bims-imicid 2023-08-20 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023–08–20
twenty-six papers selected by
Dylan Ryan, University of Cambridge

A conserved family of immune effectors cleaves cellular ATP upon viral infection.
Short-term dietary changes can result in mucosal and systemic immune depression.
Boosting NAD preferentially blunts Th17 inflammation via arginine biosynthesis and redox control in healthy and psoriasis subjects.
Loss of CD4+ T cell-intrinsic arginase 1 accelerates Th1 response kinetics and reduces lung pathology during influenza infection.
Methylglyoxal suppresses microglia inflammatory response through NRF2-IκBζ pathway.
NAD+ salvage governs the immunosuppressive capacity of mesenchymal stem cells.
PFKFB3-meditated glycolysis via ROS-HIF1α axis contributes to inflammation and proliferation of Staphylococcus aureus in epithelial cells.
4-Octyl Itaconate and Dimethyl Fumarate Induce Secretion of the Anti-Inflammatory Protein Annexin A1 via NRF2.
The mitochondrial succinate dehydrogenase complex controls the STAT3-IL-10 pathway in inflammatory macrophages.
Characterization of progesterone-induced dendritic cells in metabolic and immunologic reprogramming.
Metabolic reprogramming in inflammatory microglia indicates a potential way of targeting inflammation in Alzheimer's disease.
ApoE expression in macrophages communicates immunometabolic signaling that controls hyperlipidemia-driven hematopoiesis & inflammation via extracellular vesicles.
Modulating the polyamine-hypusine axis controls generation of CD8+ tissue resident memory T cells.
Metabolic reprogramming and polarization of microglia in Parkinson's disease: Role of inflammasome and iron.
Porcine reproductive and respiratory syndrome virus-mediated lactate facilitates virus replication by targeting MAVS.
Immunometabolism changes in fibrosis: from mechanisms to therapeutic strategies.
Metabolomic analysis of pig spleen reveals African swine fever virus infection increased acylcarnitine levels to facilitate viral replication.
L-Kynurenine participates in cancer immune evasion by downregulating hypoxic signaling in T lymphocytes.
SOCS3 deletion in effector T cells confers an anti-tumorigenic role of IL-6 to the pro-tumorigenic cytokine.
Lactate activates the mitochondrial electron transport chain independent of its metabolism.
The gut microbiota-induced kynurenic acid recruits GPR35-positive macrophages to promote experimental encephalitis.
Short-chain fatty acids in diseases.
Cholesterol metabolism in T-cell aging: Accomplices or victims.
Integrated analysis of whole blood oxylipin and cytokine responses after bacterial, viral, and T cell stimulation reveals new immune networks.
Targeting ACC1 in T cells ameliorates psoriatic skin inflammation.
NCoR1 controls Mycobacterium tuberculosis growth in myeloid cells by regulating the AMPK-mTOR-TFEB axis.

Cell. 2023 Aug 17. pii: S0092-8674(23)00797-3. [Epub ahead of print]186(17): 3619-3631.e13

A conserved family of immune effectors cleaves cellular ATP upon viral infection.

Francois Rousset, Erez Yirmiya, Shahar Nesher, Alexander Brandis, Tevie Mehlman, Maxim Itkin, Sergey Malitsky, Adi Millman, Sarah Melamed, Rotem Sorek.

  During viral infection, cells can deploy immune strategies that deprive viruses of molecules essential for their replication. Here, we report a family of immune effectors in bacteria that, upon phage infection, degrade cellular adenosine triphosphate (ATP) and deoxyadenosine triphosphate (dATP) by cleaving the N-glycosidic bond between the adenine and sugar moieties. These ATP nucleosidase effectors are widely distributed within multiple bacterial defense systems, including cyclic oligonucleotide-based antiviral signaling systems (CBASS), prokaryotic argonautes, and nucleotide-binding leucine-rich repeat (NLR)-like proteins, and we show that ATP and dATP degradation during infection halts phage propagation. By analyzing homologs of the immune ATP nucleosidase domain, we discover and characterize Detocs, a family of bacterial defense systems with a two-component phosphotransfer-signaling architecture. The immune ATP nucleosidase domain is also encoded within diverse eukaryotic proteins with immune-like architectures, and we show biochemically that eukaryotic homologs preserve the ATP nucleosidase activity. Our findings suggest that ATP and dATP degradation is a cell-autonomous innate immune strategy conserved across the tree of life.

Keywords:  ATP; CBASS; anti-phage; bacterial defense systems; innate immunity; phage; two-component system

DOI:  https://doi.org/10.1016/j.cell.2023.07.020
Nat Immunol. 2023 Aug 14.

Short-term dietary changes can result in mucosal and systemic immune depression.

Francesco Siracusa, Nicola Schaltenberg, Yogesh Kumar, Till R Lesker, Babett Steglich, Timur Liwinski, Filippo Cortesi, Laura Frommann, Björn-Phillip Diercks, Friedericke Bönisch, Alexander W Fischer, Pasquale Scognamiglio, Mira J Pauly, Christian Casar, Yotam Cohen, Penelope Pelczar, Theodora Agalioti, Flemming Delfs, Anna Worthmann, Ramez Wahib, Bettina Jagemann, Hans-Willi Mittrücker, Oliver Kretz, Andreas H Guse, Jakob R Izbicki, Kara G Lassen, Till Strowig, Michaela Schweizer, Eduardo J Villablanca, Eran Elinav, Samuel Huber, Joerg Heeren, Nicola Gagliani.

Omnivorous animals, including mice and humans, tend to prefer energy-dense nutrients rich in fat over plant-based diets, especially for short periods of time, but the health consequences of this short-term consumption of energy-dense nutrients are unclear. Here, we show that short-term reiterative switching to 'feast diets', mimicking our social eating behavior, breaches the potential buffering effect of the intestinal microbiota and reorganizes the immunological architecture of mucosa-associated lymphoid tissues. The first dietary switch was sufficient to induce transient mucosal immune depression and suppress systemic immunity, leading to higher susceptibility to Salmonella enterica serovar Typhimurium and Listeria monocytogenes infections. The ability to respond to antigenic challenges with a model antigen was also impaired. These observations could be explained by a reduction of CD4+ T cell metabolic fitness and cytokine production due to impaired mTOR activity in response to reduced microbial provision of fiber metabolites. Reintroducing dietary fiber rewired T cell metabolism and restored mucosal and systemic CD4+ T cell functions and immunity. Finally, dietary intervention with human volunteers confirmed the effect of short-term dietary switches on human CD4+ T cell functionality. Therefore, short-term nutritional changes cause a transient depression of mucosal and systemic immunity, creating a window of opportunity for pathogenic infection.

DOI: https://doi.org/10.1038/s41590-023-01587-x
Cell Rep Med. 2023 Aug 09. pii: S2666-3791(23)00310-5. [Epub ahead of print] 101157

Boosting NAD preferentially blunts Th17 inflammation via arginine biosynthesis and redox control in healthy and psoriasis subjects.

Kim Han, Komudi Singh, Allison M Meadows, Rahul Sharma, Shahin Hassanzadeh, Jing Wu, Haley Goss-Holmes, Rebecca D Huffstutler, Heather L Teague, Nehal N Mehta, Julian L Griffin, Rong Tian, Javier Traba, Michael N Sack.

  To evaluate whether nicotinamide adenine dinucleotide-positive (NAD+) boosting modulates adaptive immunity, primary CD4+ T cells from healthy control and psoriasis subjects were exposed to vehicle or nicotinamide riboside (NR) supplementation. NR blunts interferon γ (IFNγ) and interleukin (IL)-17 secretion with greater effects on T helper (Th) 17 polarization. RNA sequencing (RNA-seq) analysis implicates NR blunting of sequestosome 1 (sqstm1/p62)-coupled oxidative stress. NR administration increases sqstm1 and reduces reactive oxygen species (ROS) levels. Furthermore, NR activates nuclear factor erythroid 2-related factor 2 (Nrf2), and genetic knockdown of nrf2 and the Nrf2-dependent gene, sqstm1, diminishes NR amelioratory effects. Metabolomics analysis identifies that NAD+ boosting increases arginine and fumarate biosynthesis, and genetic knockdown of argininosuccinate lyase ameliorates NR effects on IL-17 production. Hence NR via amino acid metabolites orchestrates Nrf2 activation, augments CD4+ T cell antioxidant defenses, and attenuates Th17 responsiveness. Oral NR supplementation in healthy volunteers similarly increases serum arginine, sqstm1, and antioxidant enzyme gene expression and blunts Th17 immune responsiveness, supporting evaluation of NAD+ boosting in CD4+ T cell-linked inflammation.

Keywords:  CD4(+) T cell; NAD(+) boosting; Th17 cell; arginine biosynthesis; nicotinamide riboside; nrf2; psoriasis

DOI:  https://doi.org/10.1016/j.xcrm.2023.101157
Immunity. 2023 Aug 03. pii: S1074-7613(23)00327-8. [Epub ahead of print]

Loss of CD4+ T cell-intrinsic arginase 1 accelerates Th1 response kinetics and reduces lung pathology during influenza infection.

Erin E West, Nicolas S Merle, Marcin M Kamiński, Gustavo Palacios, Dhaneshwar Kumar, Luopin Wang, Jack A Bibby, Kirsten Overdahl, Alan K Jarmusch, Simon Freeley, Duck-Yeon Lee, J Will Thompson, Zu-Xi Yu, Naomi Taylor, Marc Sitbon, Douglas R Green, Andrea Bohrer, Katrin D Mayer-Barber, Behdad Afzali, Majid Kazemian, Sabine Scholl-Buergi, Daniela Karall, Martina Huemer, Claudia Kemper.

  Arginase 1 (Arg1), the enzyme catalyzing the conversion of arginine to ornithine, is a hallmark of IL-10-producing immunoregulatory M2 macrophages. However, its expression in T cells is disputed. Here, we demonstrate that induction of Arg1 expression is a key feature of lung CD4+ T cells during mouse in vivo influenza infection. Conditional ablation of Arg1 in CD4+ T cells accelerated both virus-specific T helper 1 (Th1) effector responses and its resolution, resulting in efficient viral clearance and reduced lung pathology. Using unbiased transcriptomics and metabolomics, we found that Arg1-deficiency was distinct from Arg2-deficiency and caused altered glutamine metabolism. Rebalancing this perturbed glutamine flux normalized the cellular Th1 response. CD4+ T cells from rare ARG1-deficient patients or CRISPR-Cas9-mediated ARG1-deletion in healthy donor cells phenocopied the murine cellular phenotype. Collectively, CD4+ T cell-intrinsic Arg1 functions as an unexpected rheostat regulating the kinetics of the mammalian Th1 lifecycle with implications for Th1-associated tissue pathologies.

Keywords:  IFN-γ; IL-10; Th1 immunity; arginase 1; arginase 1 deficiency; autoimmunity; cell metabolism; complement; glutamine; influenza infection

DOI:  https://doi.org/10.1016/j.immuni.2023.07.014
Redox Biol. 2023 Aug 08. pii: S2213-2317(23)00244-6. [Epub ahead of print]65 102843

Methylglyoxal suppresses microglia inflammatory response through NRF2-IκBζ pathway.

Shu-Li Wei, Ying Yang, Wei-Yue Si, Yang Zhou, Tao Li, Tong Du, Peng Zhang, Xiao-Li Li, Ruo-Nan Duan, Rui-Sheng Duan, Chun-Lin Yang.

  Methylglyoxal (MGO) is a highly reactive metabolite generated by glycolysis. Although abnormal accumulation of MGO has been reported in several autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, the role of MGO in autoimmune diseases has not yet been fully investigated. In this study, we found that the intracellular MGO levels increased in activated immune cells, such as microglia and lymphocytes. Treatment with MGO inhibited inflammatory cell accumulation in the spinal cord and ameliorated the clinical symptoms in EAE mice. Further analysis indicated that MGO suppressed M1-polarization of microglia cells and diminished their inflammatory cytokine production. MGO also inhibited the ability of microglial cells to recruit and activate lymphocytes by decreasing chemokine secretion and expression of co-stimulatory molecules. Furthermore, MGO negatively regulated glycolysis by suppressing glucose transporter 1 expression. Mechanically, we found that MGO could activate nuclear factor erythroid 2-related factor 2 (NRF2) pathway and NRF2 could bind to the promoter of IκBζ gene and suppressed its transcription and subsequently pro-inflammatory cytokine production. In conclusion, our results showed that MGO acts as an immunosuppressive metabolite by activating the NRF2-IκBζ.

Keywords:  Experimental autoimmune encephalomyelitis (EAE); Methylglyoxal; Microglia; Nuclear factor erythroid 2-related factor 2 (NRF2)

DOI:  https://doi.org/10.1016/j.redox.2023.102843
Cell Mol Immunol. 2023 Aug 14.

NAD+ salvage governs the immunosuppressive capacity of mesenchymal stem cells.

Jiankai Fang, Pengbo Hou, Shisong Liu, Muqiu Zuo, Zhanhong Liu, Wangwang Chen, Yuyi Han, Yanan Li, Tingting Wang, Chao Feng, Peishan Li, Changshun Shao, Yufang Shi.

  Mesenchymal stem/stromal cells (MSCs) possess robust immunoregulatory functions and are promising therapeutics for inflammatory disorders. This capacity is not innate but is activated or 'licensed' by inflammatory cytokines. The licensing mechanism remains unclear. Here, we examined whether inflammatory cytokines metabolically reprogrammed MSCs to confer this immunoregulatory capacity. In response to stimulation by inflammatory cytokines, MSCs exhibited a dramatic increase in the consumption of glucose, which was accompanied by an enhanced use of nicotinamide adenine dinucleotide (NAD+) and increased expression of nicotinamide phosphoribosyltransferase (NAMPT), a central enzyme in the salvage pathway for NAD+ production. When NAD+ synthesis was blocked by inhibiting or depleting NAMPT, the immunosuppressive function of MSCs induced by inflammatory cytokines was greatly attenuated. Consequently, when NAD+ metabolism in MSCs was perturbed, their therapeutic benefit was decreased in mice suffering from inflammatory bowel disease and acute liver injury. Further analysis revealed that NAMPT-driven production of NAD+ was critical for the inflammatory cytokine-induced increase in glycolysis in MSCs. Furthermore, the increase in glycolysis led to succinate accumulation in the tricarboxylic acid cycle, which led to hypoxia-inducible factor 1α (HIF-1α) stabilization and subsequently increased the transcription of key glycolytic genes, thereby persistently maintaining glycolytic flux. This study demonstrated that unlike its proinflammatory role in immune cells, NAD+ metabolism governs the anti-inflammatory function of MSCs during inflammation.

Keywords:  Glycolysis; HIF-1α; Immunomodulation; Mesenchymal stem/stromal cells; NAD+ metabolism; Succinate

DOI:  https://doi.org/10.1038/s41423-023-01073-2
J Infect Dis. 2023 Aug 18. pii: jiad339. [Epub ahead of print]

PFKFB3-meditated glycolysis via ROS-HIF1α axis contributes to inflammation and proliferation of Staphylococcus aureus in epithelial cells.

Xing Gao, Zhenglei Wang, Yuanyuan Xu, Shiyuan Feng, Shaodong Fu, Zhenhua Luo, Jinfeng Miao.

  Mastitis caused by antibiotic-resistant strains of Staphylococcus aureus (S. aureus) is a significant concern in the livestock industry due to the economic losses it incurs. Regulating immunometabolism has emerged as a promising approach for preventing bacterial inflammation. To investigate the possibility of alleviating inflammation caused by S. aureus infection by regulating host glycolysis, we subjected the murine mammary epithelial cell line (EpH4-Ev) to S. aureus challenge. Our study revealed that S. aureus can colonize EpH4-Ev cells and promote inflammation through HIF1α-driven glycolysis. Notably, the activation of HIF1α was found to be dependent on the production of reactive oxygen species (ROS). By inhibiting PFKFB3, a key regulator in the host glycolytic pathway, we successfully modulated HIF1α-triggered metabolic reprogramming by reducing ROS production in S. aureus-induced mastitis. Our findings suggest that there is a high potential for the development of novel anti-inflammatory therapies that safely inhibit the glycolytic rate-limiting enzyme PFKFB3.

Keywords:   Staphylococcus aureus ; HIF1α; PFKFB3; glycolysis; mastitis

DOI:  https://doi.org/10.1093/infdis/jiad339
J Immunol. 2023 Aug 14. pii: ji2200848. [Epub ahead of print]

4-Octyl Itaconate and Dimethyl Fumarate Induce Secretion of the Anti-Inflammatory Protein Annexin A1 via NRF2.

Ciana Diskin, Emily A Day, Órlaith C Henry, Juliana E Toller-Kawahisa, Luke A J O'Neill.

Annexin A1 is a key anti-inflammatory effector protein that is involved in the anti-inflammatory effects of glucocorticoids. 4-Octyl itaconate (4-OI), a derivative of the endogenous metabolite itaconate, which is abundantly produced by LPS-activated macrophages, has recently been identified as a potent anti-inflammatory agent. The anti-inflammatory effects of 4-OI share a significant overlap with those of dimethyl fumarate (DMF), a derivate of another Krebs cycle metabolite fumarate, which is already in use clinically for the treatment of inflammatory diseases. In this study we show that both 4-OI and DMF induce secretion of the 33-kDa form of annexin A1 from murine bone marrow-derived macrophages, an effect that is much more pronounced in LPS-stimulated cells. We also show that this 4-OI- and DMF-driven annexin A1 secretion is NRF2-dependent and that other means of activating NRF2 give rise to the same response. Lastly, we demonstrate that the cholesterol transporter ABCA1, which has previously been implicated in annexin A1 secretion, is required for this process in macrophages. Our findings contribute to the growing body of knowledge on the anti-inflammatory effects of the Krebs cycle metabolite derivatives 4-OI and DMF.

DOI: https://doi.org/10.4049/jimmunol.2200848
iScience. 2023 Aug 18. 26(8): 107473

The mitochondrial succinate dehydrogenase complex controls the STAT3-IL-10 pathway in inflammatory macrophages.

Dino Gobelli, Pablo Serrano-Lorenzo, María J Esteban-Amo, Julia Serna, M Teresa Pérez-García, Antonio Orduña, Alexis A Jourdain, Miguel Á Martín-Casanueva, Miguel Á de la Fuente, María Simarro.

  The functions of macrophages are tightly regulated by their metabolic state. However, the role of the mitochondrial electron transport chain (ETC) in macrophage functions remains understudied. Here, we provide evidence that the succinate dehydrogenase (SDH)/complex II (CII) is required for respiration and plays a role in controlling effector responses in macrophages. We find that the absence of the catalytic subunits Sdha and Sdhb in macrophages impairs their ability to effectively stabilize HIF-1α and produce the pro-inflammatory cytokine IL-1β in response to LPS stimulation. We also arrive at the novel result that both subunits are essential for the LPS-driven production of IL-10, a potent negative feedback regulator of the macrophage inflammatory response. This phenomenon is explained by the fact that the absence of Sdha and Sdhb leads to the inhibition of Stat3 tyrosine phosphorylation, caused partially by the excessive accumulation of mitochondrial reactive oxygen species (mitoROS) in the knockout cells.

Keywords:  Biological sciences; Cell biology; Immunology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2023.107473
J Reprod Immunol. 2023 Aug 03. pii: S0165-0378(23)00334-0. [Epub ahead of print]159 104128

Characterization of progesterone-induced dendritic cells in metabolic and immunologic reprogramming.

Su Liu, Sainan Zhang, Ling Hong, Lianghui Diao, Songchen Cai, Tailang Yin, Yong Zeng.

  The role of maternal-fetal immune tolerance in the establishment and maintenance of pregnancy has been well established. Dendritic cells (DCs) as a crucial part of the decidual microenvironment, have high plasticity in immunogenicity and tolerogenicity. The regulatory mechanisms of DCs phenotype or function at the maternal-fetal interface, however, have not been fully developed. Studies from the field of immunometabolism have highlighted that the metabolic pathways of DCs are closely associated with their immunity. Our previous study showed that progesterone (P4) up-regulated a series of enzymes involved in DCs mitochondrial oxidative phosphorylation and fatty acid metabolism. In this study, we confirmed that P4 induced significant alternations in DCs metabolic pathways, promoting their glycolysis, mitochondrial function, and the dependency and capacity of fatty acids as mitochondrial fuel. Moreover, P4 also increased the inhibitory molecule ILT4 expression on DCs and down-regulated the CD86, which may coordinate their immune tolerance function in pregnancy. Together, our study helps to understand the role of P4 in DCs metabolic and immunologic reprogramming and may provide novel insights into the hormonal immunometabolism regulation of DCs during normal pregnancy.

Keywords:  Dendritic cells; Fatty acid metabolism; Immune tolerance; Mitochondrial function; Progesterone

DOI:  https://doi.org/10.1016/j.jri.2023.104128
Redox Biol. 2023 Aug 09. pii: S2213-2317(23)00247-1. [Epub ahead of print]66 102846

Metabolic reprogramming in inflammatory microglia indicates a potential way of targeting inflammation in Alzheimer's disease.

Moris Sangineto, Martina Ciarnelli, Tommaso Cassano, Antonio Radesco, Archana Moola, Vidyasagar Naik Bukke, Antonino Romano, Rosanna Villani, Hina Kanwal, Nazzareno Capitanio, Loren Duda, Carlo Avolio, Gaetano Serviddio.

  Microglia activation drives the pro-inflammatory activity in the early stages of Alzheimer's disease (AD). However, the mechanistic basis is elusive, and the hypothesis of targeting microglia to prevent AD onset is little explored. Here, we demonstrated that upon LPS exposure, microglia shift towards an energetic phenotype characterised by high glycolysis and high mitochondrial respiration with dysfunction. Although the activity of electron transport chain (ETC) complexes is boosted by LPS, this is mostly devoted to the generation of reactive oxygen species. We showed that by inhibiting succinate dehydrogenase (SDH) with dimethyl malonate (DMM), it is possible to modulate the LPS-induced metabolic rewiring, facilitating an anti-inflammatory phenotype. DMM improves mitochondrial function in a direct way and by reducing LPS-induced mitochondrial biogenesis. Moreover, the block of SDH with DMM inhibits the recruitment of hypoxia inducible-factor 1 α (HIF-1α), which mediates the induction of glycolysis and cytokine expression. Similar bioenergetic alterations were observed in the microglia isolated from AD mice (3xTg-AD), which present high levels of circulating LPS and brain toll-like receptor4 (TLR4). Moreover, this well-established model of AD was used to show a potential effect of SDH inhibition in vivo as DMM administration abrogated brain inflammation and modulated the microglia metabolic alterations of 3xTg-AD mice. The RNA-sequencing analysis from a public dataset confirmed the consistent transcription of genes encoding for ETC subunits in the microglia of AD mice (5xFAD). In conclusion, TLR4 activation promotes metabolic changes and the pro-inflammatory activity in microglia, and SDH might represent a promising therapeutic target to prevent AD development.

Keywords:  3xTg-AD mice; Alzheimer's disease; Bioenergetics; Dimethyl malonate; Immunometabolism; Macrophage; Microglia

DOI:  https://doi.org/10.1016/j.redox.2023.102846
J Extracell Vesicles. 2023 Aug;12(8): e12345

ApoE expression in macrophages communicates immunometabolic signaling that controls hyperlipidemia-driven hematopoiesis & inflammation via extracellular vesicles.

Tuan Anh Phu, Martin Ng, Ngan K Vu, Alex S Gao, Robert L Raffai.

  While apolipoprotein E (apoE) expression by myeloid cells is recognized to control inflammation, whether such benefits can be communicated via extracellular vesicles is not known. Through the study of extracellular vesicles produced by macrophages derived from the bone marrow of Wildtype (WT-BMDM-EV) and ApoE deficient (EKO-BMDM-EV) mice, we uncovered a critical role for apoE expression in regulating their cell signaling properties. WT-BMDM-EV communicated anti-inflammatory properties to recipient myeloid cells by increasing cellular levels of apoE and miR-146a-5p, that reduced NF-κB signalling. They also downregulated cellular levels of miR-142a-3p, resulting in increased levels of its target carnitine palmitoyl transferase 1A (CPT1A) which improved fatty acid oxidation (FAO) and oxidative phosphorylation (OxPHOS) in recipient cells. Such favorable metabolic polarization enhanced cell-surface MerTK levels and the phagocytic uptake of apoptotic cells. In contrast, EKO-BMDM-EV exerted opposite effects by reducing cellular levels of apoE and miR-146a-5p, which increased NF-κB-driven GLUT1-mediated glucose uptake, aerobic glycolysis, and oxidative stress. Furthermore, EKO-BMDM-EV increased cellular miR-142a-3p levels, which reduced CPT1A levels and impaired FAO and OxPHOS in recipient myeloid cells. When cultured with naïve CD4+ T lymphocytes, EKO-BMDM-EV drove their activation and proliferation, and fostered their transition to a Th1 phenotype. While infusions of WT-BMDM-EV into hyperlipidemic mice resolved inflammation, infusions of EKO-BMDM-EV increased hematopoiesis and drove inflammatory responses in myeloid cells and T lymphocytes. ApoE-dependent immunometabolic signaling by macrophage extracellular vesicles was dependent on transcriptional axes controlled by miR-146a-5p and miR-142a-3p that could be reproduced by infusing miR-146a mimics & miR-142a antagonists into hyperlipidemic apoE-deficient mice. Together, our findings unveil a novel property for apoE expression in macrophages that modulates the immunometabolic regulatory properties of their secreted extracellular vesicles.

Keywords:  ApoE; extracellular vesicles; immunometabolism; inflammation; macrophage; microRNA; oxidative stress

DOI:  https://doi.org/10.1002/jev2.12345
JCI Insight. 2023 Aug 15. pii: e169308. [Epub ahead of print]

Modulating the polyamine-hypusine axis controls generation of CD8+ tissue resident memory T cells.

Aya G Elmarsafawi, Rebecca S Hesterberg, Mario R Fernandez, Chunying Yang, Lancia Nf Darville, Min Liu, John M Koomen, Otto Phanstiel Iv, Reginald Atkins, John E Mullinax, Shari A Pilon-Thomas, Frederick L Locke, Pearlie K Epling-Burnette, John L Cleveland.

  Glutaminolysis is a hallmark of the activation and metabolic reprogramming of T cells. Isotopic tracer analyses of antigen-activated effector CD8+ T cells revealed that glutamine is the principal carbon source for the biosynthesis of polyamines putrescine, spermidine and spermine. These metabolites play critical roles in activation-induced T-cell proliferation, as well as for the production of hypusine, which is derived from spermidine and is covalently linked to the translation elongation factor eIF5A. Here, we demonstrated that the glutamine-polyamine-hypusine axis controls the expression of CD69, an important regulator of tissue resident memory T cells (TRM). Inhibition of this circuit augmented the development of TRM cells ex vivo and in vivo in the bone marrow, a well-established niche for TRM cells. Furthermore, blocking the polyamine-hypusine axis augmented CD69 expression and IFN-γ and TNF-α production in human CD8+ T cells from peripheral blood and sarcoma tumor infiltrating lymphocytes, as well as in human CD8+ CAR-T cells. Collectively, these findings support the notion that the polyamine-hypusine circuit can be exploited to modulate TRM cells for therapeutic benefit.

Keywords:  Immunology; Metabolism; Polyamines; T cells

DOI:  https://doi.org/10.1172/jci.insight.169308
Ageing Res Rev. 2023 Aug 10. pii: S1568-1637(23)00191-5. [Epub ahead of print]90 102032

Metabolic reprogramming and polarization of microglia in Parkinson's disease: Role of inflammasome and iron.

Haiyang Yu, Qing Chang, Tong Sun, Xin He, Lulu Wen, Jing An, Juan Feng, Yuhong Zhao.

  Parkinson's disease (PD) is a slowly progressive neurodegenerative disease characterized by α-synuclein aggregation and dopaminergic neuronal death. Recent evidence suggests that neuroinflammation is an early event in the pathogenesis of PD. Microglia are resident immune cells in the central nervous system that can be activated into either pro-inflammatory M1 or anti-inflammatory M2 phenotypes as found in peripheral macrophages. To exert their immune functions, microglia respond to various stimuli, resulting in the flexible regulation of their metabolic pathways. Inflammasomes activation in microglia induces metabolic shift from oxidative phosphorylation to glycolysis, and leads to the polarization of microglia to pro-inflammatory M1 phenotype, finally causing neuroinflammation and neurodegeneration. In addition, iron accumulation induces microglia take an inflammatory and glycolytic phenotype. M2 phenotype microglia is more sensitive to ferroptosis, inhibition of which can attenuate neuroinflammation. Therefore, this review highlights the interplay between microglial polarization and metabolic reprogramming of microglia. Moreover, it will interpret how inflammasomes and iron regulate microglial metabolism and phenotypic shifts, which provides a promising therapeutic target to modulate neuroinflammation and neurodegeneration in PD and other neurodegenerative diseases.

Keywords:  Glycolysis; Inflammasome; Iron; Microglia; Neuroinflammation; Parkinson’s disease

DOI:  https://doi.org/10.1016/j.arr.2023.102032
Vet Microbiol. 2023 Aug 09. pii: S0378-1135(23)00198-0. [Epub ahead of print]284 109846

Porcine reproductive and respiratory syndrome virus-mediated lactate facilitates virus replication by targeting MAVS.

Lujie Zhang, Xing Liu, Jian Mao, Yangyang Sun, Yanni Gao, Juan Bai, Ping Jiang.

  Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important causative agents in the pig industry worldwide, causing reproductive failure in sows and respiratory problems in growing pigs. Glucose metabolism is a major pathway for energy production and interacts with many cellular processes, such as innate immunity response. It is unclear whether PRRSV infection can use the glucose metabolic pathway to generate immune escape in favor of viral replication. Here, we found that high glucose promotes PRRSV replication and glycolysis, and inhibits poly(I:C)-induced RLR signaling. Conversely, inhibition of the glycolysis pathway significantly promoted poly(I:C)-induced RLR signaling and inhibited PRRSV replication, suggesting that glycolysis promotes PRRSV replication by inhibiting interferon signaling. Furthermore, PRRSV promotes glycolysis to produce lactate, which acts as a key metabolite to promote viral replication by inhibiting RLR signaling by targeting MAVS. And the glycolytic inhibitors targeting HK2 and LDHA in glycolysis could inhibit PRRSV replication. Taken together, these findings suggested that PRRSV infection promotes glycolysis to produce lactate, which targets MAVS to inhibit RLR signaling and thus promote viral replication. Our findings provide an insight into the pathogenesis of PRRSV and offer a theoretical basis for further development of antiviral therapeutic targets.

Keywords:  Glycolysis; Lactate; MAVS; PRRSV

DOI:  https://doi.org/10.1016/j.vetmic.2023.109846
Front Pharmacol. 2023 ;14 1243675

Immunometabolism changes in fibrosis: from mechanisms to therapeutic strategies.

Lixiang Feng, Xingyu Chen, Yujing Huang, Xiaodian Zhang, Shaojiang Zheng, Na Xie.

  Immune cells are essential for initiating and developing the fibrotic process by releasing cytokines and growth factors that activate fibroblasts and promote extracellular matrix deposition. Immunometabolism describes how metabolic alterations affect the function of immune cells and how inflammation and immune responses regulate systemic metabolism. The disturbed immune cell function and their interactions with other cells in the tissue microenvironment lead to the origin and advancement of fibrosis. Understanding the dysregulated metabolic alterations and interactions between fibroblasts and the immune cells is critical for providing new therapeutic targets for fibrosis. This review provides an overview of recent advances in the pathophysiology of fibrosis from the immunometabolism aspect, highlighting the altered metabolic pathways in critical immune cell populations and the impact of inflammation on fibroblast metabolism during the development of fibrosis. We also discuss how this knowledge could be leveraged to develop novel therapeutic strategies for treating fibrotic diseases.

Keywords:  fibroblast; fibrosis; immunometabolism; inflammation; therapies

DOI:  https://doi.org/10.3389/fphar.2023.1243675
J Virol. 2023 Aug 15. e0058623

Metabolomic analysis of pig spleen reveals African swine fever virus infection increased acylcarnitine levels to facilitate viral replication.

Xing Yang, Xintian Bie, Huanan Liu, Xijuan Shi, Dajun Zhang, DengShuai Zhao, Yu Hao, Jinke Yang, Wenqian Yan, Guohui Chen, Lingling Chen, Zixiang Zhu, Fan Yang, Xusheng Ma, Xiangtao Liu, Haixue Zheng, Keshan Zhang.

  African swine fever (ASF) is a devastating disease caused by the African swine fever virus (ASFV) that adversely affects the pig industry. The spleen is the main target organ of ASFV; however, the function of metabolites in the spleen during ASFV infection is yet to be investigated. To define the metabolic changes in the spleen after ASFV infection, untargeted and targeted metabolomics analyses of spleens from ASFV-infected pigs were conducted. Untargeted metabolomics analysis revealed 540 metabolites with significant differential levels. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that these metabolites were mainly enriched in metabolic pathways, including nucleotide metabolism, purine metabolism, arginine biosynthesis, and neuroactive ligand-receptor interaction. Moreover, 134 of 540 metabolites quantified by targeted metabolomics analysis had differential levels and were enriched in metabolic pathways such as the biosynthesis of cofactors, ABC transporters, and biosynthesis of amino acids. Furthermore, coalition analysis of untargeted and targeted metabolomics data revealed that the levels of acylcarnitines, which are intermediates of fatty acid β-oxidation, were significantly increased in ASFV-infected spleens compared with those in the uninfected spleens. Moreover, inhibiting fatty acid β-oxidation significantly reduced ASFV replication, indicating that fatty acid β-oxidation is essential for this process. To our knowledge, this is the first report presenting the metabolite profiles of ASFV-infected pigs. This study revealed a new mechanism of ASFV-mediated regulation of host metabolism. These findings provide new insights into the pathogenic mechanisms of ASFV, which will benefit the development of target drugs for ASFV replication. IMPORTANCE African swine fever virus, the only member of the Asfarviridae family, relies on hijacking host metabolism to meet the demand for self-replication. However, the change in host metabolism after African swine fever virus (ASFV) infection remains unknown. Here, we analyzed the metabolic changes in the pig spleen after ASFV infection for the first time. ASFV infection increased the levels of acylcarnitines. Inhibition of the production and metabolism of acylcarnitines inhibited ASFV replication. Acylcarnitines are the vital intermediates of fatty acid β-oxidation. This study highlights the critical role of fatty acid β-oxidation in ASFV infection, which may help identify target drugs to control African swine fever disease.

Keywords:  African swine fever virus; acyl-carnitines; fatty acid β-oxidation; metabolomics; spleen

DOI:  https://doi.org/10.1128/jvi.00586-23
Oncoimmunology. 2023 ;12(1): 2244330

L-Kynurenine participates in cancer immune evasion by downregulating hypoxic signaling in T lymphocytes.

Stephanie Schlichtner, Inna M Yasinska, Elena Klenova, Maryam Abooali, Gurprit S Lall, Steffen M Berger, Sabrina Ruggiero, Dietmar Cholewa, Milan Milošević, Bernhard F Gibbs, Elizaveta Fasler-Kan, Vadim V Sumbayev.

  Malignant tumors often escape anticancer immune surveillance by suppressing the cytotoxic functions of T lymphocytes. While many of these immune evasion networks include checkpoint proteins, small molecular weight compounds, such as the amino acid L-kynurenine (LKU), could also substantially contribute to the suppression of anti-cancer immunity. However, the biochemical mechanisms underlying the suppressive effects of LKU on T-cells remain unclear. Here, we report for the first time that LKU suppresses T cell function as an aryl hydrocarbon receptor (AhR) ligand. The presence of LKU in T cells is associated with AhR activation, which results in competition between AhR and hypoxia-inducible factor 1 alpha (HIF-1α) for the AhR nuclear translocator, ARNT, leading to T cell exhaustion. The expression of indoleamine 2,3-dioxygenase 1 (IDO1, the enzyme that leads to LKU generation) is induced by the TGF-β-Smad-3 pathway. We also show that IDO-negative cancers utilize an alternative route for LKU production via the endogenous inflammatory mediator, the high mobility group box 1 (HMGB-1)-interferon-gamma (IFN-γ) axis. In addition, other IDO-negative tumors (like T-cell lymphomas) trigger IDO1 activation in eosinophils present in the tumor microenvironment (TME). These mechanisms suppress cytotoxic T cell function, and thus support the tumor immune evasion machinery.

Keywords:  T cells; cancer; immune checkpoints; immune escape; kynurenine

DOI:  https://doi.org/10.1080/2162402X.2023.2244330
Cell Rep. 2023 Aug 08. pii: S2211-1247(23)00951-8. [Epub ahead of print] 112940

SOCS3 deletion in effector T cells confers an anti-tumorigenic role of IL-6 to the pro-tumorigenic cytokine.

Setsuko Mise-Omata, Makoto Ando, Tanakorn Srirat, Kensuke Nakagawara, Taeko Hayakawa, Mana Iizuka-Koga, Hiroshi Nishimasu, Osamu Nureki, Minako Ito, Akihiko Yoshimura.

  Interleukin (IL)-6 is abundantly expressed in the tumor microenvironment and is associated with poor patient outcomes. Here, we demonstrate that the deletion of the suppressor of cytokine signaling 3 (SOCS3) in T cells potentiates anti-tumor immune responses by conferring the anti-tumorigenic function of IL-6 in mouse and human models. In Socs3-deficient CD8+ T cells, IL-6 upregulates the expression of type I interferon (IFN)-regulated genes and enhances the anti-tumor effector function of T cells, while also modifying mitochondrial fitness to increase mitochondrial membrane potential and reactive oxygen species (ROS) levels and to promote metabolic glycolysis in the energy state. Furthermore, Socs3 deficiency reduces regulatory T cells and increases T helper 1 (Th1) cells. SOCS3 knockdown in human chimeric antigen receptor T (CAR-T) cells exhibits a strong anti-tumor response in humanized mice. Thus, genetic disruption of SOCS3 offers an avenue to improve the therapeutic efficacy of adoptive T cell therapy.

Keywords:  CAR-T therapy; CP: Cancer; IL-6; anti-tumor immunity; cytotoxic T cell; effector T cells; mitochondrial fitness; regulatory T cells; suppressor of cytokine signaling 3

DOI:  https://doi.org/10.1016/j.celrep.2023.112940
bioRxiv. 2023 Aug 04. pii: 2023.08.02.551712. [Epub ahead of print]

Lactate activates the mitochondrial electron transport chain independent of its metabolism.

Xin Cai, Charles C Ng, Olivia Jones, Tak Shun Fung, Keunwoo Ryu, Dayi Li, Craig B Thompson.

Lactate has long been considered a cellular waste product. However, we found that as extracellular lactate accumulates, it also enters the mitochondrial matrix and stimulates mitochondrial electron transport chain (ETC) activity. The resulting increase in mitochondrial ATP synthesis suppresses glycolysis and increases the utilization of pyruvate and/or alternative respiratory substrates. The ability of lactate to increase oxidative phosphorylation does not depend on its metabolism. Both L- and D-lactate are effective at enhancing ETC activity and suppressing glycolysis. Furthermore, the selective induction of mitochondrial oxidative phosphorylation by unmetabolized D-lactate reversibly suppressed aerobic glycolysis in both cancer cell lines and proliferating primary cells in an ATP-dependent manner and enabled cell growth on respiratory-dependent bioenergetic substrates. In primary T cells, D-lactate enhanced cell proliferation and effector function. Together, these findings demonstrate that lactate is a critical regulator of the ability of mitochondrial oxidative phosphorylation to suppress glucose fermentation.

DOI: https://doi.org/10.1101/2023.08.02.551712
Cell Rep. 2023 Aug 16. pii: S2211-1247(23)01016-1. [Epub ahead of print]42(8): 113005

The gut microbiota-induced kynurenic acid recruits GPR35-positive macrophages to promote experimental encephalitis.

Kentaro Miyamoto, Tomohisa Sujino, Yosuke Harada, Hiroshi Ashida, Yusuke Yoshimatsu, Yuki Yonemoto, Yasuhiro Nemoto, Michio Tomura, Hassan Melhem, Jan Hendrik Niess, Toshihiko Suzuki, Toru Suzuki, Shohei Suzuki, Yuzo Koda, Ryuichi Okamoto, Yohei Mikami, Toshiaki Teratani, Kenji Tanaka, Akihiko Yoshimura, Toshiro Sato, Takanori Kanai.

  The intricate interplay between gut microbes and the onset of experimental autoimmune encephalomyelitis (EAE) remains poorly understood. Here, we uncover remarkable similarities between CD4+ T cells in the spinal cord and their counterparts in the small intestine. Furthermore, we unveil a synergistic relationship between the microbiota, particularly enriched with the tryptophan metabolism gene EC:1.13.11.11, and intestinal cells. This symbiotic collaboration results in the biosynthesis of kynurenic acid (KYNA), which modulates the recruitment and aggregation of GPR35-positive macrophages. Subsequently, a robust T helper 17 (Th17) immune response is activated, ultimately triggering the onset of EAE. Conversely, modulating the KYNA-mediated GPR35 signaling in Cx3cr1+ macrophages leads to a remarkable amelioration of EAE. These findings shed light on the crucial role of microbial-derived tryptophan metabolites in regulating immune responses within extraintestinal tissues.

Keywords:  CD4(+) T cells; CP: Immunology; CP: Microbiology; GPR35; encephalomyelitis; gut microbes; immune system; kynurenic acid; macrophages; multiple sclerosis; spinal cord; tryptophan metabolites

DOI:  https://doi.org/10.1016/j.celrep.2023.113005
Cell Commun Signal. 2023 Aug 18. 21(1): 212

Short-chain fatty acids in diseases.

Dan Zhang, Yong-Ping Jian, Yu-Ning Zhang, Yao Li, Li-Ting Gu, Hui-Hui Sun, Ming-Di Liu, Hong-Lan Zhou, Yi-Shu Wang, Zhi-Xiang Xu.

  Short-chain fatty acids (SCFAs) are the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract. The absorption of SCFAs is mediated by substrate transporters, such as monocarboxylate transporter 1 and sodium-coupled monocarboxylate transporter 1, which promote cellular metabolism. An increasing number of studies have implicated metabolites produced by microorganisms as crucial executors of diet-based microbial influence on the host. SCFAs are important fuels for intestinal epithelial cells (IECs) and represent a major carbon flux from the diet, that is decomposed by the gut microbiota. SCFAs play a vital role in multiple molecular biological processes, such as promoting the secretion of glucagon-like peptide-1 by IECs to inhibit the elevation of blood glucose, increasing the expression of G protein-coupled receptors such as GPR41 and GPR43, and inhibiting histone deacetylases, which participate in the regulation of the proliferation, differentiation, and function of IECs. SCFAs affect intestinal motility, barrier function, and host metabolism. Furthermore, SCFAs play important regulatory roles in local, intermediate, and peripheral metabolisms. Acetate, propionate, and butyrate are the major SCFAs, they are involved in the regulation of immunity, apoptosis, inflammation, and lipid metabolism. Herein, we review the diverse functional roles of this major class of bacterial metabolites and reflect on their ability to affect intestine, metabolic, and other diseases. Video Abstract.

Keywords:  Gut microbiota; Immunity; Inflammation; Metabolism; Short-chain fatty acids

DOI:  https://doi.org/10.1186/s12964-023-01219-9
FASEB J. 2023 09;37(9): e23136

Cholesterol metabolism in T-cell aging: Accomplices or victims.

Cexun Hu, Hongliang Wu, Qun Zhu, Na Cao, Hui Wang.

  Aging has a significant impact on the function and metabolism of T cells. Cholesterol, the most important sterol in mammals, is known as the "gold of the body" because it maintains membrane fluidity, rigidity, and signal transduction while also serving as a precursor of oxysterols, bile acids, and steroid hormones. Cholesterol homeostasis is primarily controlled by uptake, biosynthesis, efflux, and regulatory mechanisms. Previous studies have suggested that there are reciprocal interactions between cholesterol metabolism and T lymphocytes. Here, we will summarize the most recent advances in the effects of cholesterol and its derivatives on T-cell aging. We will furthermore discuss interventions that might be used to help older individuals with immune deficiencies or diminishing immune competence.

Keywords:  T-cell aging; cholesterol; liver X receptor; sterol regulatory element-binding protein 2; thymic involution

DOI:  https://doi.org/10.1096/fj.202300515R
iScience. 2023 Aug 18. 26(8): 107422

Integrated analysis of whole blood oxylipin and cytokine responses after bacterial, viral, and T cell stimulation reveals new immune networks.

Milieu Interieur Consortium

  Oxylipins are major immunomodulating mediators, yet studies of inflammation focus mainly on cytokines. Here, using a standardized whole-blood stimulation system, we characterized the oxylipin-driven inflammatory responses to various stimuli and their relationships with cytokine responses. We performed a pilot study in 25 healthy individuals using 6 different stimuli: 2 bacterial stimuli (LPS and live BCG), 2 viral stimuli (vaccine-grade poly I:C and live H1N1 attenuated influenza), an enterotoxin superantigen and a Null control. All stimuli induced a strong production of oxylipins but most importantly, bacterial, viral, and T cell immune responses show distinct oxylipin signatures. Integration of the oxylipin and cytokine responses for each condition revealed new immune networks improving our understanding of inflammation regulation. Finally, the oxylipin responses and oxylipin-cytokine networks were compared in patients with active tuberculosis or with latent infection. This revealed different responses to BCG but not LPS stimulation highlighting new regulatory pathways for further investigations.

Keywords:  Immune response; Immunology; Microbiology

DOI:  https://doi.org/10.1016/j.isci.2023.107422
J Mol Med (Berl). 2023 Aug 18.

Targeting ACC1 in T cells ameliorates psoriatic skin inflammation.

Yu-San Kao, Panagiota Mamareli, Ayesha Dhillon-LaBrooy, Philipp Stüve, Gloria Janet Godoy, Lis Noelia Velasquez, Verena Katharina Raker, Beate Weidenthaler-Barth, Fatima Boukhallouk, Francesca Rampoldi, Luciana Berod, Tim Sparwasser.

  Psoriasis is a chronic inflammatory skin disease driven by the IL-23/IL-17 axis. It results from excessive activation of effector T cells, including T helper (Th) and cytotoxic T (Tc) cells, and is associated with dysfunctional regulatory T cells (Tregs). Acetyl-CoA carboxylase 1 (ACC1), a rate-limiting enzyme of fatty acid synthesis (FAS), directs cell fate decisions between Th17 and Tregs and thus could be a promising therapeutic target for psoriasis treatment. Here, we demonstrate that targeting ACC1 in T cells by genetic ablation ameliorates skin inflammation in an experimental model of psoriasis by limiting Th17, Tc17, Th1, and Tc1 cells in skin lesions and increasing the frequency of effector Tregs in skin-draining lymph nodes (LNs). KEY MESSAGES : ACC1 deficiency in T cells ameliorates psoriatic skin inflammation in mice. ACC1 deficiency in T cells reduces IL-17A-producing Th17/Tc17/dysfunctional Treg populations in psoriatic lesions. ACC1 deficiency in T cells restrains IFN-γ-producing Th1/Tc1 populations in psoriatic skin lesions and skin-draining LNs. ACC1 deficiency promotes activated CD44+CD25+ Tregs and effector CD62L-CD44+ Tregs under homeostasis and psoriatic conditions.

Keywords:  ACC1; Fatty acid synthesis; Psoriasis; Regulatory T cells (Tregs); Skin inflammation

DOI:  https://doi.org/10.1007/s00109-023-02349-w
PLoS Biol. 2023 Aug 17. 21(8): e3002231

NCoR1 controls Mycobacterium tuberculosis growth in myeloid cells by regulating the AMPK-mTOR-TFEB axis.

Viplov Kumar Biswas, Kaushik Sen, Abdul Ahad, Arup Ghosh, Surbhi Verma, Rashmirekha Pati, Subhasish Prusty, Sourya Prakash Nayak, Sreeparna Podder, Dhiraj Kumar, Bhawna Gupta, Sunil Kumar Raghav.

Mycobacterium tuberculosis (Mtb) defends host-mediated killing by repressing the autophagolysosome machinery. For the first time, we report NCoR1 co-repressor as a crucial host factor, controlling Mtb growth in myeloid cells by regulating both autophagosome maturation and lysosome biogenesis. We found that the dynamic expression of NCoR1 is compromised in human peripheral blood mononuclear cells (PBMCs) during active Mtb infection, which is rescued upon prolonged anti-mycobacterial therapy. In addition, a loss of function in myeloid-specific NCoR1 considerably exacerbates the growth of M. tuberculosis in vitro in THP1 differentiated macrophages, ex vivo in bone marrow-derived macrophages (BMDMs), and in vivo in NCoR1MyeKO mice. We showed that NCoR1 depletion controls the AMPK-mTOR-TFEB signalling axis by fine-tuning cellular adenosine triphosphate (ATP) homeostasis, which in turn changes the expression of proteins involved in autophagy and lysosomal biogenesis. Moreover, we also showed that the treatment of NCoR1 depleted cells by Rapamycin, Antimycin-A, or Metformin rescued the TFEB activity and LC3 levels, resulting in enhanced Mtb clearance. Similarly, expressing NCoR1 exogenously rescued the AMPK-mTOR-TFEB signalling axis and Mtb killing. Overall, our data revealed a central role of NCoR1 in Mtb pathogenesis in myeloid cells.

DOI: https://doi.org/10.1371/journal.pbio.3002231