behavior of pathological B cells. Herein, we review molecular switches that control B-cell metabolism and fuel utilization, as well as the emerging awareness of the impact of dynamic metabolic adaptations of B cells throughout the different phases of the humoral response.

Keywords:  B-cell activation; Oxphos; anabolism; glycolysis; humoral response; metabolic plasticity

DOI:  https://doi.org/10.3389/fmolb.2022.991188
Cell Biol Int. 2022 Oct 13.

Long noncoding RNA THRIL promotes foam cell formation and inflammation in macrophages.

Xiaosu Song, Fen Gao, Hong Li, Weiwei Qin, Chanjuan Chai, Guojuan Shi, Huiyu Yang.

  Tumor necrosis factor-α (TNF-α) and heterogenous nuclear ribonucleoprotein L (hnRNPL)-related immunoregulatory lincRNA (THRIL) is a long noncoding RNA (lncRNA) involved in various inflammatory diseases. However, its role in atherosclerosis is not known. In this study, we aimed to investigate the function of THRIL in mediating macrophage inflammation and foam cell formation. The expression of THRIL was quantified in THP-1 macrophages after treatment with oxidized low-density lipoprotein (oxLDL). The effect of THRIL overexpression and knockdown on oxLDL-induced inflammatory responses and lipid accumulation was determined. THRIL-associated protein partners were identified by RNA pull-down and RNA immunoprecipitation assays. We show that THRIL is upregulated in macrophages after oxLDL treatment. Knockdown of THRIL blocks oxLDL-induced expression of interleukin-1β (IL-1β), IL-6, and TNF-α and lipid accumulation. Conversely, ectopic expression of THRIL enhances inflammatory gene expression and lipid deposition in oxLDL-treated macrophages. Moreover, THRIL depletion increases cholesterol efflux from macrophages and the expression of ATP-binding cassette transporter (ABC) A1 and ABCG1. FOXO1 is identified as a protein partner of THRIL and promotes macrophage inflammation and lipid accumulation. Furthermore, overexpression of FOXO1 restores lipid accumulation and inflammatory cytokine production in THRIL-depleted macrophages. In conclusion, our data suggest a model where THRIL interacts with FOXO1 to promote macrophage inflammation and foam cell formation. THRIL may represent a therapeutic target for atherosclerosis.

Keywords:  FOXO1; atherosclerosis; cholesterol efflux; inflammation; lipid accumulation

DOI:  https://doi.org/10.1002/cbin.11934
Front Med (Lausanne). 2022 ;9 1017650

Rheumatoid arthritis and mitochondrial homeostasis: The crossroads of metabolism and immunity.

Liu Cui, Jing Weiyao, Su Chenghong, Liu Limei, Zhang Xinghua, Yuan Bo, Du Xiaozheng, Wang Haidong.

  Rheumatoid arthritis is an autoimmune disease characterized by chronic symmetric synovial inflammation and erosive bone destruction. Mitochondria are the main site of cellular energy supply and play a key role in the process of energy metabolism. They possess certain self-regulatory and repair capabilities. Mitochondria maintain relative stability in number, morphology, and spatial structure through biological processes, such as biogenesis, fission, fusion, and autophagy, which are collectively called mitochondrial homeostasis. An imbalance in the mitochondrial homeostatic environment will affect immune cell energy metabolism, synovial cell proliferation, apoptosis, and inflammatory signaling. These biological processes are involved in the onset and development of rheumatoid arthritis. In this review, we found that in rheumatoid arthritis, abnormal mitochondrial homeostasis can mediate various immune cell metabolic disorders, and the reprogramming of immune cell metabolism is closely related to their inflammatory activation. In turn, mitochondrial damage and homeostatic imbalance can lead to mtDNA leakage and increased mtROS production. mtDNA and mtROS are active substances mediating multiple inflammatory pathways. Several rheumatoid arthritis therapeutic agents regulate mitochondrial homeostasis and repair mitochondrial damage. Therefore, modulation of mitochondrial homeostasis would be one of the most attractive targets for the treatment of rheumatoid arthritis.

Keywords:  apoptosis and proliferation; energy metabolism; immune cells; inflammatory pathways; mitochondrial homeostasis; rheumatoid arthritis

DOI:  https://doi.org/10.3389/fmed.2022.1017650
Immunology. 2022 Oct 09.

The Hippo kinase MST1 negatively regulates the differentiation of follicular helper T cells.

Lin Dong, Yejin Cao, Hui Yang, Yueru Hou, Ying He, Yufei Wang, Qiuli Yang, Yujing Bi, Guangwei Liu.

  Follicular helper T (TFH ) cells are essential for inducing germinal center (GC) reactions to mediate humoral adaptive immunity and antiviral effects, but the mechanisms of TFH cell differentiation remain unclear. Here, we found that the Hippo kinase MST1 is critical for TFH cell differentiation, GC formation and antibody production under steady-state conditions and viral infection. MST1 deficiency intrinsically enhanced TFH cell differentiation and GC reactions in vivo and in vitro. Mechanistically, mTOR and HIF1α signaling is involved in glucose metabolism and increased glycolysis and decreased OXPHOS, which are critically required for MST1 deficiency-directed TFH cell differentiation. Moreover, upregulated Foxo3 expression is critically responsible for TFH cell differentiation induced by Mst1-/- . Thus, our findings identify a previously unrecognized relationship between Hippo kinase MST1 signaling and mTOR-HIF1α-metabolic reprogramming coupled with Foxo3 signaling in reprogramming TFH cell differentiation.

Keywords:  GC reaction; T cell differentiation; TFH; follicular helper T cells; infectious diseases; kinase MST1; metabolism; virus infection

DOI:  https://doi.org/10.1111/imm.13590
Cell Mol Gastroenterol Hepatol. 2022 Oct 10. pii: S2352-345X(22)00211-9. [Epub ahead of print]

Inhibition of pyruvate dehydrogenase kinase 4 in CD4+ T cells ameliorates intestinal inflammation.

Hoyul Lee, Jae Han Jeon, Yu-Jeong Lee, Mi-Jin Kim, Woong Hee Kwon, Dipanjan Chanda, Themis Thoudam, Haushabhau S Pagire, Suvarna H Pagire, Jin Hee Ahn, Robert A Harris, Eun Soo Kim, In-Kyu Lee.

  BACKGROUND AND AIMS: Despite recent evidence supporting the metabolic plasticity of CD4+ T cells, it is uncertain whether the metabolic checkpoint pyruvate dehydrogenase kinase (PDK) in T cells plays a role in the pathogenesis of colitis.METHODS: To investigate the role of PDK4 in colitis, we used dextran sulfate sodium (DSS)-induced colitis and T cell transfer colitis models based on mice with constitutive knockout (KO) or CD4+ T cell-specific KO of PDK4 (Pdk4fl/flCD4Cre). The effect of PDK4 deletion on T cell activation was also studied in vitro. Furthermore, we examined the effects of a pharmacological inhibitor of PDK4 on colitis.
RESULTS: Expression of PDK4 increased during colitis development in a DSS-induced colitis model. Phosphorylated PDHE1α, a substrate of PDK4, accumulated in CD4+ T cells in the lamina propria of patients with inflammatory bowel disease (IBD). Both constitutive KO and CD4+ T cell-specific deletion of PDK4 delayed DSS-induced colitis. Adoptive transfer of PDK4-deficient CD4+ T cells attenuated murine colitis, and PDK4 deficiency resulted in decreased activation of CD4+ T cells and attenuated aerobic glycolysis. Mechanistically, there were fewer endoplasmic reticulum-mitochondria contact sites, which are responsible for interorganelle calcium transfer, in PDK4-deficient CD4+ T cells. Consistent with this, GM-10395, a novel inhibitor of PDK4, suppressed T cell activation by reducing ER-mitochondria calcium transfer, thereby ameliorating murine colitis.
CONCLUSIONS: PDK4 deletion from CD4+ T cells mitigates colitis by metabolic and calcium signaling modulation, suggesting PDK4 as a potential therapeutic target for IBD.

Keywords:  Inflammatory bowel disease; Mitochondria-associated ER membrane; Pyruvate dehydrogenase kinase

DOI:  https://doi.org/10.1016/j.jcmgh.2022.09.016
Front Immunol. 2022 ;13 962175

Modeling the effect of environmental cytokines, nutrient conditions and hypoxia on CD4+ T cell differentiation.

David Martínez-Méndez, Leonor Huerta, Carlos Villarreal.

  Upon antigen stimulation and co-stimulation, CD4+ T lymphocytes produce soluble factors that promote the activity of other immune cells against pathogens or modified tissues; this task must be performed in presence of a variety of environmental cytokines, nutrient, and oxygen conditions, which necessarily impact T cell function. The complexity of the early intracellular processes taking place upon lymphocyte stimulation is addressed by means of a mathematical model based on a network that integrates variable microenvironmental conditions with intracellular activating, regulatory, and metabolic signals. Besides the phenotype subsets considered in previous works (Th1, Th2, Th17, and Treg) the model includes the main early events in differentiation to the T FH phenotype. The model describes how cytokines, nutrients and oxygen availability regulate the differentiation of naïve CD4+ T cells into distinct subsets. Particularly, it shows that elevated amounts of an all-type mixture of effector cytokines under optimal nutrient and oxygen availability conduces the system towards a highly-polarized Th1 or Th2 state, while reduced cytokine levels allow the expression of the Th17, Treg or T FH subsets, or even hybrid phenotypes. On the other hand, optimal levels of an all-type cytokine mixture in combination with glutamine or tryptophan restriction implies a shift from Th1 to Th2 expression, while decreased levels of the Th2-inducing cytokine IL-4 leads to the rupture of the Th1-Th2 axis, allowing the manifestation of different (or hybrid) subsets. Modeling proposes that, even under reduced levels of pro-inflammatory cytokines, the sole action of hypoxia boost Th17 expression.

Keywords:  CD4+ T cells; hybrid phenotypes; hypoxia; lymphocytes; mathematical model; metabolism; nutrients

DOI:  https://doi.org/10.3389/fimmu.2022.962175
Trends Immunol. 2022 Oct 01. pii: S1471-4906(22)00183-1. [Epub ahead of print]

Linking nutrient sensing, mitochondrial function, and PRR immune cell signaling in liver disease.

Claudia Kemper, Michael N Sack.

  Caloric overconsumption in vertebrates promotes adipose and liver fat accumulation while perturbing the gut microbiome. This triad triggers pattern recognition receptor (PRR)-mediated immune cell signaling and sterile inflammation. Moreover, immune system activation perpetuates metabolic consequences, including the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic hepatic steatohepatitis (NASH). Recent findings show that sensing of nutrient overabundance disrupts the activity and homeostasis of the central cellular energy-generating organelle, the mitochondrion. In parallel, whether caloric excess-initiated PRR signaling and mitochondrial perturbations are coordinated to amplify this inflammatory process in NASH progression remains in question. We hypothesize that altered mitochondrial function, classic PRR signaling, and complement activation in response to nutrient overload together play an integrated role across the immune cell landscape, leading to liver inflammation and NASH progression.

Keywords:  cardiometabolic disease; complement; liver; mitochondria; pattern recognition receptors

DOI:  https://doi.org/10.1016/j.it.2022.09.002
Front Immunol. 2022 ;13 859228

Mannose inhibits Plasmodium parasite growth and cerebral malaria development via regulation of host immune responses.

Li Lv, Zihao Xu, Meichen Zhao, Jian Gao, Rumeng Jiang, Qian Wang, Xiaoyu Shi.

  D-mannose can be transported into a variety of cells via glucose transporter (GLUT), and supraphysiological levels of D-mannose impairs tumor growth and modulates immune cell function through mechanisms such as interference with glycolysis and induction of oxidative stress. Blood-stage Plasmodium mainly depends on glycolysis for energy supply and pathological immune response plays a vital role in cerebral malaria. However, it is not clear whether mannose affects malaria blood-stage infection. Here, we fed D-mannose to Plasmodium berghei-infected mice and found weight loss and reduced parasitemia without apparent side effects. Compromised parasitemia in C57BL/6 mice was accompanied by an increase in splenic macrophages compared to an untreated group. When mannose was applied to a rodent experimental cerebral malaria (ECM) model, the incidence of ECM decreased. Expression of activation marker CD69 on T cells in peripheral blood and the brain were reduced, and cerebral migration of activated T cells was prevented by decreased expression of CXCR3. These findings suggest that mannose inhibits Plasmodium infection by regulating multiple host immune responses and could serve as a potential strategy for facilitating malaria treatment.

Keywords:  D-mannose; T cell; cerebral malaria; macrophage; parasitemia

DOI:  https://doi.org/10.3389/fimmu.2022.859228
Front Immunol. 2022 ;13 1003006

You are what you eat: How to best fuel your immune system.

Charlotte Hellmich, Edyta E Wojtowicz.

  Normal bone marrow (BM) homeostasis ensures consistent production of progenitor cells and mature blood cells. This requires a reliable supply of nutrients in particular free fatty acids, carbohydrates and protein. Furthermore, rapid changes can occur in response to stress such as infection which can alter the demand for each of these metabolites. In response to infection the haematopoietic stem cells (HSCs) must respond and expand rapidly to facilitate the process of emergency granulopoiesis required for the immediate immune response. This involves a shift from the use of glycolysis to oxidative phosphorylation for energy production and therefore an increased demand for metabolites. Thus, the right balance of each dietary component helps to maintain not only normal homeostasis but also the ability to quickly respond to systemic stress. In addition, some dietary components can drive chronic inflammatory changes in the absence of infection or immune stress, which in turn can impact on overall immune function. The optimal nutrition for the best immunological outcomes would therefore be a diet that supports the functions of immune cells allowing them to initiate effective responses against pathogens but also to resolve the response rapidly when necessary and to avoid any underlying chronic inflammation. In this review we discuss how these key dietary components can alter immune function, what is their impact on bone marrow metabolism and how changes in dietary intake of each of these can improve the outcomes of infections.

Keywords:  bone marrow; diet; hematopoiesis; infection; metabolism

DOI:  https://doi.org/10.3389/fimmu.2022.1003006
Hum Immunol. 2022 Oct 10. pii: S0198-8859(22)00204-X. [Epub ahead of print]

Loss of immune regulation in aged T-cells: A metabolic review to show lack of ability to control responses within the self.

Bharat Singh, Ambak Kumar Rai.

  The progressive decline of the anatomical architecture and loss of functional integrity of an individual is aging. Accumulation of degenerative cellular and molecular changes in the aging cells increases the fragility at the cellular and molecular levels. It pushes towards age-associated diseases like Alzheimer's disease, hypertension, cancer, cardiovascular diseases, etc. The impaired T cell function in aging is a leading contributor to increased susceptibility to pathogens, minimized vaccine response, and skewed inflammation. Recent studies about the role of T cells in the remodelling of the immune system have provided ways to examine and explore aging puzzles and their correlation with T cell functions. Here we review the metabolic aspect of T cell function and its possible restoration. IL-7 and mTOR mediated pathways and their association with reactivation of effector T cell function could help understanding the dark side of the compromised adaptive immune system, particularly T cell response, in aging. Understanding these crucial fundamentals could help design and target new molecules to prevent loss of T cell functionality in aging.

Keywords:  Aging; Immune system; Metabolism; T cells; mTOR

DOI:  https://doi.org/10.1016/j.humimm.2022.10.002
Cytokine. 2022 Oct 05. pii: S1043-4666(22)00266-6. [Epub ahead of print]161 156057

Acute cytokine treatment stimulates glucose uptake and glycolysis in human keratinocytes.

Vance Holt, Björn Morén, Claes Fryklund, Robert A Colbert, Karin G Stenkula.

  During inflammation, cellular glucose uptake and glycolysis are upregulated to meet an increased energy demand. For example, keratinocyte glycolysis is essential for progression of psoriasis. Therefore, understanding the regulation of glucose metabolism in keratinocytes is of importance. Here, we show that the pro-inflammatory cytokines IFNγ and TNF together rapidly induce glucose uptake, glycolysis, and glycolytic capacity in cultured keratinocytes. Furthermore, we found that acute IFNγ and TNF stimulation induces glucose transporter 4 (GLUT4) translocation to the plasma membrane and engages AMPK-dependent intracellular signaling. Together, these findings suggest acute cytokine-induced glucose metabolism in keratinocytes could contribute to inflammation in psoriatic disease, and that GLUT4 is involved in these processes.

Keywords:  GLUT4; Glucose uptake; IFNγ; Keratinocytes; TNF

DOI:  https://doi.org/10.1016/j.cyto.2022.156057
J Clin Invest. 2022 Oct 13. pii: e153805. [Epub ahead of print]

Meningeal dendritic cells drive neuropathic pain through elevation of the kynurenine metabolic pathway in mice.

Alexandre Gm Maganin, Guilherme R Souza, Miriam D Fonseca, Alexandre H Lopes, Rafaela M Mano Guimarães, André Dagostin, Nerry T Cecilio, Atlante S Mendes, William A Gonçalves, Conceição Ea Silva, Francisco I Fernandes Gomes, Lucas M Mauriz Marques, Rangel L Silva, Letícia M Arruda, Denis A Santana, Henrique Lemos, Lei Huang, Marcela Davoli-Ferreira, Danielle S Santana-Coelho, Morena B Sant'Anna, Ricardo Kusuda, Jhimmy Talbot, Gabriela Pacholczyk, Gabriela A Buqui, Norberto Lopes, Jose C Alves-Filho, Ricardo M Leão, Jason C O'Connor, Fernando Q Cunha, Andrew Mellor, Thiago Cunha.

  Neuropathic pain is one of the most important clinical consequences of injury to the somatosensory system. Nevertheless, the critical pathophysiological mechanisms involved in neuropathic pain development are poorly understood. In this study, we found that neuropathic pain is abrogated when the kynurenine metabolic pathway initiated by the enzyme indoleamine 2,3-dioxygenase (IDO1) is ablated pharmacologically or genetically. Mechanistically, it was found that IDO1-expressing dendritic cells (DCs) accumulated in the dorsal root leptomeninges and led to an increase in kynurenine levels in the spinal cord. In the spinal cord, kynurenine was metabolized by kynurenine-3-monooxygenase-expressing astrocytes into a pro-nociceptive metabolite 3-hydroxykynurenine. Ultimately, 3-hydroxyanthranilate 3,4-dioxygenase-derived quinolinic acid formed in the final step of the canonical KYNPATH was also involved in neuropathic pain development through the activation of the glutamatergic N-methyl-D-aspartate (NMDA) receptor. In conclusion, these data revealed a novel role for DCs driving neuropathic pain development through elevation of the kynurenine metabolic pathway. This novel paradigm offers potential new targets for drug development against this type of chronic pain.

Keywords:  Amino acid metabolism; Dendritic cells; Metabolism; Neuroscience; Pain

DOI:  https://doi.org/10.1172/JCI153805
Nat Commun. 2022 Oct 10. 13(1): 5974

Visualizing inflammation with an M1 macrophage selective probe via GLUT1 as the gating target.

Heewon Cho, Haw-Young Kwon, Amit Sharma, Sun Hyeok Lee, Xiao Liu, Naoki Miyamoto, Jong-Jin Kim, Sin-Hyeog Im, Nam-Young Kang, Young-Tae Chang.

Macrophages play crucial roles in protecting our bodies from infection and cancers. As macrophages are multi-functional immune cells, they have diverse plastic subsets, such as M1 and M2, derived from naïve M0 cells. Subset-specific macrophage probes are essential for deciphering and monitoring the various activation of macrophages, but developing such probes has been challenging. Here we report a fluorescent probe, CDr17, which is selective for M1 macrophages over M2 or M0. The selective staining mechanism of CDr17 is explicated as Gating-Oriented Live-cell Distinction (GOLD) through overexpressed GLUT1 in M1 macrophages. Finally, we demonstrate the suitability of CDr17 to track M1 macrophages in vivo in a rheumatoid arthritis animal model.

DOI: https://doi.org/10.1038/s41467-022-33526-z
J Clin Invest. 2022 Oct 13. pii: e157302. [Epub ahead of print]

The interferon-inducible protein viperin controls cancer metabolic reprogramming to enhance cancer progression.

Kyung Mi Choi, Jeong Jin Kim, Jihye Yoo, Ku Sul Kim, Youngeun Gu, John Eom, Haengdueng Jeong, Kyungeun Kim, Ki Taek Nam, Young Soo Park, Joon-Yong Chung, Jun-Young Seo.

  Metabolic reprogramming is an important cancer hallmark. However, the mechanisms driving metabolic phenotypes of cancer cells are unclear. Here, we showed that the interferon (IFN)-inducible protein, viperin, drives metabolic alteration in cancer cells. Viperin was observed in various types of cancer and inversely correlated with the survival rate of patients with gastric, lung, breast, renal, pancreatic, or brain cancer. By generating viperin knockdown or stably expressing cancer cells, we showed that viperin, but not a mutant lacking its iron-sulfur cluster-binding motif, increased lipogenesis and glycolysis via inhibition of fatty acid β-oxidation in cancer cells. In the tumor microenvironment, deficiency of fatty acids and oxygen as well as production of IFNs upregulated viperin expression via the PI3K/AKT/mTOR/HIF-1α and JAK/STAT pathways. Moreover, viperin was primarily expressed in cancer stem-like cells (CSCs) and functioned to promote metabolic reprogramming and enhance CSC properties, thereby facilitating tumor growth in xenograft mouse models. Collectively, our data indicate that viperin-mediated metabolic alteration drives the metabolic phenotype and progression of cancer.

Keywords:  Cancer; Fatty acid oxidation; Glucose metabolism; Metabolism; Oncology

DOI:  https://doi.org/10.1172/JCI157302
Trends Immunol. 2022 Oct 07. pii: S1471-4906(22)00206-X. [Epub ahead of print]

T-bet+ B cells exacerbate obesity-related metabolic disease.

Saad Khan, Daniel A Winer.

B cells are associated with the development of obesity-associated metabolic disease. Recently, Hägglöf, Vanz, et al. identified a novel obesity-related subset of B cells that are demarcated by the transcription factor T-bet and their pathogenic ability to worsen metabolic disease outcomes.

DOI: https://doi.org/10.1016/j.it.2022.09.011
Exp Hematol. 2022 Oct 09. pii: S0301-472X(22)00704-4. [Epub ahead of print]

HSC derived fatty acid oxidation in steady state and stressed haematopoiesis.

Jayna J Mistry, Kristian Bowles, Stuart A Rushworth.

  Metabolism impacts all cellular functions and plays a fundamental role in physiology. Metabolic regulation in hematopoiesis is dynamically regulated under steady state and stress conditions. It is clear, that hematopoietic stem cells (HSCs) impose different energy demands and flexibility during maintenance compared to stressed conditions. However, the cellular and molecular mechanism underlying the metabolic regulation in HSCs remains poorly understand. In this review we focus on defining the role of fatty acid oxidation (FAO) in HSC. We will first review the existing literature describing FAO in HSCs under steady state hematopoiesis. Next, we will describe the models used to examine HSCs under stress conditions and finally, we will describe how infection causes a shift towards FAO in HSC and the impact of using this pathway has on emergency hematopoiesis.

Keywords:  Mitochondria; Stem cell; b-oxidation; metabolism

DOI:  https://doi.org/10.1016/j.exphem.2022.10.003
J Neuroinflammation. 2022 Oct 11. 19(1): 255

Early effects of LPS-induced neuroinflammation on the rat hippocampal glycolytic pathway.

Adriana Fernanda K Vizuete, Fernanda Fróes, Marina Seady, Caroline Zanotto, Larissa Daniele Bobermin, Ana Cristina Roginski, Moacir Wajner, André Quincozes-Santos, Carlos Alberto Gonçalves.

  Neuroinflammation is a common feature during the development of neurological disorders and neurodegenerative diseases, where glial cells, such as microglia and astrocytes, play key roles in the activation and maintenance of inflammatory responses in the central nervous system. Neuroinflammation is now known to involve a neurometabolic shift, in addition to an increase in energy consumption. We used two approaches (in vivo and ex vivo) to evaluate the effects of lipopolysaccharide (LPS)-induced neuroinflammation on neurometabolic reprogramming, and on the modulation of the glycolytic pathway during the neuroinflammatory response. For this, we investigated inflammatory cytokines and receptors in the rat hippocampus, as well as markers of glial reactivity. Mitochondrial respirometry and the glycolytic pathway were evaluated by multiple parameters, including enzymatic activity, gene expression and regulation by protein kinases. Metabolic (e.g., metformin, 3PO, oxamic acid, fluorocitrate) and inflammatory (e.g., minocycline, MCC950, arundic acid) inhibitors were used in ex vivo hippocampal slices. The induction of early inflammatory changes by LPS (both in vivo and ex vivo) enhanced glycolytic parameters, such as glucose uptake, PFK1 activity and lactate release. This increased glucose consumption was independent of the energy expenditure for glutamate uptake, which was in fact diverted for the maintenance of the immune response. Accordingly, inhibitors of the glycolytic pathway and Krebs cycle reverted neuroinflammation (reducing IL-1β and S100B) and the changes in glycolytic parameters induced by LPS in acute hippocampal slices. Moreover, the inhibition of S100B, a protein predominantly synthesized and secreted by astrocytes, inhibition of microglia activation and abrogation of NLRP3 inflammasome assembly confirmed the role of neuroinflammation in the upregulation of glycolysis in the hippocampus. Our data indicate a neurometabolic glycolytic shift, induced by inflammatory activation, as well as a central and integrative role of astrocytes, and suggest that interference in the control of neurometabolism may be a promising strategy for downregulating neuroinflammation and consequently for diminishing negative neurological outcomes.

Keywords:  Glucose uptake; Glycolysis; IL-1β; Neuroinflammation; PFK1; S100B

DOI:  https://doi.org/10.1186/s12974-022-02612-w
Cell Rep. 2022 Oct 11. pii: S2211-1247(22)01307-9. [Epub ahead of print]41(2): 111462

PARP-inhibition reprograms macrophages toward an anti-tumor phenotype.

Lin Wang, Dan Wang, Olmo Sonzogni, Shizhong Ke, Qi Wang, Abhishek Thavamani, Felipe Batalini, Sylwia A Stopka, Michael S Regan, Steven Vandal, Shengya Tian, Jocelin Pinto, Andrew M Cyr, Vanessa C Bret-Mounet, Gerard Baquer, Hans P Eikesdal, Min Yuan, John M Asara, Yujing J Heng, Peter Bai, Nathalie Y R Agar, Gerburg M Wulf.

  Poly(ADP)ribosylation inhibitors (PARPis) are toxic to cancer cells with homologous recombination (HR) deficiency but not to HR-proficient cells in the tumor microenvironment (TME), including tumor-associated macrophages (TAMs). As TAMs can promote or inhibit tumor growth, we set out to examine the effects of PARP inhibition on TAMs in BRCA1-related breast cancer (BC). The PARPi olaparib causes reprogramming of TAMs toward higher cytotoxicity and phagocytosis. A PARPi-related surge in NAD+ increases glycolysis, blunts oxidative phosphorylation, and induces reverse mitochondrial electron transport (RET) with an increase in reactive oxygen species (ROS) and transcriptional reprogramming. This reprogramming occurs in the absence or presence of PARP1 or PARP2 and is partially recapitulated by addition of NAD derivative methyl-nicotinamide (MNA). In vivo and ex vivo, the effect of olaparib on TAMs contributes to the anti-tumor efficacy of the PARPi. In vivo blockade of the "don't-eat-me signal" with CD47 antibodies in combination with olaparib improves outcomes in a BRCA1-related BC model.

Keywords:  CP: Cancer; NAD+; PARP-inhibitor; macrophages; tumor immunology; tumor metabolism

DOI:  https://doi.org/10.1016/j.celrep.2022.111462
Molecules. 2022 Sep 27. pii: 6384. [Epub ahead of print]27(19):

High Endogenously Synthesized N-3 Polyunsaturated Fatty Acids in Fat-1 Mice Attenuate High-Fat Diet-Induced Insulin Resistance by Inhibiting NLRP3 Inflammasome Activation via Akt/GSK-3β/TXNIP Pathway.

Pan Zhu, Jin-Jie Zhang, Yi Cen, Yong Yang, Feng Wang, Kun-Peng Gu, Hai-Tao Yang, Yun-Zhi Wang, Zu-Quan Zou.

  High-fat (HF) diets and low-grade chronic inflammation contribute to the development of insulin resistance and type 2 diabetes (T2D), whereas n-3 polyunsaturated fatty acids (PUFAs), due to their anti-inflammatory effects, protect against insulin resistance. Interleukin (IL)-1β is implicated in insulin resistance, yet how n-3 PUFAs modulate IL-1β secretion and attenuate HF diet-induced insulin resistance remains elusive. In this study, a HF diet activated NLRP3 inflammasome via inducing reactive oxygen species (ROS) generation and promoted IL-1β production primarily from adipose tissue preadipocytes, but not from adipocytes and induced insulin resistance in wild type (WT) mice. Interestingly, endogenous synthesized n-3 polyunsaturated fatty acids (PUFAs) reversed this process in HF diet-fed fat-1 transgenic mice although the HF diet induced higher weight gain in fat-1 mice, compared with the control diet. Mechanistically, palmitic acid (PA), the main saturated fatty acid in an HF diet inactivated AMPK and led to decreased GSK-3β phosphorylation, at least partially through reducing Akt activity, which ultimately blocked the Nrf2/Trx1 antioxidant pathway and induced TXNIP cytoplasm translocation and NLRP3 inflammasome activation, whereas docosahexaenoic acid (DHA), the most abundant n-3 PUFA in fat-1 adipose tissue, reversed this process via inducing Akt activation. Our GSK-3β shRNA knockdown study further revealed that GSK-3β played a pivot role between the upstream AMPK/Akt pathway and downstream Nrf2/Trx1/TXNIP pathway. Given that NLRP3 inflammasome is implicated in the development of most inflammatory diseases, our results suggest the potential of n-3 PUFAs in the prevention or adjuvant treatment of NLRP3 inflammasome-driven diseases.

Keywords:  IL-1β; NLRP3 inflammasome; docosahexaenoic acid; fat-1; insulin resistance; n-3 PUFAs; obesity

DOI:  https://doi.org/10.3390/molecules27196384
Sci Immunol. 2022 Oct 21. 7(76): eadd3263

Resident TH2 cells orchestrate adipose tissue remodeling at a site adjacent to infection.

Agnieszka M Kabat, Alexandra Hackl, David E Sanin, Patrice Zeis, Katarzyna M Grzes, Francesc Baixauli, Ryan Kyle, George Caputa, Joy Edwards-Hicks, Matteo Villa, Nisha Rana, Jonathan D Curtis, Angela Castoldi, Jovana Cupovic, Leentje Dreesen, Maria Sibilia, J Andrew Pospisilik, Joseph F Urban, Dominic Grün, Erika L Pearce, Edward J Pearce.

Type 2 immunity is associated with adipose tissue (AT) homeostasis and infection with parasitic helminths, but whether AT participates in immunity to these parasites is unknown. We found that the fat content of mesenteric AT (mAT) declined in mice during infection with a gut-restricted helminth. This was associated with the accumulation of metabolically activated, interleukin-33 (IL-33), thymic stromal lymphopoietin (TSLP), and extracellular matrix (ECM)-producing stromal cells. These cells shared transcriptional features, including the expression of Dpp4 and Pi16, with multipotent progenitor cells (MPC) that have been identified in numerous tissues and are reported to be capable of differentiating into fibroblasts and adipocytes. Concomitantly, mAT became infiltrated with resident T helper 2 (TH2) cells that responded to TSLP and IL-33 by producing stromal cell-stimulating cytokines, including transforming growth factor β1 (TGFβ1) and amphiregulin. These TH2 cells expressed genes previously associated with type 2 innate lymphoid cells (ILC2), including Nmur1, Calca, Klrg1, and Arg1, and persisted in mAT for at least 11 months after anthelmintic drug-mediated clearance of infection. We found that MPC and TH2 cells localized to ECM-rich interstitial spaces that appeared shared between mesenteric lymph node, mAT, and intestine. Stromal cell expression of epidermal growth factor receptor (EGFR), the receptor for amphiregulin, was required for immunity to infection. Our findings point to the importance of MPC and TH2 cell interactions within the interstitium in orchestrating AT remodeling and immunity to an intestinal infection.

DOI: https://doi.org/10.1126/sciimmunol.add3263
J Inflamm Res. 2022 ;15 5635-5648

Sustained Inflammation Induced by LPS Leads to Tolerable Anorexia and Fat Loss via Tlr4 in Mice.

Yale Yang, Wuling Zhong, Yali Zhang, Yalan Cheng, Hejin Lai, Huimin Yu, Ning Feng, Yumo Han, Rui Huang, Qiwei Zhai.

  Background: Sustained inflammation is implicated in a variety of pathological conditions like infection, obesity and type 2 diabetes. Lipid metabolism is crucial to support immune response during infection of bacteria. However, how sustained inflammation affects lipid metabolism, especially in white adipose tissue remains largely unknown.Methods: Sustained inflammation was induced by daily injection of Lipopolysaccharide (LPS). Tlr4 knockout mice were used to study the mechanism. Inflammation and lipid metabolism were evaluated by quantitative PCR, white blood cell counting, nuclear magnetic resonance, fat cell size quantification, lipolysis and fatty acid uptake assays, respiratory exchange ratio, and energy expenditure.
Results: Here, we found that sustained inflammation leads to fat loss in mice with a quick loss and gradual increase manner. Moreover, LPS injection leads to inflammation, anorexia, decreased lipid anabolism, and increased lipid catabolism. Mechanically, we show that LPS induces fat loss, inflammation, anorexia, and alteration of lipid metabolism mainly dependent on Tlr4. Interestingly, sustained inflammation induces less fat loss, especially in epididymal white adipose tissue, than pair-feeding, and pair-feeding has no significant effect on inflammation and leads to less fatty acid uptake, more lipid catabolism and energy expenditure than LPS injection. In addition, we demonstrate that short-term sustained inflammation leads to relative long-term tolerance for LPS-induced anorexia, inflammation and altered lipid metabolism.
Conclusion: These findings demonstrate that sustained inflammation induced by LPS leads to tolerable anorexia and fat loss via Tlr4 in mice, and provide new insights into the effect of sustained inflammation on lipid metabolism and subsequent tolerance.

Keywords:  lipid metabolism; lipopolysaccharide; sustained inflammation; tolerance; white adipose tissue

DOI:  https://doi.org/10.2147/JIR.S358518
Nat Commun. 2022 Oct 11. 13(1): 5956

S100A8-mediated metabolic adaptation controls HIV-1 persistence in macrophages in vivo.

Fernando Real, Aiwei Zhu, Boxin Huang, Ania Belmellat, Alexis Sennepin, Thomas Vogl, Céline Ransy, Marc Revol, Riccardo Arrigucci, Anne Lombès, Johannes Roth, Maria Laura Gennaro, Frédéric Bouillaud, Sarra Cristofari, Morgane Bomsel.

HIV-1 eradication is hindered by viral persistence in cell reservoirs, established not only in circulatory CD4+T-cells but also in tissue-resident macrophages. The nature of macrophage reservoirs and mechanisms of persistence despite combined anti-retroviral therapy (cART) remain unclear. Using genital mucosa from cART-suppressed HIV-1-infected individuals, we evaluated the implication of macrophage immunometabolic pathways in HIV-1 persistence. We demonstrate that ex vivo, macrophage tissue reservoirs contain transcriptionally active HIV-1 and viral particles accumulated in virus-containing compartments, and harbor an inflammatory IL-1R+S100A8+MMP7+M4-phenotype prone to glycolysis. Reactivation of infectious virus production and release from these reservoirs in vitro are induced by the alarmin S100A8, an endogenous factor produced by M4-macrophages and implicated in "sterile" inflammation. This process metabolically depends on glycolysis. Altogether, inflammatory M4-macrophages form a major tissue reservoir of replication-competent HIV-1, which reactivate viral production upon autocrine/paracrine S100A8-mediated glycolytic stimulation. This HIV-1 persistence pathway needs to be targeted in future HIV eradication strategies.

DOI: https://doi.org/10.1038/s41467-022-33401-x
J Clin Med. 2022 Sep 27. pii: 5715. [Epub ahead of print]11(19):

Pleiotropic Effects of Vitamin D in Patients with Inflammatory Bowel Diseases.

Aleksandra Szymczak-Tomczak, Alicja Ewa Ratajczak, Marta Kaczmarek-Ryś, Szymon Hryhorowicz, Anna Maria Rychter, Agnieszka Zawada, Ryszard Słomski, Agnieszka Dobrowolska, Iwona Krela-Kaźmierczak.

  The multifaceted activity of vitamin D in patients with inflammatory bowel disease (IBD) presents a challenge for further research in this area. Vitamin D is involved in the regulation of bone mineral metabolism, it participates in the regulation of the immune system, and it is an underlying factor in the pathogenesis of IBD. Additionally, vitamin D affects Th1 and Th2 lymphocytes, influencing the release of cytokines and inhibiting tumor necrosis factor (TNF) expression and the wnt/β-catenin pathway. As far as IBDs are concerned, they are associated with microbiota dysbiosis, abnormal inflammatory response, and micronutrient deficiency, including vitamin D hypovitaminosis. In turn, the biological activity of active vitamin D is regulated by the vitamin D receptor (VDR) which is associated with several processes related to IBD. Therefore, in terms of research on vitamin D supplementation in IBD patients, it is essential to understand the metabolic pathways and genetic determinants of vitamin D, as well as to identify the environmental factors they are subject to, not only in view of osteoporosis prevention and therapy, but primarily concerning modulating the course and supplementation of IBD pharmacotherapy.

Keywords:  inflammatory bowel disease; vitamin D; vitamin D receptor (VDR)

DOI:  https://doi.org/10.3390/jcm11195715
J Innate Immun. 2022 Oct 11. 1-22

Obesity Exacerbates Lupus Activity in Fc Gamma Receptor IIb Deficient Lupus Mice Partly through Saturated Fatty Acid-Induced Gut Barrier Defect and Systemic Inflammation.

Kanyarat Udompornpitak, Awirut Charoensappakit, Kritsanawan Sae-Khow, Thansita Bhunyakarnjanarat, Cong Phi Dang, Wilasinee Saisorn, Peerapat Visitchanakun, Pornpimol Phuengmaung, Tanapat Palaga, Patcharee Ritprajak, Somkanya Tungsanga, Asada Leelahavanichkul.

  The prevalence of obesity is increasing, and the coexistence of obesity and systemic lupus erythematosus (lupus) is possible. A high-fat diet (HFD) was orally administered for 6 months in female 8-week-old Fc gamma receptor IIb deficient (FcgRIIb-/-) lupus or age and gender-matched wild-type (WT) mice. Lupus nephritis (anti-dsDNA, proteinuria, and increased creatinine), gut barrier defect (fluorescein isothiocyanate dextran), serum lipopolysaccharide (LPS), serum interleukin (IL)-6, liver injury (alanine transaminase), organ fibrosis (liver and kidney pathology), spleen apoptosis (activated caspase 3), and aorta thickness (but not weight gain and lipid profiles) were more prominent in HFD-administered FcgRIIb-/- mice than the obese WT, without injury in regular diet-administered mice (both FcgRIIb-/- and WT). In parallel, combined palmitic acid (PA; a saturated fatty acid) with LPS (PA + LPS) induced higher tumor necrotic factor-α, IL-6, and IL-10 in the supernatant, inflammatory genes (inducible nitric oxide synthase and IL-1β), reactive oxygen species (dihydroethidium), and glycolysis with reduced mitochondrial activity (extracellular flux analysis) when compared with the activation by each molecule alone in both FcgRIIb-/- and WT macrophages. However, the alterations of these parameters were more prominent in PA + LPS-administered FcgRIIb-/- than in the WT cells. In conclusion, obesity accelerated inflammation in FcgRIIb-/- mice, partly due to the more potent responses from the loss of inhibitory FcgRIIb against PA + LPS with obesity-induced gut barrier defect.

Keywords:  Gut barrier defect; High-fat diet; Lupus; Obesity; Systemic inflammation

DOI:  https://doi.org/10.1159/000526206
Mol Nutr Food Res. 2022 Oct 14. e2200196

Dietary D-Lactate Intake Facilitates Inflammatory Resolution by Modulating M1 Macrophage Polarization.

Yongheng Yan, Xiu Li, Qin Yang, Hao Zhang, Kasper Hettinga, Haitao Li, Wei Chen.

  SCOPE: Given the D-lactate dehydrogenase (D-LDH) deficiency, L- but not D-lactate is assumed to be the physiological isomer in mammals. Paradoxically, many fermented foods (e.g., yogurt, sauerkraut, cheeses) often contain substantial amounts of D-lactate. In the present study, we hypothesized that dietary D-lactate may be a previously unrecognized nutrient aiding in inflammatory resolution.METHODS AND RESULTS: The anti-inflammatory properties of D-lactate were evaluated in experimental colitis and endotoxemia. Oral administration of D-lactate favourably affected acute inflammation in two different mouse models. Analysis of lactate-the lactate receptor (the hydroxycarboxylic acid receptor 1 HCA1, formerly GPR81) signal axis in inflammation was performed in primary peritoneal macrophages and wild-type (WT) or GPR81 knockout (KO) mice. GPR81 KO mice are susceptible to endotoxic shock than WT mice, while D-lactate exerted its anti-inflammatory activities in a GPR81-dependent manner. Mechanistically, the activation of lactate-GPR81 axis might suppress LPS-TLR4 signaling by modulating M1 macrophage polarization. Although D-LDH deficiency in mammals impairs D-lactate clearance, it might prolong its plasma terminal half-life, and thus provide a pharmacokinetic advantage of D-lactate over L-lactate.
CONCLUSION: This study highlights housekeeping function of the lactate-GPR81 axis in inflammation control, and suggests that dietary intake of D-lactate may underlies Metchnikoff's probiotic yogurt theory of life prolongation. This article is protected by copyright. All rights reserved.

Keywords:  D-Lactate; GPR81; inflammation; macrophage polarization; yogurt

DOI:  https://doi.org/10.1002/mnfr.202200196
Science. 2022 Oct 14. 378(6616): eabq0132

A bacterial phospholipid phosphatase inhibits host pyroptosis by hijacking ubiquitin.

Qiyao Chai, Shanshan Yu, Yanzhao Zhong, Zhe Lu, Changgen Qiu, Yang Yu, Xinwen Zhang, Yong Zhang, Zehui Lei, Lihua Qiang, Bing-Xi Li, Yu Pang, Xiao-Bo Qiu, Jing Wang, Cui Hua Liu.

The inflammasome-mediated cleavage of gasdermin D (GSDMD) causes pyroptosis and inflammatory cytokine release to control pathogen infection, but how pathogens evade this immune response remains largely unexplored. Here we identify the known protein phosphatase PtpB from Mycobacterium tuberculosis as a phospholipid phosphatase inhibiting the host inflammasome-pyroptosis pathway. Mechanistically, PtpB dephosphorylated phosphatidylinositol-4-monophosphate and phosphatidylinositol-(4,5)-bisphosphate in host cell membrane, thus disrupting the membrane localization of the cleaved GSDMD to inhibit cytokine release and pyroptosis of macrophages. Notably, this phosphatase activity requires PtpB binding to ubiquitin. Disrupting phospholipid phosphatase activity or the ubiquitin-interacting motif of PtpB enhanced host GSDMD-dependent immune responses and reduced intracellular pathogen survival. Thus, pathogens inhibit pyroptosis and counteract host immunity by altering host membrane composition.

DOI: https://doi.org/10.1126/science.abq0132
Biol Chem. 2022 Oct 14.

The role of host heme in bacterial infection.

Rebecca K Donegan.

  Heme is an indispensable cofactor for almost all aerobic life, including the human host and many bacterial pathogens. During infection, heme and hemoproteins are the largest source of bioavailable iron, and pathogens have evolved various heme acquisition pathways to satisfy their need for iron and heme. Many of these pathways are regulated transcriptionally by intracellular iron levels, however, host heme availability and intracellular heme levels have also been found to regulate heme uptake in some species. Knowledge of these pathways has helped to uncover not only how these bacteria incorporate host heme into their metabolism but also provided insight into the importance of host heme as a nutrient source during infection. Within this review is covered multiple aspects of the role of heme at the host pathogen interface, including the various routes of heme biosynthesis, how heme is sequestered by the host, and how heme is scavenged by bacterial pathogens. Also discussed is how heme and hemoproteins alter the behavior of the host immune system and bacterial pathogens. Finally, some unanswered questions about the regulation of heme uptake and how host heme is integrated into bacterial metabolism are highlighted.

Keywords:  heme homeostasis; heme transport; heme uptake; hemoglobin; hemophore

DOI:  https://doi.org/10.1515/hsz-2022-0192