bims-imicid 2023-10-08 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023‒10‒08
thirty-six papers selected by
Dylan Ryan, University of Cambridge

Iron acquisition by a commensal bacterium modifies host nutritional immunity during Salmonella infection.
Ketogenesis promotes tolerance to Pseudomonas aeruginosa pulmonary infection.
Gut microbial metabolite deoxycholic acid facilitates Th17 differentiation through modulating cholesterol biosynthesis and participates in high-fat diet-associated colonic inflammation.
Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1.
USP47 inhibits m6A-dependent c-Myc translation to maintain regulatory T cell metabolic and functional homeostasis.
Cystine/Glutamate antiporter system xc- deficiency impairs macrophage glutathione metabolism and cytokine production.
α-ketoglutarate-dependent KDM6 histone demethylases regulate Interferon Stimulated Gene expression in Lupus.
Early initiation of antiretroviral therapy preserves the metabolic function of CD4+ T-cells in subtype C HIV-1 infection.
Staphylococcus aureus adapts to the immunometabolite itaconic acid by inducing acid and oxidative stress responses including S-bacillithiolations and S-itaconations.
Activation of the JNK/COX-2/HIF-1α axis promotes M1 macrophage via glycolytic shift in HIV-1 infection.
Mitochondria Dictate Function and Fate of HSCs and T Cells.
Peroxisomal ROS control cytosolic Mycobacterium tuberculosis replication in human macrophages.
Bcl-3 regulates T cell function through energy metabolism.
Metabolic Regulation of Aged Hematopoietic Stem Cells: Key Players and Mechanisms.
Metabolic control from the endolysosome: lysosome-resident amino acid transporters open novel therapeutic possibilities.
Lactate promotes Salmonella intracellular replication and systemic infection via driving macrophage M2 polarization.
Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve checkpoint blockade.
Spatially Resolved Metabolomics Combined with the 3D Tumor-Immune Cell Coculture Spheroid Highlights Metabolic Alterations during Antitumor Immune Response.
Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity.
Bacteria- and Fungus-derived PAMPs Induce Innate Immune Memory via Similar Functional, Metabolic and Transcriptional Adaptations.
TSC2 S1365A mutation potently regulates CD8+T cell function and differentiation improving adoptive cellular cancer therapy.
Repeated social defeat stress leads to immunometabolic shifts in innate immune cells of the spleen.
Aberrant glucose metabolism underlies impaired macrophage differentiation in glycogen storage disease type Ib.
GLUT1 Mediates the Metabolic Reprogramming and Inflammation of CCR2$^+$ Monocytes/Macrophages from Patients with DCM.
Fatty Acids and their Proteins in Adipose Tissue Inflammation.
Inflammasome-mediated glucose limitation induces antibiotic tolerance in Staphylococcus aureus.
Rapid intestinal and systemic metabolic reprogramming in an immunosuppressed environment.
Erdr1 orchestrates macrophage polarization and determines cell fate via dynamic interaction with YAP1 and Mid1.
Carbon metabolism in the regulation of macrophage functions.
Gene signature based on glycolysis is closely related to immune infiltration of patients with osteoarthritis.
CSF1R inhibition with PLX5622 affects multiple immune cell compartments and induces tissue-specific metabolic effects in lean mice.
Short-chain fatty acids ameliorate allergic airway inflammation via sequential induction of PMN-MDSCs and Treg cells.
Respiratory syncytial virus co-opts hypoxia-inducible factor-1α-mediated glycolysis to favor the production of infectious virus.
Immuno-metabolic signaling in leishmaniasis: insights gained from mathematical modeling.
Targeting the lipid metabolic reprogramming of tumor-associated macrophages: A novel insight into cancer immunotherapy.
Lactobacillus gallinarum-derived metabolites boost anti-PD1 efficacy in colorectal cancer by inhibiting regulatory T cells through modulating IDO1/Kyn/AHR axis.

Cell Host Microbe. 2023 Sep 25. pii: S1931-3128(23)00343-8. [Epub ahead of print]

Iron acquisition by a commensal bacterium modifies host nutritional immunity during Salmonella infection.

Luisella Spiga, Ryan T Fansler, Yasiru R Perera, Nicolas G Shealy, Matthew J Munneke, Holly E David, Teresa P Torres, Andrew Lemoff, Xinchun Ran, Katrina L Richardson, Nicholas Pudlo, Eric C Martens, Ewa Folta-Stogniew, Zhongyue J Yang, Eric P Skaar, Mariana X Byndloss, Walter J Chazin, Wenhan Zhu.

  During intestinal inflammation, host nutritional immunity starves microbes of essential micronutrients, such as iron. Pathogens scavenge iron using siderophores, including enterobactin; however, this strategy is counteracted by host protein lipocalin-2, which sequesters iron-laden enterobactin. Although this iron competition occurs in the presence of gut bacteria, the roles of commensals in nutritional immunity involving iron remain unexplored. Here, we report that the gut commensal Bacteroides thetaiotaomicron acquires iron and sustains its resilience in the inflamed gut by utilizing siderophores produced by other bacteria, including Salmonella, via a secreted siderophore-binding lipoprotein XusB. Notably, XusB-bound enterobactin is less accessible to host sequestration by lipocalin-2 but can be "re-acquired" by Salmonella, allowing the pathogen to evade nutritional immunity. Because the host and pathogen have been the focus of studies of nutritional immunity, this work adds commensal iron metabolism as a previously unrecognized mechanism modulating the host-pathogen interactions and nutritional immunity.

Keywords:  Salmonella; commensal iron metabolism; enteric pathogen; gut microbiota resilience; intestinal inflammation; nutritional immunity; siderophore

DOI:  https://doi.org/10.1016/j.chom.2023.08.018
Cell Metab. 2023 Oct 03. pii: S1550-4131(23)00332-7. [Epub ahead of print]35(10): 1767-1781.e6

Ketogenesis promotes tolerance to Pseudomonas aeruginosa pulmonary infection.

Kira L Tomlinson, Ying-Tsun Chen, Alex Junker, AndreaCarola Urso, Tania Wong Fok Lung, Danielle Ahn, Casey E Hofstaedter, Swikrity U Baskota, Robert K Ernst, Alice Prince, Sebastián A Riquelme.

  Pseudomonas aeruginosa is a common cause of pulmonary infection. As a Gram-negative pathogen, it can initiate a brisk and highly destructive inflammatory response; however, most hosts become tolerant to the bacterial burden, developing chronic infection. Using a murine model of pneumonia, we demonstrate that this shift from inflammation to disease tolerance is promoted by ketogenesis. In response to pulmonary infection, ketone bodies are generated in the liver and circulate to the lungs where they impose selection for P. aeruginosa strains unable to display surface lipopolysaccharide (LPS). Such keto-adapted LPS strains fail to activate glycolysis and tissue-damaging cytokines and, instead, facilitate mitochondrial catabolism of fats and oxidative phosphorylation (OXPHOS), which maintains airway homeostasis. Within the lung, P. aeruginosa exploits the host immunometabolite itaconate to further stimulate ketogenesis. This environment enables host-P. aeruginosa coexistence, supporting both pathoadaptive changes in the bacteria and the maintenance of respiratory integrity via OXPHOS.

Keywords:  OXPHOS; Pseudomonas aeruginosa; bioenergetics; disease tolerance; infection; inflammation; itaconate; ketogenesis; ketogenic diet; pneumonia

DOI:  https://doi.org/10.1016/j.cmet.2023.09.001
Cell Biosci. 2023 Oct 03. 13(1): 186

Gut microbial metabolite deoxycholic acid facilitates Th17 differentiation through modulating cholesterol biosynthesis and participates in high-fat diet-associated colonic inflammation.

Dan Li, Jiefei Zhou, Lingyu Wang, Zizhen Gong, Huijuan Le, Ye Huang, Congfeng Xu, Chunyan Tian, Wei Cai, Jin Wu.

  BACKGROUND: High-fat diet (HFD) is closely associated with the increased prevalence of inflammatory bowel disease (IBD). Excessive gut microbial metabolite deoxycholic acid (DCA) caused by HFD plays significant roles in eliciting intestinal inflammation, however, the mechanism underlining the induction of inflammatory response by DCA has not been fully elucidated. The purpose of this study was to investigate the role of DCA in the triggering of inflammation via affecting CD4+ T cell differentiation.RESULTS: Murine CD4+T cells were cultured under Th1, Th2 or Th17-polarizing conditions treated with or without different dosage of DCA, and flowcytometry was conducted to detect the effect of DCA on CD4+ T cell differentiation. Alteration of gene expression in CD4+ T cells upon DCA treatment was determined by RNA-sequencing and qRT-PCR. Bioinformatic analysis, cholesterol metabolic profiling, ChIP assay and immuno-fluorescent staining were further applied to explore the DCA-regulated pathway that involved in CD4+T cell differentiation. The results showed that DCA could dose-dependently promote the differentiation of CD4+ T cell into Th17 linage with pathogenic signature. Mechanistically, DCA stimulated the expression of cholesterol biosynthetic enzymes CYP51 and led to the increased generation of endogenous RORγt agonists, including zymosterol and desmosterol, therefore facilitating Th17 differentiation. Up-regulation of CYP51 by DCA was largely mediated via targeting transcription factor SREBP2 and at least partially through bile acid receptor TGR5. In addition, DCA-supplemented diet significantly increased intestinal Th17 cell infiltration and exacerbated TNBS-induced colitis. Administration of cholestyramine to eliminate fecal bile acid obviously alleviated colonic inflammation accompanied by decreased Th17 cells in HFD-fed mice.
CONCLUSIONS: Our data establish a link between DCA-induced cholesterol biosynthesis in immune cells and gut inflammation. Modulation of bile acid level or targeting cholesterol metabolic pathway may be potential therapeutic measurements for HFD-related colitis.

Keywords:  Bile acid; Colonic inflammation; High fat diet; Th17 differentiation

DOI:  https://doi.org/10.1186/s13578-023-01109-0
Cell Metab. 2023 Oct 03. pii: S1550-4131(23)00336-4. [Epub ahead of print]35(10): 1688-1703.e10

Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1.

Yun Zhao, Zhongshun Liu, Guoqiang Liu, Yuting Zhang, Sheng Liu, Dailin Gan, Wennan Chang, Xiaoxia Peng, Eun Suh Sung, Keegan Gilbert, Yini Zhu, Xuechun Wang, Ziyu Zeng, Hope Baldwin, Guanzhu Ren, Jessica Weaver, Anna Huron, Toni Mayberry, Qingfei Wang, Yujue Wang, Maria Elena Diaz-Rubio, Xiaoyang Su, M Sharon Stack, Siyuan Zhang, Xuemin Lu, Ryan D Sheldon, Jun Li, Chi Zhang, Jun Wan, Xin Lu.

  Metastasis causes breast cancer-related mortality. Tumor-infiltrating neutrophils (TINs) inflict immunosuppression and promote metastasis. Therapeutic debilitation of TINs may enhance immunotherapy, yet it remains a challenge to identify therapeutic targets highly expressed and functionally essential in TINs but under-expressed in extra-tumoral neutrophils. Here, using single-cell RNA sequencing to compare TINs and circulating neutrophils in murine mammary tumor models, we identified aconitate decarboxylase 1 (Acod1) as the most upregulated metabolic enzyme in mouse TINs and validated high Acod1 expression in human TINs. Activated through the GM-CSF-JAK/STAT5-C/EBPβ pathway, Acod1 produces itaconate, which mediates Nrf2-dependent defense against ferroptosis and upholds the persistence of TINs. Acod1 ablation abates TIN infiltration, constrains metastasis (but not primary tumors), bolsters antitumor T cell immunity, and boosts the efficacy of immune checkpoint blockade. Our findings reveal how TINs escape from ferroptosis through the Acod1-dependent immunometabolism switch and establish Acod1 as a target to offset immunosuppression and improve immunotherapy against metastasis.

Keywords:  Acod1; MDSC; breast cancer; ferroptosis; immune checkpoint blockade; immune metabolism; itaconate; metastasis; neutrophil; single-cell RNA sequencing

DOI:  https://doi.org/10.1016/j.cmet.2023.09.004
J Clin Invest. 2023 Oct 03. pii: e169365. [Epub ahead of print]

USP47 inhibits m6A-dependent c-Myc translation to maintain regulatory T cell metabolic and functional homeostasis.

Aiting Wang, Haiyan Huang, Jian-Hong Shi, Xiaoyan Yu, Rui Ding, Yuerong Zhang, Qiaoqiao Han, Zhi-Yu Ni, Xia Li, Ren Zhao, Qiang Zou.

  The functional integrity of Treg cells is interwoven with cellular metabolism; however, the mechanisms governing Treg cell metabolic programs remain elusive. Here, we identified that the deubiquitinase USP47 inhibited RNA m6A reader YTHDF1-mediated c-Myc translation to maintain Treg cell metabolic and functional homeostasis. USP47 positively correlated with the tumor-infiltrating Treg cell signature in colorectal cancer and gastric cancer patient samples. USP47 ablation compromised Treg cell homeostasis and function in vivo, resulting in the development of inflammatory disorders, and boosted antitumor immune responses. USP47 deficiency in Treg cells triggered the accumulation of the c-Myc protein and in turn exacerbated hyperglycolysis. Mechanistically, USP47 prevented YTHDF1 ubiquitination to attenuate the association of YTHDF1 with translation initiation machinery, thereby decreasing m6A-based c-Myc translation efficiency. Our findings reveal that USP47 directs m6A-dependent metabolic programs to orchestrate Treg cell homeostasis and suggest novel approaches for selective immune modulation in cancer and autoimmune diseases by targeting USP47.

Keywords:  Adaptive immunity; Autoimmunity; Immunology

DOI:  https://doi.org/10.1172/JCI169365
PLoS One. 2023 ;18(10): e0291950

Cystine/Glutamate antiporter system xc- deficiency impairs macrophage glutathione metabolism and cytokine production.

Axel de Baat, Daniel T Meier, Adriano Fontana, Marianne Böni-Schnetzler, Marc Y Donath.

System xc-, encoded by Slc7a11, is an antiporter responsible for exporting glutamate while importing cystine, which is essential for protein synthesis and the formation of thiol peptides, such as glutathione. Glutathione acts as a co-factor for enzymes responsible for scavenging reactive oxygen species. Upon exposure to bacterial products, macrophages exhibit a rapid upregulation of system xc-. This study investigates the impact of Slc7a11 deficiency on the functionality of peritoneal and bone marrow-derived macrophages. Our findings reveal that the absence of Slc7a11 results in significantly reduced glutathione levels, compromised mitochondrial flexibility, and hindered cytokine production in bone marrow-derived macrophages. Conversely, system xc- has a lesser impact on peritoneal macrophages in vivo. These results indicate that system xc- is essential for maintaining glutathione levels, mitochondrial functionality, and cytokine production, with a heightened importance under atmospheric oxygen tension.

DOI: https://doi.org/10.1371/journal.pone.0291950
Arthritis Rheumatol. 2023 Oct 06.

α-ketoglutarate-dependent KDM6 histone demethylases regulate Interferon Stimulated Gene expression in Lupus.

Erica N Montano, Moumita Bose, Lihong Huo, Gantsetseg Tumurkhuu, Gabriela De Los Santos, Brianna Simental, Aleksandr B Stotland, Janet Wei, C Noel Bairey Merz, Jo Suda, Gislaine Martins, Sarfaraz Lalani, Kate Lawrenson, Yizhou Wang, Sarah Parker, Swamy Venuturupalli, Mariko Ishimori, Daniel J Wallace, Caroline A Jefferies.

OBJECTIVE: Investigate the hypothesis that interferon (IFN) stimulated gene (ISG) expression in systemic lupus erythematosus (SLE) monocytes is linked to changes in metabolic reprogramming and epigenetic regulation of ISG expression.METHODS: Monocytes from healthy volunteers and SLE patients at baseline or following IFNα treatment were analyzed by extracellular flux analysis, proteomics, metabolomics, chromatin immunoprecipitation and gene expression. The histone demethylases KDM6A/B were inhibited using GSK-J4. GSK-J4 was tested in pristane and resiquimod (R848) models of IFN-driven SLE.
RESULTS: SLE monocytes had enhanced rates of glycolysis and oxidative phosphorylation compared to healthy control (HC) monocytes, as well as increased levels of isocitrate dehydrogenase (IDH2) and its product, α-ketoglutarate (α-KG). As α-KG is a required cofactor for histone demethylases KDM6A and KDM6B, we hypothesized that IFNα may be driving 'trained immune' responses through altering histone methylation. IFNα priming (day 1) resulted in a sustained increase in the expression of ISGs in primed cells (day 5) and enhanced expression on restimulation with IFNα. Importantly decreased H3K27 trimethylation was observed at the promoters of ISGs following IFNα priming. Finally, GSK-J4 (KDM6A/B inhibitor) resulted in decreased ISG expression in SLE patient monocytes, as well as reduced autoantibody production, ISG expression and kidney pathology in R848-treated Balb/c mice.
CONCLUSION: Our study suggests chronic IFNα exposure alters epigenetic regulation of ISG expression in SLE monocytes via changes in immunometabolism, a mechanism reflecting trained immunity to type I IFN. Importantly, it opens the possibility that targeting histone modifying enzymes such as KDM6A/B may reduce IFN responses in SLE.

DOI: https://doi.org/10.1002/art.42724
J Infect Dis. 2023 Oct 06. pii: jiad432. [Epub ahead of print]

Early initiation of antiretroviral therapy preserves the metabolic function of CD4+ T-cells in subtype C HIV-1 infection.

Kewreshini K Naidoo, Andrew J Highton, Omolara O Baiyegunhi, Sindiswa P Bhengu, Krista L Dong, Madeleine J Bunders, Marcus Altfeld, Thumbi Ndung'u.

  BACKGROUND: Immune dysfunction often persists in people living with HIV (PLWH) on antiretroviral therapy (ART), clinically manifesting as HIV-1-associated comorbidities. Early ART initiation may reduce incidence of HIV-1-associated immune dysfunction and comorbidities. Immunometabolism is a critical determinant of functional immunity. We investigated the effect of HIV-1 infection and timing of ART initiation on CD4+ T-cell metabolism and function.METHODS: Longitudinal blood samples from PLWH that initiated ART either in hyperacute HIV-1 infection (HHI, before peak viremia) or chronic HIV-1 infection (CHI) were assessed for metabolic and immune functions of CD4+ T-cells. Metabolite uptake and mitochondrial mass (MM) were measured using fluorescent analogues and MitoTracker Green accumulation respectively, and were correlated to CD4+ T-cell effector functions.
RESULTS: Initiation of ART during HHI prevented dysregulation of glucose uptake by CD4+ T-cells; but glucose uptake was reduced pre- and post-ART initiation in CHI. Glucose uptake positively correlated with IL-2 and TNF-⍺ production by CD4+ T-cells. CHI associated with elevated MM in CD4+ TEM that persisted post-ART and correlated with PD-1 expression.
CONCLUSION: ART initiation in HHI largely prevented metabolic impairment of CD4+ T-cells. ART initiation in CHI associated with persistently dysregulated immunometabolism of CD4+ T-cells that associated with impaired cellular functions and exhaustion.

Keywords:  CD4+ T-cells; acute HIV-1 infection; antiretroviral therapy; immune dysfunction; immunometabolism

DOI:  https://doi.org/10.1093/infdis/jiad432
Free Radic Biol Med. 2023 Oct 02. pii: S0891-5849(23)00656-1. [Epub ahead of print]

Staphylococcus aureus adapts to the immunometabolite itaconic acid by inducing acid and oxidative stress responses including S-bacillithiolations and S-itaconations.

Vu Van Loi, Tobias Busche, Benno Kuropka, Susanne Müller, Karen Methling, Michael Lalk, Jörn Kalinowski, Haike Antelmann.

  Staphylococcus aureus is a major pathogen, which has to defend against reactive oxygen and electrophilic species encountered during infections. Activated macrophages produce the immunometabolite itaconate as potent electrophile and antimicrobial upon pathogen infection. In this work, we used transcriptomics, metabolomics and shotgun redox proteomics to investigate the specific stress responses, metabolic changes and redox modifications caused by sublethal concentrations of itaconic acid in S. aureus. In the RNA-seq transcriptome, itaconic acid caused the induction of the GlnR, KdpDE, CidR, SigB, GraRS, PerR, CtsR and HrcA regulons and the urease-encoding operon, revealing an acid and oxidative stress response and impaired proteostasis. Neutralization using external urea as ammonium source improved the growth and decreased the expression of the glutamine synthetase-controlling GlnR regulon, indicating that S. aureus experienced ammonium starvation upon itaconic acid stress. In the extracellular metabolome, the amounts of acetate and formate were decreased, while secretion of pyruvate and the neutral product acetoin were strongly enhanced to avoid intracellular acidification. Exposure to itaconic acid affected the amino acid uptake and metabolism as revealed by the strong intracellular accumulation of lysine, threonine, histidine, aspartate, alanine, valine, leucine, isoleucine, cysteine and methionine. In the proteome, itaconic acid caused widespread S-bacillithiolation and S-itaconation of redox-sensitive antioxidant and metabolic enzymes, ribosomal proteins and translation factors in S. aureus, supporting its oxidative and electrophilic mode of action in S. aureus. In phenotype analyses, the catalase KatA, the low molecular weight thiol bacillithiol and the urease provided protection against itaconic acid-induced oxidative and acid stress in S. aureus. Altogether, our results revealed that under physiological infection conditions, such as in the acidic phagolysome, itaconic acid is a highly effective antimicrobial against multi-resistant S. aureus isolates, which acts as weak acid causing an acid, oxidative and electrophilic stress response, leading to S-bacillithiolation and itaconation.

Keywords:  Itaconation; Itaconic acid; Metabolome; S-bacillithiolation; Staphylococcus aureus; Transcriptome

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.09.031
Life Sci Alliance. 2023 Dec;pii: e202302148. [Epub ahead of print]6(12):

Activation of the JNK/COX-2/HIF-1α axis promotes M1 macrophage via glycolytic shift in HIV-1 infection.

Junhan Zhang, Zongxiang Yuan, Xuanrong Li, Fengyi Wang, Xueqin Wei, Yiwen Kang, Chuye Mo, Junjun Jiang, Hao Liang, Li Ye.

Chronic inflammation is recognized as a major risk factor for the severity of HIV infection. Whether metabolism reprogramming of macrophages caused by HIV-1 is related to chronic inflammatory activation, especially M1 polarization of macrophages, is inconclusive. Here, we show that HIV-1 infection induces M1 polarization and enhanced glycolysis in macrophages. Blockade of glycolysis inhibits M1 polarization of macrophages, indicating that HIV-1-induced M1 polarization is supported by enhanced glycolysis. Moreover, we find that this immunometabolic adaptation is dependent on hypoxia-inducible factor 1α (HIF-1α), a strong inducer of glycolysis. HIF-1α-target genes, including HK2, PDK1, and LDHA, are also involved in this process. Further research discovers that COX-2 regulates HIF-1α-dependent glycolysis. However, the elevated expression of COX-2, enhanced glycolysis, and M1 polarization of macrophages could be reversed by inactivation of JNK in the context of HIV-1 infection. Our study mechanistically elucidates that the JNK/COX-2/HIF-1α axis is activated to strengthen glycolysis, thereby promoting M1 polarization in macrophages in HIV-1 infection, providing a new idea for resolving chronic inflammation in clinical AIDS patients.

DOI: https://doi.org/10.26508/lsa.202302148
Cancer Immunol Res. 2023 10 04. 11(10): 1303-1313

Mitochondria Dictate Function and Fate of HSCs and T Cells.

Yingxi Xu, Yi-Hsuan Chiang, Ping-Chih Ho, Nicola Vannini.

Hematopoietic stem cells (HSC) and T cells are intimately related, lineage-dependent cell populations that are extensively used as therapeutic products for the treatment of hematologic malignancies and certain types of solid tumors. These cellular therapies can be life-saving treatments; however, their efficacies are often limited by factors influencing their activity and cellular properties. Among these factors is mitochondrial metabolism, which influences the function and fate commitment of both HSCs and T cells. Mitochondria, besides being the "cellular powerhouse," provide metabolic intermediates that are used as substrates for epigenetic modifications and chromatin remodeling, thus, driving cell fate decisions during differentiation. Moreover, mitochondrial fitness and mitochondrial quality control mechanisms are closely related to cellular function, and impairment of these mitochondrial properties associates with cellular dysfunction due to factors such as T-cell exhaustion and aging. Here, we give an overview of the role of mitochondria in shaping the behavior of these lineage-related cell populations. Moreover, we discuss the potential of novel mitochondria-targeting strategies for enhancing HSC- and T cell-based cancer immunotherapies and highlight how design and application of such approaches requires consideration of the metabolic similarities and differences between HSCs and T cells. See related article on p. 1302.

DOI: https://doi.org/10.1158/2326-6066.CIR-22-0685
J Cell Biol. 2023 Dec 04. pii: e202303066. [Epub ahead of print]222(12):

Peroxisomal ROS control cytosolic Mycobacterium tuberculosis replication in human macrophages.

Enrica Pellegrino, Beren Aylan, Claudio Bussi, Antony Fearns, Elliott M Bernard, Natalia Athanasiadi, Pierre Santucci, Laure Botella, Maximiliano G Gutierrez.

Peroxisomes are organelles involved in many metabolic processes including lipid metabolism, reactive oxygen species (ROS) turnover, and antimicrobial immune responses. However, the cellular mechanisms by which peroxisomes contribute to bacterial elimination in macrophages remain elusive. Here, we investigated peroxisome function in iPSC-derived human macrophages (iPSDM) during infection with Mycobacterium tuberculosis (Mtb). We discovered that Mtb-triggered peroxisome biogenesis requires the ESX-1 type 7 secretion system, critical for cytosolic access. iPSDM lacking peroxisomes were permissive to Mtb wild-type (WT) replication but were able to restrict an Mtb mutant missing functional ESX-1, suggesting a role for peroxisomes in the control of cytosolic but not phagosomal Mtb. Using genetically encoded localization-dependent ROS probes, we found peroxisomes increased ROS levels during Mtb WT infection. Thus, human macrophages respond to the infection by increasing peroxisomes that generate ROS primarily to restrict cytosolic Mtb. Our data uncover a peroxisome-controlled, ROS-mediated mechanism that contributes to the restriction of cytosolic bacteria.

DOI: https://doi.org/10.1083/jcb.202303066
BMC Immunol. 2023 Oct 04. 24(1): 35

Bcl-3 regulates T cell function through energy metabolism.

Hui Liu, Lin Zeng, Mengmeng Pan, Liwenhui Huang, Hanying Li, Mengxia Liu, Xinqing Niu, Chenguang Zhang, Hui Wang.

  BACKGROUND: Bcl-3 is a member of the IκB protein family and an essential modulator of NF-κB activity. It is well established that Bcl-3 is critical for the normal development, survival and differentiation of adaptive immune cells, especially T cells. However, the regulation of immune cell function by Bcl-3 through metabolic pathways has rarely been studied.RESULTS: In this study, we explored the role of Bcl-3 in the metabolism and function of T cells via the mTOR pathway. We verified that the proliferation of Bcl-3-deficient Jurkat T cells was inhibited, but their activation was promoted, and Bcl-3 depletion regulated cellular energy metabolism by reducing intracellular ATP and ROS production levels and mitochondrial membrane potential. Bcl-3 also regulates cellular energy metabolism in naive CD4+ T cells. In addition, the knockout of Bcl-3 altered the expression of mTOR, Akt, and Raptor, which are metabolism-related genes, in Jurkat cells.
CONCLUSIONS: This finding indicates that Bcl-3 may mediate the energy metabolism of T cells through the mTOR pathway, thereby affecting their function. Overall, we provide novel insights into the regulatory role of Bcl-3 in T-cell energy metabolism for the prevention and treatment of immune diseases.

Keywords:  Bcl-3; Jurkat; Metabolism; T cells

DOI:  https://doi.org/10.1186/s12865-023-00570-3
Exp Hematol. 2023 Sep 29. pii: S0301-472X(23)01733-2. [Epub ahead of print]

Metabolic Regulation of Aged Hematopoietic Stem Cells: Key Players and Mechanisms.

Nazanin Karimnia, James Harris, Shen Y Heazlewood, Benjamin Cao, Susan K Nilsson.

  Aging is accompanied by a gradual decline in the function and regenerative capacity of hematopoietic stem cells (HSCs), which leads to increased susceptibility to blood disorders. Recent studies have highlighted the critical role of metabolic regulation in governing the fate and function of HSCs, and alterations in metabolism play a critical role in the age-related changes observed in HSCs. Metabolic processes including glycolysis, mitochondrial function, nutrient sensing and inflammation, profoundly influence the maintenance, self-renewal and differentiation potential of the HSC pool. This review focuses on the metabolic alterations that occur in HSCs during aging and the systemic factors which contribute to HSC metabolic dysregulation, leading to impaired cellular function and reduced regenerative capacity. We highlight the impact of age-associated changes in oxidative stress, mitochondrial dysfunction, nutrient availability and inflammation on HSC metabolism and function. Targeting metabolic pathways and modulating key regulators of metabolism hold promise for reducing age-related HSC dysregulation, thus maintaining functional potential as a path towards healthy aging. Exploiting these metabolic interventions has the potential to improve hemopoietic recovery, enhance immune function and pave the way for novel therapeutic interventions to combat age-related blood disorders.

Keywords:  Aging; autophagy; hematopoietic stem cell; metabolism; mitochondria; niche; nutrients

DOI:  https://doi.org/10.1016/j.exphem.2023.09.006
Front Immunol. 2023 ;14 1243104

Metabolic control from the endolysosome: lysosome-resident amino acid transporters open novel therapeutic possibilities.

Toshihiko Kobayashi, Noriko Toyama-Sorimachi.

  Amino acid transporters are generally recognized as machinery that transport amino acids from the extracellular environment into the cytoplasm. Although their primary function is the uptake of amino acids to supply the cell with nutrients and energy, endolysosome-resident amino acid (EL-aa) transporters possess several unique functions in accordance with their localization in intracellular vesicular membranes. They play pivotal roles in the maintenance of metabolic homeostasis via direct involvement in the amino acid sensing pathway, which regulates the activity of mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of cellular metabolism. Additionally, some EL-aa transporters contribute to the maintenance of dynamic homeostasis of endolysosomes, including the regulation of endolysosomal acidity, by carrying amino acids out of endolysosomes. In addition, EL-aa transporters act as a scaffold to gather signaling molecules and multiple enzymes to control cellular metabolism on the endolysosomal membrane. Among EL-aa transporters, solute carrier family 15 member 4 (SLC15A4) is preferentially expressed in immune cells, including macrophages, dendritic cells, and B cells, and plays a key role in the integration of metabolic and inflammatory signals. In this review, we summarize our recent findings on EL-aa transporter contributions to inflammatory and metabolic signaling in the endolysosomes of immune cells by focusing on the SLC15 family, including SLC15A4 and SLC15A3, and discuss their uniqueness and universality. We also discuss the potential of targeting these EL-aa transporters in immune cells for the development of novel therapeutic strategies for inflammatory diseases. Because these transporters are highly expressed in immune cells and significantly alter the functions of immune cells, targeting them would provide a great advantage in ensuring a wide safety margin.

Keywords:  amino acid transporter; endolysosome; immune cells; inflammation; mTORC1; metabolism; solute carrier family 15; therapeutic target

DOI:  https://doi.org/10.3389/fimmu.2023.1243104
Microbiol Spectr. 2023 Oct 05. e0225323

Lactate promotes Salmonella intracellular replication and systemic infection via driving macrophage M2 polarization.

Xinyue Wang, Bin Yang, Shuangshuang Ma, Xiaolin Yan, Shuai Ma, Hongmin Sun, Yuyang Sun, Lingyan Jiang.

  Salmonella is one of the most important enteric pathogens worldwide, which is able to cause lethal systemic infection via survival and replication in host macrophages. Lactate, a byproduct of anaerobic or aerobic glycolysis, can induce macrophage M2 polarization, but the relationship between lactate-mediated macrophage M2 polarization and bacterial infection is poorly understood. Here, we evaluated the role of lactate and lactate-mediated macrophage M2 polarization in the pathogenicity of Salmonella. We found that lactate levels were significantly increased in Salmonella-infected macrophages, and the increased lactate was derived from the host. Macrophage and mouse infection assays showed that the addition of lactate enhanced Salmonella replication within macrophages and the colonization of mouse systemic loci, while pharmacological or genetic inhibition of host lactate production impaired Salmonella intracellular replication and its virulence in mice. Further analysis revealed that lactate promotes M2 polarization of Salmonella-infected macrophages, and the induction of macrophage M2 polarization by lactate is responsible for lactate-mediated Salmonella growth promotion. Moreover, we showed that macrophage-derived lactate induces the Salmonella pathogenicity island (SPI)-2 type III secretion system, leading to increased translocation of the SPI-2 effector SteE, which is responsible for driving M2 polarization. Overall, these findings suggest that lactate promotes Salmonella intracellular replication and systemic infection via driving macrophage M2 polarization and highlight the complex interactions between Salmonella and macrophages. IMPORTANCE The important enteropathogen Salmonella can cause lethal systemic infection via survival and replication in host macrophages. Lactate represents an abundant intracellular metabolite during bacterial infection, which can also induce macrophage M2 polarization. In this study, we found that macrophage-derived lactate promotes the intracellular replication and systemic infection of Salmonella. During Salmonella infection, lactate via the Salmonella type III secretion system effector SteE promotes macrophage M2 polarization, and the induction of macrophage M2 polarization by lactate is responsible for lactate-mediated Salmonella growth promotion. This study highlights the complex interactions between Salmonella and macrophages and provides an additional perspective on host-pathogen crosstalk at the metabolic interface.

Keywords:  Salmonella; infection; lactate; macrophage polarization; macrophages

DOI:  https://doi.org/10.1128/spectrum.02253-23
Res Sq. 2023 Sep 21. pii: rs.3.rs-3356477. [Epub ahead of print]

Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve checkpoint blockade.

Geoffrey J Markowitz, Yi Ban, Diamile A Tavarez, Liron Yoffe, Enrique Podaza, Yongfeng He, Mitchell T Martin, Michael J P Crowley, Tito A Sandoval, Dingcheng Gao, M Laura Martin, Olivier Elemento, Juan R Cubillos-Ruiz, Timothy E McGraw, Nasser K Altorki, Vivek Mittal.

TCF1 high progenitor CD8+ T cells mediate the efficacy of PD-1 blockade, however the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1 high central memory-like phenotype and increased responsiveness to PD-1 blockade in vivo . PKM2 KO CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites, and increased PPP cycling as determined by 1,2 13 C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8+ T cells towards a TCF1 high population, generated a unique transcriptional landscape, enhanced tumor control in mice in combination with PD-1 blockade, and promoted tumor killing in patient-derived tumor organoids. Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state amenable to checkpoint blockade.

DOI: https://doi.org/10.21203/rs.3.rs-3356477/v1
Anal Chem. 2023 Oct 06.

Spatially Resolved Metabolomics Combined with the 3D Tumor-Immune Cell Coculture Spheroid Highlights Metabolic Alterations during Antitumor Immune Response.

Panpan Chen, Yuhao Han, Lei Wang, Yurong Zheng, Zihan Zhu, Yuan Zhao, Mingqi Zhang, Xiangfeng Chen, Xiao Wang, Chenglong Sun.

The metabolic cross-talk between tumor and immune cells plays key roles in immune cell function and immune checkpoint blockade therapy. However, the characterization of tumor immunometabolism and its spatiotemporal alterations during immune response in a complex tumor microenvironment is challenging. Here, a 3D tumor-immune cell coculture spheroid model was developed to mimic tumor-immune interactions, combined with mass spectrometry imaging-based spatially resolved metabolomics to visualize tumor immunometabolic alterations during immune response. The inhibition of T cells was simulated by coculturing breast tumor spheroids with Jurkat T cells, and the reactivation of T cells can be monitored through diminishing cancer PD-L1 expressions by berberine. This system enables simultaneously screening and imaging discriminatory metabolites that are altered during T cell-mediated antitumor immune response and characterizing the distributions of berberine and its metabolites in tumor spheroids. We discovered that the transport and catabolism of glutamine were significantly reprogrammed during the antitumor immune response at both metabolite and enzyme levels, corresponding to its indispensable roles in energy metabolism and building new biomass. The combination of spatially resolved metabolomics with the 3D tumor-immune cell coculture spheroid visually reveals metabolic interactions between tumor and immune cells and possibly helps decipher the role of immunometabolic alterations in tumor immunotherapy.

DOI: https://doi.org/10.1021/acs.analchem.2c05734
J Clin Invest. 2023 Oct 02. pii: e169173. [Epub ahead of print]133(19):

Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity.

Seungjin Ryu, Olga Spadaro, Sviatoslav Sidorov, Aileen H Lee, Sonia Caprio, Christopher Morrison, Steven R Smith, Eric Ravussin, Irina Shchukina, Maxim N Artyomov, Yun-Hee Youm, Vishwa Deep Dixit.

  The comprehensive assessment of long-term effects of reducing intake of energy (CALERIE-II; NCT00427193) clinical trial established that caloric restriction (CR) in humans lowers inflammation. The identity and mechanism of endogenous CR-mimetics that can be deployed to control obesity-associated inflammation and diseases are not well understood. Our studies have found that 2 years of 14% sustained CR in humans inhibits the expression of the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), in adipose tissue. In mice, adipose tissue remodeling caused by weight loss through CR and low-protein diet feeding decreased, while high-fat diet-induced (HFD-induced) obesity increased SPARC expression in adipose tissue. Inducible SPARC downregulation in adult mice mimicked CR's effects on lowering adiposity by regulating energy expenditure. Deletion of SPARC in adipocytes was sufficient to protect mice against HFD-induced adiposity, chronic inflammation, and metabolic dysfunction. Mechanistically, SPARC activates the NLRP3 inflammasome at the priming step and downregulation of SPARC lowers macrophage inflammation in adipose tissue, while excess SPARC activated macrophages via JNK signaling. Collectively, reduction of adipocyte-derived SPARC confers CR-like metabolic and antiinflammatory benefits in obesity by serving as an immunometabolic checkpoint of inflammation.

Keywords:  Adipose tissue; Inflammation; Innate immunity; Metabolism; Obesity

DOI:  https://doi.org/10.1172/JCI169173
J Leukoc Biol. 2023 Oct 04. pii: qiad120. [Epub ahead of print]

Bacteria- and Fungus-derived PAMPs Induce Innate Immune Memory via Similar Functional, Metabolic and Transcriptional Adaptations.

Margaret A McBride, Cody L Stothers, Benjamin A Fensterheim, Katherine R Caja, Allison M Owen, Antonio Hernandez, Julia K Bohannon, Naeem K Patil, Sabah Ali, Sujata Dalal, Mohsin Rahim, Irina A Trenary, Jamey D Young, David L Williams, Edward R Sherwood.

  Exposure to pathogen-associated molecular patterns (PAMPs) induces an augmented, broad-spectrum antimicrobial response to subsequent infection, a phenomenon termed innate immune memory. This study examined the effects of treatment with β-glucan, a fungus-derived Dectin-1 ligand, or monophosphoryl lipid A (MPLA), a bacteria-derived TLR4 ligand, on innate immune memory with a focus on identifying common cellular and molecular pathways activated by these diverse PAMPs. Treatment with either PAMP prepared the innate immune system to respond more robustly to Pseudomonas aeruginosa infection in vivo by facilitating mobilization of innate leukocytes into blood, recruitment of leukocytes to the site of infection, augmentation of microbial clearance and attenuation of cytokine production. Examination of macrophages ex vivo showed amplification of metabolism, phagocytosis, and respiratory burst after treatment with either agent, although MPLA more robustly augmented these activities and more effectively facilitated killing of bacteria. Both agents activated gene expression pathways in macrophages that control inflammation, antimicrobial functions and protein synthesis and suppressed pathways regulating cell division. β-glucan treatment minimally altered macrophage differential gene expression in response to LPS challenge whereas MPLA attenuated the magnitude of the LPS-induced transcriptional response, especially cytokine gene expression. These results show that β-glucan and MPLA similarly augment the innate response to infection in vivo. Yet, MPLA more potently induces alterations in macrophage metabolism, antimicrobial functions, gene transcription and the response to LPS.

Keywords:  Innate Immune Memory; Macrophages; Monophosphoryl Lipid A; β-glucan

DOI:  https://doi.org/10.1093/jleuko/qiad120
JCI Insight. 2023 Oct 03. pii: e167829. [Epub ahead of print]

TSC2 S1365A mutation potently regulates CD8+T cell function and differentiation improving adoptive cellular cancer therapy.

Chirag H Patel, Yi Dong, Navid Koleini, Xiaoxu Wang, Brittany L Dunkerly-Eyring, Jiayu Wen, Mark J Ranek, Laura M Bartle, Daniel B Henderson, Jason G Sagert, David A Kass, Jonathan D Powell.

  MTORC1 integrates signaling from the immune microenvironment to regulate T cell activation, differentiation, and function. TSC2 in the tuberous sclerosis complex tightly regulates mTORC1 activation. CD8+ T cells lacking TSC2 have constitutively enhanced mTORC1 activity and generate robust effector T cells; however sustained mTORC1 activation prevents generation of long-lived memory CD8+ T cells. Here we show manipulating TSC2 at Ser1365 potently regulates activated but not basal mTORC1 signaling in CD8+ T cells. Unlike non-stimulated TSC2 knockout cells, CD8+ T cells expressing a phospho-silencing mutant TSC2-S1365A (SA) retain normal basal mTORC1 activity. PKC and T-cell Receptor (TCR) stimulation induces TSC2 S1365 phosphorylation and preventing this with the SA mutation markedly increases mTORC1 activation and T-cell effector function. Consequently, SA CD8+ T cells display greater effector responses while retaining their capacity to become long-lived memory T cells. SA CD8+ T cells also display enhanced effector function under hypoxic and acidic conditions. In murine and human solid-tumor models, CD8+ SA T cells used as adoptive cell therapy display greater anti-tumor immunity than WT CD8+ T cells. These findings reveal an upstream mechanism to regulate mTORC1 activity in T cells. The TSC2-SA mutation enhances both T cell effector function and long-term persistence/memory formation, supporting an approach to engineer better CAR-T cells for treating cancer.

Keywords:  Adaptive immunity; Cancer immunotherapy; Cell Biology; Immunology; T cells

DOI:  https://doi.org/10.1172/jci.insight.167829
Brain Behav Immun Health. 2023 Dec;34 100690

Repeated social defeat stress leads to immunometabolic shifts in innate immune cells of the spleen.

Mandakh Bekhbat, John Drake, Emily C Reed, Tatlock H Lauten, Tamara Natour, Vladimir I Vladimirov, Adam J Case.

Psychosocial stress has been shown to prime peripheral innate immune cells, which take on hyper-inflammatory phenotypes and are implicated in depressive-like behavior in mouse models. However, the impact of stress on cellular metabolic states that are thought to fuel inflammatory phenotypes in immune cells are unknown. Using single cell RNA-sequencing, we investigated mRNA enrichment of immunometabolic pathways in innate immune cells of the spleen in mice subjected to repeated social defeat stress (RSDS) or no stress (NS). RSDS mice displayed a significant increase in the number of splenic macrophages and granulocytes (p < 0.05) compared to NS littermates. RSDS-upregulated genes in macrophages, monocytes, and granulocytes significantly enriched immunometabolic pathways thought to play a role in myeloid-driven inflammation (glycolysis, HIF-1 signaling, MTORC1 signaling) as well as pathways related to oxidative phosphorylation (OXPHOS) and oxidative stress (p < 0.05 and FDR<0.1). These results suggest that the metabolic enhancement reflected by upregulation of glycolytic and OXPHOS pathways may be important for cellular proliferation of splenic macrophages and granulocytes following repeated stress exposure. A better understanding of these intracellular metabolic mechanisms may ultimately help develop novel strategies to reverse the impact of stress and associated peripheral immune changes on the brain and behavior.

DOI: https://doi.org/10.1016/j.bbih.2023.100690
FASEB J. 2023 Nov;37(11): e23216

Aberrant glucose metabolism underlies impaired macrophage differentiation in glycogen storage disease type Ib.

Yuyeon Jang, Tae Sub Park, Byung-Chul Park, Young Mok Lee, Tae-Hwe Heo, Hyun Sik Jun.

  Glycogen storage disease type Ib (GSD-Ib) is an autosomal recessive disorder caused by a deficiency in the glucose-6-phosphate (G6P) transporter (G6PT) that is responsible for transporting G6P into the endoplasmic reticulum. GSD-Ib is characterized by disturbances in glucose homeostasis, neutropenia, and neutrophil dysfunction. Although some studies have explored neutrophils abnormalities in GSD-Ib, investigations regarding monocytes/macrophages remain limited so far. In this study, we examined the impact of G6PT deficiency on monocyte-to-macrophage differentiation using bone marrow-derived monocytes from G6pt-/- mice as well as G6PT-deficient human THP-1 monocytes. Our findings revealed that G6PT-deficient monocytes exhibited immature differentiation into macrophages. Notably, the impaired differentiation observed in G6PT-deficient monocytes seemed to be associated with abnormal glucose metabolism, characterized by enhanced glucose consumption through glycolysis, even under quiescent conditions with oxidative phosphorylation. Furthermore, we observed a reduced secretion of inflammatory cytokines in G6PT-deficient THP-1 monocytes during the inflammatory response, despite their elevated glucose consumption. In conclusion, this study sheds light on the significance of G6PT in monocyte-to-macrophage differentiation and underscores its importance in maintaining glucose homeostasis and supporting immune response in GSD-Ib. These findings may contribute to a better understanding of the pathogenesis of GSD-Ib and potentially pave the way for the development of targeted therapeutic interventions.

Keywords:  differentiation; glucose metabolism; glucose-6-phosphate transporter; macrophages; metabolic reprogramming; monocytes

DOI:  https://doi.org/10.1096/fj.202300592RR
Front Biosci (Landmark Ed). 2023 Sep 25. 28(9): 223

GLUT1 Mediates the Metabolic Reprogramming and Inflammation of CCR2$^+$ Monocytes/Macrophages from Patients with DCM.

Chao Feng, Hantao Jiang, Xueyuan Yang, Hongliang Cong, Lan Li, Jinping Feng.

  BACKGROUND: Macrophages expressing CC chemokine receptor 2 (CCR2) possess characteristics and performance akin to M1 polarized macrophages, which promote inflammation. Advanced heart failure (HF) patients with higher abundance of CCR2+ macrophages are more likely to experience adverse remodeling. The precise mechanism of CCR2+ macrophages in how they affect the progression of dilated cardiomyopathy remains unknown.METHODS: Cardiac biopsy samples from dilated cardiomyopathy patients (DCM) were used for immunohistochemistry and immunofluorescence staining. PCR is employed to identify the IL-1β, IL-6, TNF-α, TGF-β, MMP2, MMP9, PKM1, PKM1, GLUT1, GLUT2, GLUT3, GLUT4, PDK1, PFKFB3, PFK1 and HK2 mRNA expression of CCR2+ monocytes/macrophages from the peripheral blood of DCM patients. Seahorse was used to evaluate the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of CCR2+ monocytes/macrophages. 2-DG was used to simulate a lack of glucose. Lentivirus containing GLUT1 inhibitory sequence was used to knockdown GLUT1 gene expression of CCR2+ monocytes/macrophages. Western Blot and immunofluorescence staining was used to evaluate the expression of NLRP3.
RESULTS: Immunostaining results of cardiac biopsy tissue from dilated cardiomyopathy (DCM) patients demonstrated that the progression to HF was associated with an increase in the number of CCR2+ macrophages. PCR results demonstrated that CCR2 monocytes and macrophages derived from the blood of DCM patients expressed elevated levels of inflammatory factors and up regulation of glycolysis related genes. In addition, OCR and glucose uptake experiments confirmed that increased glucose uptake of these cells was associated with greater inflammation and correlated with a worsening of cardiac function. limiting the glucose supply to CCR2+ monocytes and macrophages, or suppressing the activity of glucose transporter 1 (GLUT1) could reduce inflammation levels.
CONCLUSIONS: These results suggest that CCR2+ monocytes and macrophages rely on metabolic reprogramming to trigger inflammatory response and contribute to myocardial injury and the progression of DCM.

Keywords:  CCR2; GLUT1; dilated cardiomyopathy; macrophages; metabolic reprogrammings

DOI:  https://doi.org/10.31083/j.fbl2809223
Cell Biochem Biophys. 2023 Oct 04.

Fatty Acids and their Proteins in Adipose Tissue Inflammation.

Rahul Mallick, Sanjay Basak, Ranjit K Das, Antara Banerjee, Sujay Paul, Surajit Pathak, Asim K Duttaroy.

  Chronic low-grade adipose tissue inflammation is associated with metabolic disorders. Inflammation results from the intertwined cross-talks of pro-inflammatory and anti-inflammatory pathways in the immune response of adipose tissue. In addition, adipose FABP4 levels and lipid droplet proteins are involved in systemic and tissue inflammation. Dysregulated adipocytes help infiltrate immune cells derived from bone marrow responsible for producing cytokines and chemokines. When adipose tissue expands in excess, adipocyte exhibits increased secretion of adipokines and is implicated in metabolic disturbances due to the release of free fatty acids. This review presents an emerging concept in adipose tissue fat metabolism, fatty acid handling and binding proteins, and lipid droplet proteins and their involvement in inflammatory disorders.

Keywords:  Dietary fats; Inflammation; LCPUFA; Metabolic syndrome; Obesity; n-3 PUFA

DOI:  https://doi.org/10.1007/s12013-023-01185-6
iScience. 2023 Oct 20. 26(10): 107942

Inflammasome-mediated glucose limitation induces antibiotic tolerance in Staphylococcus aureus.

Jenna E Beam, Nikki J Wagner, Kuan-Yi Lu, Joshua B Parsons, Vance G Fowler, Sarah E Rowe, Brian P Conlon.

  Staphylococcus aureus is a leading human pathogen that frequently causes relapsing infections. The failure of antibiotics to eradicate infection contributes to infection relapse. Host-pathogen interactions have a substantial impact on antibiotic susceptibility and the formation of antibiotic tolerant cells. In this study, we interrogate how a major S. aureus virulence factor, α-toxin, interacts with macrophages to alter the microenvironment of the pathogen, thereby influencing its susceptibility to antibiotics. We find α-toxin-mediated activation of the NLRP3 inflammasome induces antibiotic tolerance. Induction of tolerance is driven by increased glycolysis in the host cells, resulting in glucose limitation and ATP depletion in S. aureus. Additionally, inhibition of NLRP3 activation improves antibiotic efficacy in vitro and in vivo, suggesting that this strategy has potential as a host-directed therapeutic to improve outcomes. Our findings identify interactions between S. aureus and the host that result in metabolic crosstalk that can determine the outcome of antimicrobial therapy.

Keywords:  Cellular physiology; Immune response; Microbial physiology; Multi-drug resistant organisms

DOI:  https://doi.org/10.1016/j.isci.2023.107942
Res Sq. 2023 Sep 22. pii: rs.3.rs-3364037. [Epub ahead of print]

Rapid intestinal and systemic metabolic reprogramming in an immunosuppressed environment.

Bing Ma, Samuel J Gavzy, Michael France, Yang Song, Hnin Wai Lwin, Allison Kensiski, Vikas Saxena, Wenji Piao, Ram Lakhan, Jegan Iyyathurai, Lushen Li, Christina Paluskievicz, Long Wu, Marina WillsonShirkey, Emmanuel F Mongodin, Valeria R Mas, Jonathan Bromberg.

Intrinsic metabolism shapes the immune environment associated with immune suppression and tolerance in settings such as organ transplantation and cancer. However, little is known about the metabolic activities in an immunosuppressive environment. In this study, we employed metagenomic, metabolomic, and immunological approaches to profile the early effects of the immunosuppressant drug tacrolimus, antibiotics, or both in gut lumen and circulation using a murine model. Tacrolimus induced rapid and profound alterations in metabolic activities within two days of treatment, prior to alterations in gut microbiota composition and structure. The metabolic profile and gut microbiome after seven days of treatment was distinct from that after two days of treatment, indicating continuous drug effects on both gut microbial ecosystem and host metabolism. The most affected taxonomic groups are Clostriales and Verrucomicrobiae (i.e., Akkermansia muciniphila ), and the most affected metabolic pathways included a group of interconnected amino acids, bile acid conjugation, glucose homeostasis, and energy production. Highly correlated metabolic changes were observed between lumen and serum metabolism, supporting their significant interactions. Despite a small sample size, this study explored the largely uncharacterized microbial and metabolic events in an immunosuppressed environment and demonstrated that early changes in metabolic activities can have significant implications that may serve as antecedent biomarkers of immune activation or quiescence. To understand the intricate relationships among gut microbiome, metabolic activities, and immune cells in an immune suppressed environment is a prerequisite for developing strategies to monitor and optimize alloimmune responses that determine transplant outcomes.

DOI: https://doi.org/10.21203/rs.3.rs-3364037/v1
bioRxiv. 2023 Sep 19. pii: 2023.09.17.557960. [Epub ahead of print]

Erdr1 orchestrates macrophage polarization and determines cell fate via dynamic interaction with YAP1 and Mid1.

Yuhang Wang.

Erythroid differentiation regulator 1 (Erdr1) is a stress-induced, widely distributed, extremely conserved secreted factor found in both humans and mice. Initially identified as an inducer of hemoglobin synthesis, it has emerged as a multifunctional protein, especially in immune cells. Although Erdr1 has been implicated in T cells and NK cell function, its role in macrophage remains unclear. This study aims to explore the precise function of Erdr1 in IL-1β production in macrophages and uncover the underlying mechanisms. Data manifest Erdr1 could play an inhibition role in IL-1β production, which also has been reported by previous research. What significance is we discovered Erdr1 has the capacity to promote IL-1β production which is associated with Erdr1 dose and cell density. We observed that Erdr1 has distinct expression patterns in pro-inflammatory (M1) and anti-inflammatory (M2) macrophages compared to naive macrophages. We hypothesized that Erdr1 dual modulates IL-1β production by binding with distinct adaptors via concentration change. Mechanistically, we demonstrated that Erdr1 has dynamic interaction with YAP1 and Mid1 by distinct domains. These intricate interplays not only govern the dynamic regulation of IL-1β production but also mediate macrophage functional and metabolic reprogramming and determine cell fate. This study highlights that Erdr1 orchestrates macrophage polarization by regulating YAP1 through the non-classical Hippo pathway.

DOI: https://doi.org/10.1101/2023.09.17.557960
Trends Endocrinol Metab. 2023 Sep 30. pii: S1043-2760(23)00192-3. [Epub ahead of print]

Carbon metabolism in the regulation of macrophage functions.

Zhending Gan, Muyang Zhao, Yaoyao Xia, Yuqi Yan, Wenkai Ren.

  Carbon metabolism, including one-carbon (1C) metabolism and central carbon metabolism (CCM), provides energy for the cell and generates metabolites with signaling activities. The regulation of macrophage polarization involves complex signals and includes an epigenetic level. Epigenetic modifications through changes in carbon metabolism allow macrophages to respond in a timely manner to their environment and adapt to metabolic demands during macrophage polarization. Here we summarize the current understanding of the crosstalk between carbon metabolism and epigenetic modifications in macrophages under physiological conditions and in the tumor microenvironment (TME) and provide targets and further directions for macrophage-associated diseases.

Keywords:  central carbon metabolism; epigenetic modification; macrophage; one-carbon metabolism

DOI:  https://doi.org/10.1016/j.tem.2023.09.003
Cytokine. 2023 Sep 26. pii: S1043-4666(23)00255-7. [Epub ahead of print]171 156377

Gene signature based on glycolysis is closely related to immune infiltration of patients with osteoarthritis.

Ziyi Chen, Yinghui Hua.

  BACKGROUND: Osteoarthritis (OA) is a degenerative arthritis with high levels of clinical heterogeneity. Aberrant metabolism such as shifting from oxidative phosphorylation to glycolysis is a response to changes in the inflammatory microenvironment of OA. Therefore, there is a pressing need to identify novel glycolysis regulators during OA progression.METHODS: We systematically studied glycolysis patterns mediated by 141 glycolysis regulators in 74 human synovial samples and discussed the characteristics of the immune microenvironment modified by glycolysis. The random forest (RF) method was applied to screen candidate hub glycolysis regulators in OA. RT-qPCR was performed to validate these key regulators. Then distinct glycolysis patterns were identified, and systematic correlation between these glycolysis patterns and immune cell infiltration was analyzed. The glycolysis score was constructed to quantify glycolysis patterns together with immune infiltration of individual OA patient.
RESULTS: 56 glycolysis-related differentially expressed genes (DEGs) were identified between OA and non-OA samples. STC1, VEGFA, KDELR3, DDIT4 and PGAM1 were selected as candidate genes to predict the probability of OA. Two glycolysis patterns in OA were identified. Glycolysis cluster A with higher glycolysis score was related to an inflamed phenotype.
CONCLUSIONS: Taken together, our results established a glycolysis-based genetic signature for OA, guided in-depth studies on the metabolic mechanism of OA, and facilitated to explore new clinical treatment strategies.

Keywords:  Glycolysis; Immune infiltration; Metabolism; Osteoarthritis

DOI:  https://doi.org/10.1016/j.cyto.2023.156377
Diabetologia. 2023 Oct 04.

CSF1R inhibition with PLX5622 affects multiple immune cell compartments and induces tissue-specific metabolic effects in lean mice.

Angela J T Bosch, Lena Keller, Laura Steiger, Theresa V Rohm, Sophia J Wiedemann, Andy J Y Low, Marc Stawiski, Leila Rachid, Julien Roux, Daniel Konrad, Stephan Wueest, Sonia Tugues, Melanie Greter, Marianne Böni-Schnetzler, Daniel T Meier, Claudia Cavelti-Weder.

  AIMS/HYPOTHESIS: Colony stimulating factor 1 (CSF1) promotes the proliferation, differentiation and survival of macrophages, which have been implicated in both beneficial and detrimental effects on glucose metabolism. However, the physiological role of CSF1 signalling in glucose homeostasis and the potential therapeutic implications of modulating this pathway are not known. We aimed to study the composition of tissue macrophages (and other immune cells) following CSF1 receptor (CSF1R) inhibition and elucidate the metabolic consequences of CSF1R inhibition.METHODS: We assessed immune cell populations in various organs by flow cytometry, and tissue-specific metabolic effects by hyperinsulinaemic-euglycaemic clamps and insulin secretion assays in mice fed a chow diet containing PLX5622 (a CSF1R inhibitor) or a control diet.
RESULTS: CSF1R inhibition depleted macrophages in multiple tissues while simultaneously increasing eosinophils and group 2 innate lymphoid cells. These immunological changes were consistent across different organs and were sex independent and reversible after cessation of the PLX5622. CSF1R inhibition improved hepatic insulin sensitivity but concomitantly impaired insulin secretion. In healthy islets, we found a high frequency of IL-1β+ islet macrophages. Their depletion by CSF1R inhibition led to downregulation of macrophage-related pathways and mediators of cytokine activity, including Nlrp3, suggesting IL-1β as a candidate insulin secretagogue. Partial restoration of physiological insulin secretion was achieved by injecting recombinant IL-1β prior to glucose stimulation in mice lacking macrophages.
CONCLUSIONS/INTERPRETATION: Macrophages and macrophage-derived factors, such as IL-1β, play an important role in physiological insulin secretion. A better understanding of the tissue-specific effects of CSF1R inhibition on immune cells and glucose homeostasis is crucial for the development of targeted immune-modulatory treatments in metabolic disease.
DATA AVAILABILITY: The RNA-Seq dataset is available in the Gene Expression Omnibus (GEO) under the accession number GSE189434 ( http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE189434 ).

Keywords:  Colony stimulating factor 1 (CSF1); Eosinophils; IL-1β; Innate lymphoid cells; Insulin secretion; Insulin sensitivity; Macrophages; PLX5622

DOI:  https://doi.org/10.1007/s00125-023-06007-1
J Allergy Clin Immunol Glob. 2023 Nov;2(4): 100163

Short-chain fatty acids ameliorate allergic airway inflammation via sequential induction of PMN-MDSCs and Treg cells.

Min-Ting Huang, Chiao-Juno Chiu, Ching-Yi Tsai, Yue-Ru Lee, Wei-Liang Liu, Hsiao-Li Chuang, Miao-Tzu Huang.

  Background: Reinforcement of the immune-regulatory pathway is a feasible strategy for prevention and therapy of allergic asthma. The short-chain fatty acids (SCFAs) acetate, propionate, and butyrate are pleiotropic microbial fermentation products known to induce regulatory T (Treg) cells and exert an immune-regulatory effect. The cellular mechanism underlying SCFA immune regulation in asthma is not fully understood.Objective: We investigated the role of myeloid-derived suppressor cells (MDSCs) and Treg cells, the immune-regulatory cells of innate and adaptive origin, respectively, in SCFA-elicited protection against allergic airway inflammation.
Methods: BALB/c mice were given SCFA-containing drinking water before being rendered asthmatic in response to ovalbumen. When indicated, mice were given a GR1-depleting antibody to investigate the function of MDSCs in allergic inflammation of the airways. MDSCs were sorted to examine their immunosuppressive function and interaction with T cells.
Results: The mice receiving SCFAs developed less severe asthma that was accompanied by expansion of PMN-MDSCs and Treg cells. Mice depleted of PMN-MDSCs exhibited aggravated asthma, and the protective effect of SCFAs was abrogated after PMN-MDSC depletion. SCFAs were able to directly induce T-cell differentiation toward Treg cells. Additionally, we found that PMN-MDSCs enhanced Treg cell expansion in a cell contact-dependent manner. Whilst membrane-bound TGF-β has been shown to induce Treg cell differentiation, we found that MDSCs upregulated surface expression of TGF-β after coculture with T-cells and that MDSC-induced Treg cell differentiation was partially inhibited by TGF-β blockage.
Conclusions: Although previous studies revealed Treg cells as the effector mechanism of SCFA immune regulation, we found that SCFAs ameliorate allergic airway inflammation by relaying immune regulation, with sequential induction of PMN-MDSCs and Treg cells.

Keywords:  Asthma; MDSCs; SCFAs; Treg cells; microbiota; myeloid-derived suppressor cells; short-chain fatty acids

DOI:  https://doi.org/10.1016/j.jacig.2023.100163
mBio. 2023 Oct 05. e0211023

Respiratory syncytial virus co-opts hypoxia-inducible factor-1α-mediated glycolysis to favor the production of infectious virus.

Li-Feng Chen, Jun-Xing Cai, Jing-Jing Zhang, Yu-Jun Tang, Jia-Yi Chen, Si Xiong, Yao-Lan Li, Hong Zhang, Zhong Liu, Man-Mei Li.

  Glycolysis, a series of oxidative reactions used to metabolize glucose and provide energy to host cells, is also required for respiratory syncytial virus (RSV) infection. However, the role of glycolysis during RSV infection and its underlying molecular mechanisms remain to be further explored. In this study, we investigated the function of hypoxia-inducible factor (HIF)-1α-mediated glycolysis in HEp-2 cells and mouse models during RSV infection. The results showed that RSV infection activated the insulin receptor (IR)-PI3K-Akt axis, upregulated the translation and activity of HIF-1α, increased the expression of glucose transporters (Glut1, Glut3, and Glut4), hexokinase (HK) 1 and 2, and platelet-type phosphofructokinase (PFKP), and promoted glucose uptake and glycolysis. In addition, mitochondrial damage induced by RSV resulted in the generation of large amounts of reactive oxygen species (ROS) in infected cells, which contributed to the stabilization and activation of HIF-1α. An energy map of the glycolytic ATP production rate (Glyco-ATP) versus the mitochondrial ATP production rate (mito-ATP) confirmed a switch from oxidative phosphorylation (OXPHOS) to glycolysis. Inhibition of IR-PI3K-Akt signaling, ROS, or HIF-1α effectively reversed the RSV-induced increase in glycolysis by blocking HIF-1α activation. Importantly, HIF-1α-mediated glycolysis provided energy for the production of progeny RSV virions. The production of infectious virions was nearly abolished after knocking down HIF-1α. PX-478, an orally active HIF-1α inhibitor, effectively inhibited RSV infection in vivo. Collectively, these results indicate the role of HIF-1α-mediated glycolysis in RSV infection and highlight HIF-1α as a potential target for anti-RSV drug development. IMPORTANCE Respiratory syncytial virus (RSV) is the leading etiological agent of lower respiratory tract illness. However, efficacious vaccines or antiviral drugs for treating RSV infections are currently not available. Indeed, RSV depends on host cells to provide energy needed to produce progeny virions. Glycolysis is a series of oxidative reactions used to metabolize glucose and provide energy to host cells. Therefore, glycolysis may be helpful for RSV infection. In this study, we show that RSV increases glycolysis by inducing the stabilization, transcription, translation, and activation of hypoxia-inducible factor (HIF)-1α in infected cells, which is important for the production of progeny RSV virions. This study contributes to understanding the molecular mechanism by which HIF-1α-mediated glycolysis controls RSV infection and reveals an effective target for the development of highly efficient anti-RSV drugs.

Keywords:  HIF-1α; IR-PI3K-Akt signaling; ROS; glycolysis; mitochondria; respiratory syncytial virus

DOI:  https://doi.org/10.1128/mbio.02110-23
Bioinform Adv. 2023 ;3(1): vbad125

Immuno-metabolic signaling in leishmaniasis: insights gained from mathematical modeling.

Shweta Khandibharad, Shailza Singh.

Motivation: Leishmaniasis is a global concern especially in underdeveloped and developing subtropical and tropical regions. The extent of infectivity in host is majorly dependent on functional polarization of macrophages. Classically activated M1 macrophage can eliminate parasite through production of iNOS and alternatively activated M2 macrophages can promote parasite growth through by providing shelter and nutrients to parasite. The biological processes involved in immune signaling and metabolism of host and parasite might be responsible for deciding fate of parasite.Results: Using systems biology approach, we constructed two mathematical models and inter-regulatory immune-metabolic networks of M1 and M2 state, through which we identified crucial components that are associated with these phenotypes. We also demonstrated how parasite may modulate M1 phenotype for its growth and proliferation and transition to M2 state. Through our previous findings as well as from recent findings we could identify SHP-1 as a key component in regulating the immune-metabolic characterization of M2 macrophage. By targeting SHP-1 at cellular level, it might be possible to modulate immuno-metabolic mechanism and thereby control parasite survival.
Availability and implementation: Mathematical modeling is implemented as a workflow and the models are deposited in BioModel database. FactoMineR is available at: https://github.com/cran/FactoMineR/tree/master.

DOI: https://doi.org/10.1093/bioadv/vbad125
Cell Oncol (Dordr). 2023 Sep 30.

Targeting the lipid metabolic reprogramming of tumor-associated macrophages: A novel insight into cancer immunotherapy.

Liang Li, Si-Rui Ma, Zi-Li Yu.

  BACKGROUND: Tumor-associated macrophages, as the major immunocytes in solid tumors, show divided loyalty and remarkable plasticity in tumorigenesis. Once the M2-to-M1 repolarization is achieved, they could be switched from the supporters for tumor development into the guardians for host immunity. Meanwhile, Lipid metabolic reprogramming is demonstrated to be one of the most important hallmarks of tumor-associated macrophages, which plays a decisive role in regulating their phenotypes and functions to promote tumorigenesis and immunotherapy resistance. Therefore, targeting the lipid metabolism of TAMs may provide a new direction for anti-tumor strategies.CONCLUSION: In this review, we first summarized the origins, classifications and general lipid metabolic process of TAMs. Then we discussed the currently available drugs and interventions that target lipid metabolic disorders of TAMs, including those targeting lipid uptake, efflux, lipolysis, FAO and lipid peroxidation. Besides, based on the recent research status, we summarized the present challenges for this cancer immunotherapy, including the precise drug delivery system, the lipid metabolic heterogeneity, and the intricate lipid metabolic interactions in the TME, and we also proposed corresponding possible solutions. Collectively, we hope this review will give researchers a better understanding of the lipid metabolism of TAMs and lead to the development of corresponding anti-tumor therapies in the future.

Keywords:  Cancer immunotherapy; Immunometabolism; Lipid metabolism; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1007/s13402-023-00881-y
Gut. 2023 Sep 28. pii: gutjnl-2023-329543. [Epub ahead of print]

Lactobacillus gallinarum-derived metabolites boost anti-PD1 efficacy in colorectal cancer by inhibiting regulatory T cells through modulating IDO1/Kyn/AHR axis.

Winnie Fong, Qing Li, Fenfen Ji, Wei Liang, Harry Cheuk Hay Lau, Xing Kang, Weixin Liu, Kenneth Kin-Wah To, Zhong Zuo, Xiaoxing Li, Xiang Zhang, Joseph Jy Sung, Jun Yu.

  OBJECTIVE: Gut microbiota is a key player in dictating immunotherapy response. We aimed to explore the immunomodulatory effect of probiotic Lactobacillus gallinarum and its role in improving anti-programmed cell death protein 1 (PD1) efficacy against colorectal cancer (CRC).DESIGN: The effects of L. gallinarum in anti-PD1 response were assessed in syngeneic mouse models and azoxymethane/dextran sulfate sodium-induced CRC model. The change of immune landscape was identified by multicolour flow cytometry and validated by immunohistochemistry staining and in vitro functional assays. Liquid chromatography-mass spectrometry was performed to identify the functional metabolites.
RESULTS: L. gallinarum significantly improved anti-PD1 efficacy in two syngeneic mouse models with different microsatellite instability (MSI) statuses (MSI-high for MC38, MSI-low for CT26). Such effect was confirmed in CRC tumourigenesis model. L. gallinarum synergised with anti-PD1 therapy by reducing Foxp3+ CD25+ regulatory T cell (Treg) intratumoural infiltration, and enhancing effector function of CD8+ T cells. L. gallinarum-derived indole-3-carboxylic acid (ICA) was identified as the functional metabolite. Mechanistically, ICA inhibited indoleamine 2,3-dioxygenase (IDO1) expression, therefore suppressing kynurenine (Kyn) production in tumours. ICA also competed with Kyn for binding site on aryl hydrocarbon receptor (AHR) and antagonised Kyn binding on CD4+ T cells, thereby inhibiting Treg differentiation in vitro. ICA phenocopied L. gallinarum effect and significantly improved anti-PD1 efficacy in vivo, which could be reversed by Kyn supplementation.
CONCLUSION: L. gallinarum-derived ICA improved anti-PD1 efficacy in CRC through suppressing CD4+Treg differentiation and enhancing CD8+T cell function by modulating the IDO1/Kyn/AHR axis. L. gallinarum is a potential adjuvant to augment anti-PD1 efficacy against CRC.

Keywords:  colorectal cancer; immunotherapy; probiotics

DOI:  https://doi.org/10.1136/gutjnl-2023-329543