bims-imicid 2022-04-17 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022–04–17
twenty-two papers selected by
Dylan Ryan, University of Cambridge

Cyclin J-CDK complexes limit innate immune responses by reducing proinflammatory changes in macrophage metabolism.
Immunometabolism of Myeloid-Derived Suppressor Cells: Implications for Mycobacterium tuberculosis Infection and Insights from Tumor Biology.
A common framework of monocyte-derived macrophage activation.
The aldehyde hypothesis: metabolic intermediates as antimicrobial effectors.
Impact of Lipid Metabolism on Antitumor Immune Response.
Disruption of Iron Homeostasis and Mitochondrial Metabolism Are Promising Targets to Inhibit Candida auris.
Unravelling the immunomodulatory role of apple phenolic rich extracts on human THP-1- derived macrophages using multiplatform metabolomics.
Impaired plasma cell differentiation associates with increased oxidative metabolism in IκBNS-deficient B cells.
Sodium butyrate reduces endoplasmic reticulum stress by modulating CHOP and empowers favorable anti-inflammatory adipose tissue immune-metabolism in HFD fed mice model of obesity.
Phosphatidylserine enhances anti-inflammatory effects of reconstituted HDL in macrophages via distinct intracellular pathways.
Myeloid Cell PKM2 Deletion Enhances Efferocytosis and Reduces Atherosclerosis.
Carbon monoxide activates PERK-regulated autophagy to induce immunometabolic reprogramming and boost anti-tumor T cell function.
Metabolic Reprogramming of Alloreactive T Cells Through TCR/MYC/mTORC1/E2F6 Signaling in aGvHD Patients.
Intravital lipid droplet labeling and imaging reveals the phenotypes and functions of individual macrophages in vivo.
Berberine Modulates Macrophage Activation by Inducing Glycolysis.
Glucocorticoid receptor modulates myeloid-derived suppressor cell function via mitochondrial metabolism in immune thrombocytopenia.
SENP1-Sirt3 signaling promotes α-ketoglutarate production during M2 macrophage polarization.
Glycolysis inhibition ameliorates brain injury after ischemic stroke by promoting the function of myeloid-derived suppressor cells.
Klebsiella pneumoniae induces host metabolic stress that promotes tolerance to pulmonary infection.
TLR8 is activated by 5'-methylthioinosine, a Plasmodium falciparum-derived intermediate of the purine salvage pathway.
SREBP1c-PARP1 axis tunes anti-senescence activity of adipocytes and ameliorates metabolic imbalance in obesity.
IFI16 Impacts Metabolic Reprogramming during Human Cytomegalovirus Infection.

Sci Signal. 2022 Apr 12. 15(729): eabm5011

Cyclin J-CDK complexes limit innate immune responses by reducing proinflammatory changes in macrophage metabolism.

Yee Kien Chong, Sarang Tartey, Yuki Yoshikawa, Koshi Imami, Songling Li, Masanori Yoshinaga, Ai Hirabayashi, Guohao Liu, Alexis Vandenbon, Fabian Hia, Takuya Uehata, Takashi Mino, Yutaka Suzuki, Takeshi Noda, Dominique Ferrandon, Daron M Standley, Yasushi Ishihama, Osamu Takeuchi.

Toll-like receptor (TLR) stimulation induces glycolysis and the production of mitochondrial reactive oxygen species (ROS), both of which are critical for inflammatory responses in macrophages. Here, we demonstrated that cyclin J, a TLR-inducible member of the cyclin family, reduced cytokine production in macrophages by coordinately controlling glycolysis and mitochondrial functions. Cyclin J interacted with cyclin-dependent kinases (CDKs), which increased the phosphorylation of a subset of CDK substrates, including the transcription factor FoxK1 and the GTPase Drp1. Cyclin J-dependent phosphorylation of FoxK1 decreased the transcription of glycolytic genes and Hif-1α activation, whereas hyperactivation of Drp1 by cyclin J-dependent phosphorylation promoted mitochondrial fragmentation and impaired the production of mitochondrial ROS. In mice, cyclin J in macrophages limited the growth of tumor xenografts and protected against LPS-induced shock but increased the susceptibility to bacterial infection. Collectively, our findings indicate that cyclin J-CDK signaling promotes antitumor immunity and the resolution of inflammation by opposing the metabolic changes that drive inflammatory responses in macrophages.

DOI: https://doi.org/10.1126/scisignal.abm5011
Int J Mol Sci. 2022 Mar 23. pii: 3512. [Epub ahead of print]23(7):

Immunometabolism of Myeloid-Derived Suppressor Cells: Implications for Mycobacterium tuberculosis Infection and Insights from Tumor Biology.

Brian S M Munansangu, Colin Kenyon, Gerhard Walzl, André G Loxton, Leigh A Kotze, Nelita du Plessis.

  The field of immunometabolism seeks to decipher the complex interplay between the immune system and the associated metabolic pathways. The role of small molecules that can target specific metabolic pathways and subsequently alter the immune landscape provides a desirable platform for new therapeutic interventions. Immunotherapeutic targeting of suppressive cell populations, such as myeloid-derived suppressor cells (MDSC), by small molecules has shown promise in pathologies such as cancer and support testing of similar host-directed therapeutic approaches in MDSC-inducing conditions such as tuberculosis (TB). MDSC exhibit a remarkable ability to suppress T-cell responses in those with TB disease. In tumors, MDSC exhibit considerable plasticity and can undergo metabolic reprogramming from glycolysis to fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) to facilitate their immunosuppressive functions. In this review we look at the role of MDSC during M. tb infection and how their metabolic reprogramming aids in the exacerbation of active disease and highlight the possible MDSC-targeted metabolic pathways utilized during M. tb infection, suggesting ways to manipulate these cells in search of novel insights for anti-TB therapies.

Keywords:  MDSC; OXPHOS; glycolysis; immunometabolism; metabolic reprogramming; tuberculosis

DOI:  https://doi.org/10.3390/ijms23073512
Sci Immunol. 2022 Apr 15. 7(70): eabl7482

A common framework of monocyte-derived macrophage activation.

David E Sanin, Yan Ge, Emilija Marinkovic, Agnieszka M Kabat, Angela Castoldi, George Caputa, Katarzyna M Grzes, Jonathan D Curtis, Elizabeth A Thompson, Sebastian Willenborg, Stefanie Dichtl, Susanne Reinhardt, Andreas Dahl, Erika L Pearce, Sabine A Eming, Alexander Gerbaulet, Axel Roers, Peter J Murray, Edward J Pearce.

Macrophages populate every organ during homeostasis and disease, displaying features of tissue imprinting and heterogeneous activation. The disconnected picture of macrophage biology that has emerged from these observations is a barrier for integration across models or with in vitro macrophage activation paradigms. We set out to contextualize macrophage heterogeneity across mouse tissues and inflammatory conditions, specifically aiming to define a common framework of macrophage activation. We built a predictive model with which we mapped the activation of macrophages across 12 tissues and 25 biological conditions, finding a notable commonality and finite number of transcriptional profiles, in particular among infiltrating macrophages, which we modeled as defined stages along four conserved activation paths. These activation paths include a "phagocytic" regulatory path, an "inflammatory" cytokine-producing path, an "oxidative stress" antimicrobial path, or a "remodeling" extracellular matrix deposition path. We verified this model with adoptive cell transfer experiments and identified transient RELMɑ expression as a feature of monocyte-derived macrophage tissue engraftment. We propose that this integrative approach of macrophage classification allows the establishment of a common predictive framework of monocyte-derived macrophage activation in inflammation and homeostasis.

DOI: https://doi.org/10.1126/sciimmunol.abl7482
Open Biol. 2022 Apr;12(4): 220010

The aldehyde hypothesis: metabolic intermediates as antimicrobial effectors.

K Heran Darwin, Sarah A Stanley.

  There are many reactive intermediates found in metabolic pathways. Could these potentially toxic molecules be exploited for an organism's benefit? We propose that during certain microbial infections, the production of inherently reactive aldehydes by an infected host is a previously unappreciated innate immune defence mechanism. While there has been a significant focus on the effects of aldehydes on mammalian physiology, the idea that they might be exploited or purposefully induced to kill pathogens is new. Given that aldehydes are made as parts of metabolic programmes that accompany immune cell activation by the cytokine interferon-gamma (IFN-γ) during infections, we hypothesize that aldehydes are among the arsenal of IFN-γ-inducible effectors needed for pathogen control.

Keywords:  Mycobacterium tuberculosis; aldehydes; innate immunity; interferon-gamma; macrophages; nitric oxide

DOI:  https://doi.org/10.1098/rsob.220010
Cancers (Basel). 2022 Apr 06. pii: 1850. [Epub ahead of print]14(7):

Impact of Lipid Metabolism on Antitumor Immune Response.

Nesrine Mabrouk, Baptiste Lecoeur, Ali Bettaieb, Catherine Paul, Frédérique Végran.

  Over the past decade, metabolic reprogramming has been defined as a hallmark of cancer. More recently, a large number of studies have demonstrated that metabolic reprogramming can modulate the differentiation and functions of immune cells, and thus modify the antitumor response. Increasing evidence suggests that modified energy metabolism could be responsible for the failure of antitumor immunity. Indeed, tumor-infiltrating immune cells play a key role in cancer, and metabolic switching in these cells has been shown to help determine their phenotype: tumor suppressive or immune suppressive. Recent studies in the field of immunometabolism focus on metabolic reprogramming in the tumor microenvironment (TME) by targeting innate and adaptive immune cells and their associated anti- or protumor phenotypes. In this review, we discuss the lipid metabolism of immune cells in the TME as well as the effects of lipids; finally, we expose the link between therapies and lipid metabolism.

Keywords:  cancer therapy; immune cells; immunosuppression; lipid metabolism

DOI:  https://doi.org/10.3390/cancers14071850
Microbiol Spectr. 2022 Apr 12. e0010022

Disruption of Iron Homeostasis and Mitochondrial Metabolism Are Promising Targets to Inhibit Candida auris.

Claudia Simm, Harshini Weerasinghe, David R Thomas, Paul F Harrison, Hayley J Newton, Traude H Beilharz, Ana Traven.

  Fungal infections are a global threat, but treatments are limited due to a paucity in antifungal drug targets and the emergence of drug-resistant fungi such as Candida auris. Metabolic adaptations enable microbial growth in nutrient-scarce host niches, and they further control immune responses to pathogens, thereby offering opportunities for therapeutic targeting. Because it is a relatively new pathogen, little is known about the metabolic requirements for C. auris growth and its adaptations to counter host defenses. Here, we establish that triggering metabolic dysfunction is a promising strategy against C. auris. Treatment with pyrvinium pamoate (PP) induced metabolic reprogramming and mitochondrial dysfunction evident in disrupted mitochondrial morphology and reduced tricarboxylic acid (TCA) cycle enzyme activity. PP also induced changes consistent with disrupted iron homeostasis. Nutrient supplementation experiments support the proposition that PP-induced metabolic dysfunction is driven by disrupted iron homeostasis, which compromises carbon and lipid metabolism and mitochondria. PP inhibited C. auris replication in macrophages, which is a relevant host niche for this yeast pathogen. We propose that PP causes a multipronged metabolic hit to C. auris: it restricts the micronutrient iron to potentiate nutritional immunity imposed by immune cells, and it further causes metabolic dysfunction that compromises the utilization of macronutrients, thereby curbing the metabolic plasticity needed for growth in host environments. Our study offers a new avenue for therapeutic development against drug-resistant C. auris, shows how complex metabolic dysfunction can be caused by a single compound triggering antifungal inhibition, and provides insights into the metabolic needs of C. auris in immune cell environments. IMPORTANCE Over the last decade, Candida auris has emerged as a human pathogen around the world causing life-threatening infections with wide-spread antifungal drug resistance, including pandrug resistance in some cases. In this study, we addressed the mechanism of action of the antiparasitic drug pyrvinium pamoate against C. auris and show how metabolism could be inhibited to curb C. auris proliferation. We show that pyrvinium pamoate triggers sweeping metabolic and mitochondrial changes and disrupts iron homeostasis. PP-induced metabolic dysfunction compromises the utilization of both micro- and macronutrients by C. auris and reduces its growth in vitro and in immune phagocytes. Our findings provide insights into the metabolic requirements for C. auris growth and define the mechanisms of action of pyrvinium pamoate against C. auris, demonstrating how this compound works by inhibiting the metabolic flexibility of the pathogen. As such, our study characterizes credible avenues for new antifungal approaches against C. auris.

Keywords:  Candida auris; antifungal agents; fungal pathogens; iron; metabolism; mitochondrial metabolism

DOI:  https://doi.org/10.1128/spectrum.00100-22
Food Res Int. 2022 May;pii: S0963-9969(22)00094-1. [Epub ahead of print]155 111037

Unravelling the immunomodulatory role of apple phenolic rich extracts on human THP-1- derived macrophages using multiplatform metabolomics.

Noelia Cambeiro-Pérez, María Figueiredo-González, María Rosa Pérez-Gregorio, Catarina Bessa-Pereira, Víctor De Freitas, Borja Sánchez, Elena Martínez-Carballo.

  Apples represent a significant source of dietary phenolic compounds with evidenced anti-inflammatory and immunomodulatory activities. Nevertheless, the effect of the whole apple matrix on human macrophages is unknown. In this context, our study attempts to evaluate the effect of apple-derived phenolic compounds-rich extracts (pulp, peel and leaf) on IL-1β production in THP-1-differentiated macrophages and derived metabolic alterations through untargeted metabolomics. Our results have showed that apple pulp treatment inhibited the release of the pro-inflammatory cytokine IL-1β induced by LPS in THP-1 macrophages by ELISA analysis. Metabolomics demonstrate that different proportions of phenolic compounds led to differential alterations in the metabolism of THP-1 macrophages. Indeed, apple extracts promoted alterations in lipid, carbohydrate, amino acid and vitamins as well as cofactors metabolism. Specifically, leaf extracts were characterized by alteration of galactose metabolism while the extracts derived from the fruit showed predominant alterations in lipids metabolism. All extracts mimicked the response observed under normal conditions in LPS-stimulated macrophages, inhibiting LPS response. Thus, the phenolic enriched extracts from apples will be a good source of natural compounds with a beneficial effect against inflammation, and they may be applied as a food supplement and/or functional ingredient for the treatment of inflammatory diseases.

Keywords:  Apple extracts; IL-1β; Immunomodulation; Phenolic compounds; THP-1 macrophages; Untargeted metabolomics

DOI:  https://doi.org/10.1016/j.foodres.2022.111037
Cell Immunol. 2022 Apr 04. pii: S0008-8749(22)00040-5. [Epub ahead of print]375 104516

Impaired plasma cell differentiation associates with increased oxidative metabolism in IκBNS-deficient B cells.

Elina Erikson, Monika Ádori, Sharesta Khoenkhoen, Jingdian Zhang, Joanna Rorbach, Xaquin Castro Dopico, Gunilla B Karlsson Hedestam.

  Mutations causing loss of the NF-κB regulator IκBNS, result in impaired development of innate-like B cells and defective plasma cell (PC) differentiation. Since productive PC differentiation requires B cell metabolic reprogramming, we sought to investigate processes important for this transition using the bumble mouse strain, deficient for IκBNS. We report that LPS-activated bumble B cells exhibited elevated mTOR activation levels, mitochondrial accumulation, increased OXPHOS and mROS production, along with a reduced capacity for autophagy, compared to wildtype B cells. Overall, our results demonstrate that PC differentiation in the absence of IκBNS is characterized by excessive activation during early rounds of B cell division, increased mitochondrial metabolism and decreased autophagic capacity, thus improving our understanding of the role of IκBNS in PC differentiation.

Keywords:  B cell activation; IκBNS; Mitochondrial metabolism; Plasma cell differentiation; mTOR

DOI:  https://doi.org/10.1016/j.cellimm.2022.104516
Food Chem (Oxf). 2022 Jul 30. 4 100079

Sodium butyrate reduces endoplasmic reticulum stress by modulating CHOP and empowers favorable anti-inflammatory adipose tissue immune-metabolism in HFD fed mice model of obesity.

Vinita Kushwaha, Prashant Rai, Salil Varshney, Sanchita Gupta, Nilesh Khandelwal, Durgesh Kumar, Anil Nilkanth Gaikwad.

  Over the past decade, the gut microbiome has been linked to several diseases including gastrointestinal diseases, cancer, immune disorder and metabolic syndrome. Shifts in the gut bacterial population affect the overall metabolic health status leading towards obesity and Type II diabetes mellitus. Secondary metabolites secreted by the gut microbiome interact with various host-sensing signalling pathways and are responsible for functional modulation of immune resident cells in metabolic tissues (Blüher, 2019). Of these, short- chain fatty acids (SCFAs) i.e., acetate, propionate and butyrate have been significantly correlated with the disposition of diabetes and metabolic disorder. The altered gut microbial population depletes the intestinal barrier causing entry of LPS into circulation and towards metabolic tissues triggering pro-inflammatory responses. As butyrate has been known to maintain intestinal integrity, we aimed to assess the apparent effect of externally given sodium butyrate [NaB] on immuno-metabolic profiling of adipose tissue, and its association with metabolic and inflammatory status of adipose tissue. To assess this, we put groups of C57BL/6 mice i.e., Control fed with a regular chow diet and another group that was fed on a high fat diet (HFD, 60%) for 8 weeks. Following this, the HFD group were further subdivided into two groups one fed with HFD and the other with HFD + NaB (5%w/w) for another 8 weeks. Body composition, weight gain, body adiposity and biochemical parameters were assessed. NaB fed group showed an improved metabolic profile compared to HFD fed group. Administration of NaB also improved glucose tolerance capacity and insulin sensitivity as determined by IPGTT and ITT profiles. Earlier reports have shown gut leakage and increased LPS in circulation is the primary cause of setting up inflammation at the tissue level. Our studies exhibited that, NaB increased the expression of tight junction proteins of intestinal linings and thereby enhanced intestinal barrier integrity. The FITC dextran permeability assay further confirmed this enhanced intestinal barrier integrity. We assessed the quantitative and relative population of different types of resident immune cells from a stromal vascular fraction of adipose tissue. Flow cytometry studies revealed significantly increased M2 (CD206+ ) macrophages and Tregs (CD25+ ) relative to the M1 macrophage population and CD4+ T cells respectively in NaB treated mice, suggesting its potential role in alleviating the inflammatory profile. In a nutshell, taken together better glucose tolerance, better gut health, reduced inflammatory adipose tissue immune cells, suggest potential beneficial role of sodium butyrate in alleviating overall inflammation and metabolic dysfunction associated with obesity.

Keywords:  Adipose tissue; ER stress; Immune cell population; Obesity; SCFA

DOI:  https://doi.org/10.1016/j.fochms.2022.100079
FASEB J. 2022 May;36(5): e22274

Phosphatidylserine enhances anti-inflammatory effects of reconstituted HDL in macrophages via distinct intracellular pathways.

Maryam Darabi, Marie Lhomme, Veronica D Dahik, Isabelle Guillas, Eric Frisdal, Emilie Tubeuf, Lucie Poupel, Mili Patel, Emmanuel L Gautier, Thierry Huby, Maryse Guerin, Kerry-Anne Rye, Philippe Lesnik, Wilfried Le Goff, Anatol Kontush.

  Phosphatidylserine (PS) is a minor phospholipid constituent of high-density lipoprotein (HDL) that exhibits potent anti-inflammatory activity. It remains indeterminate whether PS incorporation can enhance anti-inflammatory effects of reconstituted HDL (rHDL). Human macrophages were treated with rHDL containing phosphatidylcholine alone (PC-rHDL) or PC and PS (PC/PS-rHDL). Interleukin (IL)-6 secretion and expression was more strongly inhibited by PC/PS-rHDL than PC-rHDL in both tumor necrosis factor (TNF)-α- and lipopolysaccharide (LPS)-stimulated macrophages. siRNA experiments revealed that the enhanced anti-inflammatory effects of PC/PS-rHDL required scavenger receptor class B type I (SR-BI). Furthermore, PC/PS-rHDL induced a greater increase in Akt1/2/3 phosphorylation than PC-rHDL. In addition, PC/PS but not PC-rHDL decreased the abundance of plasma membrane lipid rafts and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation. Finally, when these rHDL formulations were administered to dyslipidemic low-density lipoprotein (LDL)-receptor knockout mice fed a high-cholesterol diet, circulating IL-6 levels were significantly reduced only in PC/PS-rHDL-treated mice. In parallel, enhanced Akt1/2/3 phosphorylation by PC/PS-rHDL was observed in the mouse aortic tissue using immunohistochemistry. We concluded that the incorporation of PS into rHDLs enhanced their anti-inflammatory activity by modulating Akt1/2/3- and p38 MAPK-mediated signaling through SR-BI in stimulated macrophages. These data identify PS as a potent anti-inflammatory component capable of enhancing therapeutic potential of rHDL-based therapy.

Keywords:  atherosclerosis; inflammation; phospholipids; rHDL

DOI:  https://doi.org/10.1096/fj.201800810R
Circ Res. 2022 Apr 11. 101161CIRCRESAHA121320704

Myeloid Cell PKM2 Deletion Enhances Efferocytosis and Reduces Atherosclerosis.

Prakash Doddapattar, Rishabh Dev, Madankumar Ghatge, Rakesh B Patel, Manish Jain, Nirav Dhanesha, Steven R Lentz, Anil K Chauhan.

   BACKGROUND: The glycolytic enzyme PKM2 (pyruvate kinase muscle 2) is upregulated in monocytes/macrophages of patients with atherosclerotic coronary artery disease. However, the role of cell type-specific PKM2 in the setting of atherosclerosis remains to be defined. We determined whether myeloid cell-specific PKM2 regulates efferocytosis and atherosclerosis.
METHODS: We generated myeloid cell-specific PKM2-/- mice on Ldlr (low-density lipoprotein receptor)-deficient background (PKM2mye-KOLdlr-/-). Controls were littermate PKM2WTLdlr-/- mice. Susceptibility to atherosclerosis was evaluated in whole aortae and cross sections of the aortic sinus in male and female mice fed a high-fat Western diet for 14 weeks, starting at 8 weeks.
RESULTS: PKM2 was upregulated in macrophages of Ldlr-/- mice fed a high-fat Western diet compared with chow diet. Myeloid cell-specific deletion of PKM2 led to a significant reduction in lesions in the whole aorta and aortic sinus despite high cholesterol and triglyceride levels. Furthermore, we found decreased macrophage content in the lesions of myeloid cell-specific PKM2-/- mice associated with decreased MCP-1 (monocyte chemoattractant protein 1) levels in plasma, reduced transmigration of macrophages in response to MCP-1, and impaired glycolytic rate. Macrophages isolated from myeloid-specific PKM2-/- mice fed the Western diet exhibited reduced expression of proinflammatory genes, including MCP-1, IL (interleukin)-1β, and IL-12. Myeloid cell-specific PKM2-/- mice exhibited reduced apoptosis concomitant with enhanced macrophage efferocytosis and upregulation of LRP (LDLR-related protein)-1 in macrophages in vitro and atherosclerotic lesions in vivo. Silencing LRP-1 in PKM2-deficient macrophages restored inflammatory gene expression and reduced efferocytosis. As a therapeutic intervention, inhibiting PKM2 nuclear translocation using a small molecule reduced glycolytic rate, enhanced efferocytosis, and reduced atherosclerosis in Ldlr-/- mice.
CONCLUSIONS: Genetic deletion of PKM2 in myeloid cells or limiting its nuclear translocation reduces atherosclerosis by suppressing inflammation and enhancing efferocytosis.

Keywords:  atherosclerosis; gene expression; inflammation; macrophages; pyruvate kinase

DOI:  https://doi.org/10.1161/CIRCRESAHA.121.320704
Cancer Res. 2022 Apr 11. pii: canres.3155.2021. [Epub ahead of print]

Carbon monoxide activates PERK-regulated autophagy to induce immunometabolic reprogramming and boost anti-tumor T cell function.

Paramita Chakraborty, Rasesh Y Parikh, Seungho Choi, Danh Tran, Monika Gooz, Zachariah T Hedley, Do-Sung Kim, Dariusz Pytel, Inhong Kang, Satish N Nadig, Gyda C Beeson, Lauren Ball, Meenal Mehrotra, Hongjun Wang, Stefano Berto, Viswanathan Palanisamy, Hong Li, Shilpak Chatterjee, Paulo C Rodriguez, Eduardo N Maldonado, J Alan Diehl, Vamsi K Gangaraju, Shikhar Mehrotra.

Mitochondria and endoplasmic reticulum (ER) share structural and functional networks and activate well-orchestrated signaling processes to shape cells' fate and function. While persistent ER stress (ERS) response leads to mitochondrial collapse, moderate ERS promotes mitochondrial function. Strategies to boost anti-tumor T-cell function by targeting ER-mitochondria crosstalk have not yet been exploited. Here, we used carbon monoxide (CO), a short-lived gaseous molecule, to test if engaging moderate ERS conditions can improve mitochondrial and anti-tumor functions in T cells. In melanoma antigen-specific T cells, CO-induced transient activation of ERS sensor protein kinase R-like endoplasmic reticulum kinase (PERK) significantly increased anti-tumor T-cell function. Furthermore, CO-induced PERK activation temporarily halted protein translation and induced protective autophagy, including mitophagy. The use of LC3-GFP enabled differentiation between the cells that prepare themselves to undergo active autophagy (LC3-GFPpos) and those that fail to enter the process (LC3-GFPneg). LC3-GFPpos T cells showed strong anti-tumor potential, whereas LC3-GFPneg cells exhibited a T regulatory-like phenotype, harbored dysfunctional mitochondria, and accumulated abnormal metabolite content. These anomalous ratios of metabolites rendered the cells with a hypermethylated state and distinct epigenetic profile, limiting their anti-tumor activity. Overall, this study shows that ERS-activated autophagy pathways modify the mitochondrial function and epigenetically reprogram T cells towards a superior anti-tumor phenotype to achieve robust tumor control.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-3155
Front Immunol. 2022 ;13 850177

Metabolic Reprogramming of Alloreactive T Cells Through TCR/MYC/mTORC1/E2F6 Signaling in aGvHD Patients.

Zengkai Pan, Aijie Huang, Yang He, Zilu Zhang, Chuanhe Jiang, Luxiang Wang, Kai Qing, Sujiang Zhang, Jianmin Wang, Xiaoxia Hu.

  Acute graft-versus-host disease (aGvHD) is the most common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and significantly linked with morbidity and mortality. Although much work has been engaged to investigate aGvHD pathogenesis, the understanding of alloreactive T-cell activation remains incomplete. To address this, we studied transcriptional activation of carbohydrate, nucleotide, tricarboxylic acid (TCA) cycle, and amino acid metabolism of T cells before aGvHD onset by mining the Gene Expression Omnibus (GEO) datasets. Glycolysis had the most extensive correlation with other activated metabolic sub-pathways. Through Pearson correlation analyses, we found that glycolytic activation was positively correlated with activated CD4 memory T-cell subset and T-cell proliferation and migration. T-cell receptor (TCR), mechanistic target of rapamycin complex 1 (mTORC1), myelocytomatosis oncogene (MYC) signaling pathways and E2F6 might be "master regulators" of glycolytic activity. aGvHD predictive model constructed by glycolytic genes (PFKP, ENO3, and GAPDH) through logistic regression showed high predictive and discriminative value. Furthermore, higher expressions of PFKP, ENO3, and GAPDH in alloreactive T cells were confirmed in our pre-aGvHD patient cohort. And the predictive value of the aGvHD risk model was also validated. In summary, our study demonstrated that glycolytic activation might play a pivotal function in alloreactive T-cell activation before aGvHD onset and would be the potential target for aGvHD therapy.

Keywords:  T cells; aGvHD; allogeneic hematopoietic stem cell transplantation; glycolytic; metabolic reprogramming

DOI:  https://doi.org/10.3389/fimmu.2022.850177
J Lipid Res. 2022 Apr 06. pii: S0022-2275(22)00040-2. [Epub ahead of print] 100207

Intravital lipid droplet labeling and imaging reveals the phenotypes and functions of individual macrophages in vivo.

Yue Li, Yuwei Du, Zhengqing Xu, Yuan He, Ran Yao, Huiran Jiang, Wen Ju, Jianlin Qiao, Kailin Xu, Tzu-Ming Liu, Lingyu Zeng.

  Macrophages play pivotal roles in the maintenance of tissue homeostasis. However, the re-activation of macrophages toward pro-inflammatory states correlates with a plethora of inflammatory diseases, including atherosclerosis, obesity, neurodegeneration, and bone marrow failure syndromes. However, the lack of methods to reveal macrophage phenotype and function in vivo impedes the translational research of these diseases. Here, we found that pro-inflammatory macrophages accumulate intracellular lipid droplets (LDs) relative to resting or non-inflammatory macrophages both in vitro and in vivo, indicating that LD accumulation serves as a structural biomarker for macrophage phenotyping. To realize the staining and imaging of macrophage LDs in vivo, we developed a fluorescent fatty acid analog-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticle to label macrophages in mice with high efficiency and specificity. Using these novel nanoparticles, we achieved in situ functional identification of single macrophages in bone marrow, liver, lung, and adipose tissues under conditions of acute or chronic inflammation. Moreover, with this intravital imaging platform, we further realized in vivo phenotyping of individual macrophages in the calvarial bone marrow of mice under systemic inflammation. In conclusion, we established an efficient in vivo LD labeling and imaging system for single macrophage phenotyping, which will aid in the development of diagnostics and therapeutic monitoring. Moreover, this method also provides new avenues for the study of lipid trafficking and dynamics in vivo.

Keywords:  Macrophage; biomarker; bone marrow; fatty acid analog; in vivo imaging; inflammation; lipid droplet; lipid trafficking; nanoparticle delivery; systemic inflammation

DOI:  https://doi.org/10.1016/j.jlr.2022.100207
J Immunol. 2022 Apr 15. pii: ji2100716. [Epub ahead of print]

Berberine Modulates Macrophage Activation by Inducing Glycolysis.

Min Li, Haifeng Zhang, Yameng Zhang, Jinting Fan, Jinhao Zhu, Xinyue Gu, Zhonghui Li, Chengyang Zhang, Zhen Liu, Yuebai Li, Mingxi Zang, Ge Jin, Guoping Li, Yang Mi.

Classical activation of macrophage and monocyte differentiation induced by β-glucan is accompanied with metabolic change in glucose. However, the role of the metabolic rewiring in monocyte/macrophage activation remains elusive. In this study, we show that berberine induces aerobic glycolysis by blocking the tricarboxylic acid cycle and modulates cytokine responses in bone marrow-derived macrophages (BMDMs) from mice and human PBMC. 13-Methyberberine had activities on glucose metabolism and BMDM activation similar to those of berberine, whereas other tested derivatives lost both activities. Glucose transporter (GLUT)1 expression and total cellular hexokinase activity increased gradually in BMDMs in the presence of berberine. In the contrast, LPS upregulated GLUT1 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) levels in 6 h. Extracellular glucose levels and replacing glucose with galactose in culture medium affected the cytokine secretion of BMDMs. Berberine alleviated enteritis of Salmonella typhimurium infection and protected mice against endotoxic shock. In mice i.p. injected with LPS, the increase of serum TNF-α and the drop of blood glucose were attenuated by berberine treatment. These data together demonstrated that macrophage activation was closely related with glucose metabolism.

DOI: https://doi.org/10.4049/jimmunol.2100716
Cell Mol Immunol. 2022 Apr 12.

Glucocorticoid receptor modulates myeloid-derived suppressor cell function via mitochondrial metabolism in immune thrombocytopenia.

Yu Hou, Jie Xie, Shuwen Wang, Daqi Li, Lingjun Wang, Haoyi Wang, Xiaofei Ni, Shaoqiu Leng, Guosheng Li, Ming Hou, Jun Peng.

  Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature cells and natural inhibitors of adaptive immunity. Intracellular metabolic changes in MDSCs exert a direct immunological influence on their suppressive activity. Our previous study demonstrated that high-dose dexamethasone (HD-DXM) corrected the functional impairment of MDSCs in immune thrombocytopenia (ITP); however, the MDSC population was not restored in nonresponders, and the mechanism remained unclear. In this study, altered mitochondrial physiology and reduced mitochondrial gene transcription were detected in MDSCs from HD-DXM nonresponders, accompanied by decreased levels of carnitine palmitoyltransferase-1 (CPT-1), a rate-limiting enzyme in fatty acid oxidation (FAO). Blockade of FAO with a CPT-1 inhibitor abolished the immunosuppressive function of MDSCs in HD-DXM responders. We also report that MDSCs from ITP patients had lower expression of the glucocorticoid receptor (GR), which can translocate into mitochondria to regulate the transcription of mitochondrial DNA (mtDNA) as well as the level of oxidative phosphorylation. It was confirmed that the expression of CPT-1 and mtDNA-encoded genes was downregulated in GR-siRNA-treated murine MDSCs. Finally, by establishing murine models of active and passive ITP via adoptive transfer of DXM-modulated MDSCs, we confirmed that GR-silenced MDSCs failed to alleviate thrombocytopenia in mice with ITP. In conclusion, our study indicated that impaired aerobic metabolism in MDSCs participates in the pathogenesis of glucocorticoid resistance in ITP and that intact control of MDSC metabolism by GR contributes to the homeostatic regulation of immunosuppressive cell function.

Keywords:  HD-DXM; glucocorticoid receptor; immune thrombocytopenia; myeloid-derived suppressor cell

DOI:  https://doi.org/10.1038/s41423-022-00859-0
Cell Rep. 2022 Apr 12. pii: S2211-1247(22)00412-0. [Epub ahead of print]39(2): 110660

SENP1-Sirt3 signaling promotes α-ketoglutarate production during M2 macrophage polarization.

Wei Zhou, Gaolei Hu, Jianli He, Tianshi Wang, Yong Zuo, Ying Cao, Quan Zheng, Jun Tu, Jiao Ma, Rong Cai, Yalan Chen, Qiuju Fan, Baijun Dong, Hongsheng Tan, Qi Wang, Wei Xue, Jinke Cheng.

  The metabolic program is altered during macrophage activation and influences macrophage polarization. Glutaminolysis promotes accumulation of α-ketoglutarate (αKG), leading to Jumonji domain-containing protein D3 (Jmjd3)-dependent demethylation at H3K27me3 during M2 polarization of macrophages. However, it remains unclear how αKG accumulation is regulated during M2 polarization of macrophages. This study shows that SENP1-Sirt3 signaling controls glutaminolysis, leading to αKG accumulation during IL-4-stimulated M2 polarization. Activation of the SENP1-Sirt3 axis augments M2 macrophage polarization through the accumulation of αKG via glutaminolysis. We also identify glutamate dehydrogenase 1 (GLUD1) as an acetylated protein in mitochondria. The SENP1-Sirt3 axis deacetylates GLUD1 and increases its activity in glutaminolysis to promote αKG production, leading to M2 polarization of macrophages. Therefore, SENP1-Sirt3 signaling plays a critical role in αKG accumulation via glutaminolysis to promote M2 polarization.

Keywords:  CP: Immunology; SENP1; SUMOylation; Sirt3; macrophage M2 polarization; α-ketoglutarate

DOI:  https://doi.org/10.1016/j.celrep.2022.110660
Pharmacol Res. 2022 Apr 06. pii: S1043-6618(22)00153-0. [Epub ahead of print] 106208

Glycolysis inhibition ameliorates brain injury after ischemic stroke by promoting the function of myeloid-derived suppressor cells.

Jingwei Yan, Anqi Li, Xianglin Chen, Kaixiang Cao, Mingchuan Song, Shuai Guo, Zou Li, Shuqi Huang, Ziling Li, Danghan Xu, Yong Wang, Xiaoyan Dai, Du Feng, Yuqing Huo, Jun He, Yiming Xu.

  Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells which are immunosuppressive and glycolytically inactive in inflammatory diseases. However, it is unknown whether MDSCs contribute to ischemic stroke and how glycolysis regulates MDSC function in such a context. Here, we showed that MDSCs arise in the blood of patients at early phase of stroke. Similar results were observed in temporary middle cerebral artery occlusion-induced cerebral ischemic mice. Pharmaceutical exhaustion of MDSCs aggravated, while adoptive transfer of MDSCs rescued the ischemic brain injury. However, the differentiation of MDSCs into immunopotent myeloid cells which coincides with increased glycolysis was observed in the context of ischemic stroke. Mechanistically, the glycolytic product lactate autonomously induces MDSC differentiation through activation of mTORC1, and paracrinely activates Th1 and Th17 cells. Moreover, gene knockout or inhibition of the glycolytic enzyme PFKFB3 increased endogenous MDSCs by blocking their differentiation, and improved ischemic brain injury. Collectively, these results revealed that glycolytic switch decreases the immunosuppressive and neuroprotective role of MDSCs in ischemic stroke and pharmacological targeting MDSCs via glycolysis inhibition constitutes a promising therapeutic strategy for ischemic stroke.

Keywords:  2,3,5-triphenyltetrazoliium chloride (Pubmed CID: 9283); 3PO (Pubmed CID: 5720233); 5-fluorouracil (Pubmed CID: 3385); Gemcitabine (Pubmed CID: 60750); Glycolysis; Inflammation; Ischemic stroke; Myeloid-derived suppressor cells; Rapamycin (Pubmed CID: 5284616)

DOI:  https://doi.org/10.1016/j.phrs.2022.106208
Cell Metab. 2022 Apr 03. pii: S1550-4131(22)00097-3. [Epub ahead of print]

Klebsiella pneumoniae induces host metabolic stress that promotes tolerance to pulmonary infection.

Tania Wong Fok Lung, Daniel Charytonowicz, Kristin G Beaumont, Shivang S Shah, Shwetha H Sridhar, Claire L Gorrie, Andre Mu, Casey E Hofstaedter, David Varisco, Thomas H McConville, Marija Drikic, Brandon Fowler, Andreacarola Urso, Wei Shi, Dario Fucich, Medini K Annavajhala, Ibrahim N Khan, Irina Oussenko, Nancy Francoeur, Melissa L Smith, Brent R Stockwell, Ian A Lewis, Abderrahman Hachani, Swikrity Upadhyay Baskota, Anne-Catrin Uhlemann, Danielle Ahn, Robert K Ernst, Benjamin P Howden, Robert Sebra, Alice Prince.

  K. pneumoniae sequence type 258 (Kp ST258) is a major cause of healthcare-associated pneumonia. However, it remains unclear how it causes protracted courses of infection in spite of its expression of immunostimulatory lipopolysaccharide, which should activate a brisk inflammatory response and bacterial clearance. We predicted that the metabolic stress induced by the bacteria in the host cells shapes an immune response that tolerates infection. We combined in situ metabolic imaging and transcriptional analyses to demonstrate that Kp ST258 activates host glutaminolysis and fatty acid oxidation. This response creates an oxidant-rich microenvironment conducive to the accumulation of anti-inflammatory myeloid cells. In this setting, metabolically active Kp ST258 elicits a disease-tolerant immune response. The bacteria, in turn, adapt to airway oxidants by upregulating the type VI secretion system, which is highly conserved across ST258 strains worldwide. Thus, much of the global success of Kp ST258 in hospital settings can be explained by the metabolic activity provoked in the host that promotes disease tolerance.

Keywords:  Klebsiella pneumoniae; M2 macrophages; MDSCs; bacterial adaptation; disease tolerance; immunometabolism; immunosuppression; itaconate; pulmonary infection; type 6 secretion system

DOI:  https://doi.org/10.1016/j.cmet.2022.03.009
Cell Rep. 2022 Apr 12. pii: S2211-1247(22)00449-1. [Epub ahead of print]39(2): 110691

TLR8 is activated by 5'-methylthioinosine, a Plasmodium falciparum-derived intermediate of the purine salvage pathway.

Gabriele Köllisch, Francisco Venegas Solis, Hannah-Lena Obermann, Jeannine Eckert, Thomas Müller, Tim Vierbuchen, Thomas Rickmeyer, Simon Muche, Jude M Przyborski, Holger Heine, Andreas Kaufmann, Stefan Baumeister, Klaus Lingelbach, Stefan Bauer.

  The innate immune recognition of the malaria-causing pathogen Plasmodium falciparum (P. falciparum) is not fully explored. Here, we identify the nucleoside 5'-methylthioinosine (MTI), a Plasmodium-specific intermediate of the purine salvage pathway, as a pathogen-derived Toll-like receptor 8 (TLR8) agonist. Co-incubation of MTI with the TLR8 enhancer poly(dT) as well as synthetic or P. falciparum-derived RNA strongly increase its stimulatory activity. Of note, MTI generated from methylthioadenosine (MTA) by P. falciparum lysates activates TLR8 when MTI metabolism is inhibited by immucillin targeting the purine nucleoside phosphorylase (PfPNP). Importantly, P. falciparum-infected red blood cells incubated with MTI or cultivated with MTA and immucillin lead to TLR8-dependent interleukin-6 (IL-6) production in human monocytes. Our data demonstrate that the nucleoside MTI is a natural human TLR8 ligand with possible in vivo relevance for innate sensing of P. falciparum.

Keywords:  5ʹ-methylthioadenosine; 5ʹ-methylthioinosine; CP: Immunology; CU-CPT9a; MTA; MTI; PBMC; Plasmodium falciparum; TLR8; immucillin; monocytes

DOI:  https://doi.org/10.1016/j.celrep.2022.110691
Cell Metab. 2022 Apr 05. pii: S1550-4131(22)00098-5. [Epub ahead of print]

SREBP1c-PARP1 axis tunes anti-senescence activity of adipocytes and ameliorates metabolic imbalance in obesity.

Gung Lee, Ye Young Kim, Hagoon Jang, Ji Seul Han, Hahn Nahmgoong, Yoon Jeong Park, Sang Mun Han, Changyun Cho, Sangsoo Lim, Jung-Ran Noh, Won Keun Oh, Chul-Ho Lee, Sun Kim, Jae Bum Kim.

  Emerging evidence indicates that the accretion of senescent cells is linked to metabolic disorders. However, the underlying mechanisms and metabolic consequences of cellular senescence in obesity remain obscure. In this study, we found that obese adipocytes are senescence-susceptible cells accompanied with genome instability. Additionally, we discovered that SREBP1c may play a key role in genome stability and senescence in adipocytes by modulating DNA-damage responses. Unexpectedly, SREBP1c interacted with PARP1 and potentiated PARP1 activity during DNA repair, independent of its canonical lipogenic function. The genetic depletion of SREBP1c accelerated adipocyte senescence, leading to immune cell recruitment into obese adipose tissue. These deleterious effects provoked unhealthy adipose tissue remodeling and insulin resistance in obesity. In contrast, the elimination of senescent adipocytes alleviated adipose tissue inflammation and improved insulin resistance. These findings revealed distinctive roles of SREBP1c-PARP1 axis in the regulation of adipocyte senescence and will help decipher the metabolic significance of senescence in obesity.

Keywords:  DNA repair process; PARP1; SASP; SREBP1c; adipocyte; adipose tissue inflammation; cellular senescence; energy homeostasis; insulin resistance; obesity

DOI:  https://doi.org/10.1016/j.cmet.2022.03.010
mBio. 2022 Apr 14. e0043522

IFI16 Impacts Metabolic Reprogramming during Human Cytomegalovirus Infection.

Gloria Griffante, Weronika Hewelt-Belka, Camilla Albano, Francesca Gugliesi, Selina Pasquero, Sergio Fernando Castillo Pacheco, Greta Bajetto, Paolo Ettore Porporato, Erica Mina, Marta Vallino, Christian Krapp, Martin Roelsgaard Jakobsen, John Purdy, Jens von Einem, Santo Landolfo, Valentina Dell'Oste, Matteo Biolatti.

  Cellular lipid metabolism plays a pivotal role in human cytomegalovirus (HCMV) infection, as increased lipogenesis in HCMV-infected cells favors the envelopment of newly synthesized viral particles. As all cells are equipped with restriction factors (RFs) able to exert a protective effect against invading pathogens, we asked whether a similar defense mechanism would also be in place to preserve the metabolic compartment from HCMV infection. Here, we show that gamma interferon (IFN-γ)-inducible protein 16 (IFI16), an RF able to block HCMV DNA synthesis, can also counteract HCMV-mediated metabolic reprogramming in infected primary human foreskin fibroblasts (HFFs), thereby limiting virion infectivity. Specifically, we find that IFI16 downregulates the transcriptional activation of the glucose transporter 4 (GLUT4) through cooperation with the carbohydrate-response element-binding protein (ChREBP), thereby reducing HCMV-induced transcription of lipogenic enzymes. The resulting decrease in glucose uptake and consumption leads to diminished lipid synthesis, which ultimately curbs the de novo formation of enveloped viral particles in infected HFFs. Consistently, untargeted lipidomic analysis shows enhanced cholesteryl ester levels in IFI16 KO versus wild-type (WT) HFFs. Overall, our data unveil a new role of IFI16 in the regulation of glucose and lipid metabolism upon HCMV replication and uncover new potential targets for the development of novel antiviral therapies. IMPORTANCE Human cytomegalovirus (HCMV) gathers all the substrates and enzymes necessary for the assembly of new virions from its host cell. For instance, HCMV is known to induce cellular metabolism of infected cells to favor virion assembly. Cells are, however, equipped with a first-line defense represented by restriction factors (RFs), which after sensing viral DNA can trigger innate and adaptive responses, thereby blocking HCMV replication. One such RF is IFN-γ-inducible protein 16 (IFI16), which we have shown to downregulate viral replication in human fibroblasts. Thus, we asked whether IFI16 would also play a role in preserving cellular metabolism upon HCMV infection. Our findings highlight an unprecedented role of IFI16 in opposing the metabolic changes elicited by HCMV, thus revealing new promising targets for antiviral therapy.

Keywords:  IFI16; glucose and lipid metabolism; human cytomegalovirus; lipidomics; virus-host interactions

DOI:  https://doi.org/10.1128/mbio.00435-22