bims-imicid 2022-01-09 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022–01–09
35 papers selected by
Dylan Ryan, University of Cambridge

STING orchestrates the crosstalk between polyunsaturated fatty acid metabolism and inflammatory responses.
A purine metabolic checkpoint that prevents autoimmunity and autoinflammation.
The transcription factor KLF14 regulates macrophage glycolysis and immune function by inhibiting HK2 in sepsis.
Genetic Ablation of the Mitochondrial Calcium Uniporter (MCU) Does not Impair T Cell-Mediated Immunity In Vivo.
Disruption of the IL-33-ST2-AKT signaling axis impairs neurodevelopment by inhibiting microglial metabolic adaptation and phagocytic function.
Diet, lipids, and antitumor immunity.
Restricting tumor lactic acid metabolism using dichloroacetate improves T cell functions.
Immunometabolism in bladder cancer microenvironment.
Foam Cell Macrophages in Tuberculosis.
A mitochondrial STAT3-methionine metabolism axis promotes ILC2-driven allergic lung inflammation.
Bilirubin ameliorates murine atherosclerosis through inhibiting cholesterol synthesis and reshaping the immune system.
Macrophages acquire a TNF-dependent inflammatory memory in allergic asthma.
Mitochondrial STAT3 exacerbates LPS-induced sepsis by driving CPT1a-mediated fatty acid oxidation.
[Research progress of itaconate on the regulation of macrophage inflammation].
Chronic IL-15 Stimulation and Impaired mTOR Signaling and Metabolism in Natural Killer Cells During Acute Myeloid Leukemia.
Tumor microenvironment metabolites directing T cell differentiation and function.
CD11c-MHC2low Macrophages Are a New Inflammatory and Dynamic Subset in Murine Adipose Tissue.
Stabilization but no functional influence of HIF-1α expression in the intestinal epithelium during Salmonella Typhimurium infection.
Identification of Profound Metabolic Alterations in Human Dendritic Cells by Progesterone Through Integrated Bioinformatics Analysis.
Mastering an exhausting marathon: how CD8+ T cells fine-tune metabolic fitness.
Protein synthesis, degradation, and energy metabolism in T cell immunity.
Conventional type 1 dendritic cells protect against age-related adipose tissue dysfunction and obesity.
GP73 links SARS-CoV-2 infection with dysglycaemia.
Targeting Metabolic Pathways of Myeloid Cells Improves Cancer Immunotherapy.
Microglial metabolic flexibility: emerging roles for lactate.
GP73 is a glucogenic hormone contributing to SARS-CoV-2-induced hyperglycemia.
Viral infection as an NAD+ battlefield.
Human CD206+ macrophages associate with diabetes and adipose tissue lymphoid clusters.
Greasing the inflammatory pathogenesis of viral pneumonias in diabetes.
Promotion of trained innate immunity by nanoparticles.
C1QBP regulates T cells mitochondrial fitness to affect their survival, proliferation and anti-tumor immune function.
Targeting memory T cell metabolism to improve immunity.
Intracellular NAD+ Depletion Confers a Priming Signal for NLRP3 Inflammasome Activation.
Costly immunometabolic remodeling in disused muscle buildup through physical exercise.
Salmonella enterica serovar Typhimurium uses anaerobic respiration to overcome propionate-mediated colonization resistance.

Cell Metab. 2022 Jan 04. pii: S1550-4131(21)00626-4. [Epub ahead of print]34(1): 125-139.e8

STING orchestrates the crosstalk between polyunsaturated fatty acid metabolism and inflammatory responses.

Isabelle K Vila, Hanane Chamma, Alizée Steer, Mathilde Saccas, Clara Taffoni, Evgenia Turtoi, Line S Reinert, Saqib Hussain, Johanna Marines, Lei Jin, Xavier Bonnefont, Mathieu Hubert, Olivier Schwartz, Soren R Paludan, Gaetan Van Simaeys, Gilles Doumont, Bijan Sobhian, Dimitrios Vlachakis, Andrei Turtoi, Nadine Laguette.

  Concerted alteration of immune and metabolic homeostasis underlies several inflammation-related pathologies, ranging from metabolic syndrome to infectious diseases. Here, we explored the coordination of nucleic acid-dependent inflammatory responses and metabolic homeostasis. We reveal that the STING (stimulator of interferon genes) protein regulates metabolic homeostasis through inhibition of the fatty acid desaturase 2 (FADS2) rate-limiting enzyme in polyunsaturated fatty acid (PUFA) desaturation. STING ablation and agonist-mediated degradation increased FADS2-associated desaturase activity and led to accumulation of PUFA derivatives that drive thermogenesis. STING agonists directly activated FADS2-dependent desaturation, promoting metabolic alterations. PUFAs in turn inhibited STING, thereby regulating antiviral responses and contributing to resolving STING-associated inflammation. Thus, we have unveiled a negative regulatory feedback loop between STING and FADS2 that fine-tunes inflammatory responses. Our results highlight the role of metabolic alterations in human pathologies associated with aberrant STING activation and STING-targeting therapies.

Keywords:  FADS2; STING; cGAS; cytosolic DNA; delta-6 Desaturase; inflammation; interferon responses; metabolism; nucleic acid immunity; polyunsaturated fatty acids

DOI:  https://doi.org/10.1016/j.cmet.2021.12.007
Cell Metab. 2022 Jan 04. pii: S1550-4131(21)00628-8. [Epub ahead of print]34(1): 106-124.e10

A purine metabolic checkpoint that prevents autoimmunity and autoinflammation.

Svetlana Saveljeva, Gavin W Sewell, Katharina Ramshorn, M Zaeem Cader, James A West, Simon Clare, Lea-Maxie Haag, Rodrigo Pereira de Almeida Rodrigues, Lukas W Unger, Ana Belén Iglesias-Romero, Lorraine M Holland, Christophe Bourges, Muhammad N Md-Ibrahim, James O Jones, Richard S Blumberg, James C Lee, Nicole C Kaneider, Trevor D Lawley, Allan Bradley, Gordon Dougan, Arthur Kaser.

  Still's disease, the paradigm of autoinflammation-cum-autoimmunity, predisposes for a cytokine storm with excessive T lymphocyte activation upon viral infection. Loss of function of the purine nucleoside enzyme FAMIN is the sole known cause for monogenic Still's disease. Here we discovered that a FAMIN-enabled purine metabolon in dendritic cells (DCs) restrains CD4+ and CD8+ T cell priming. DCs with absent FAMIN activity prime for enhanced antigen-specific cytotoxicity, IFNγ secretion, and T cell expansion, resulting in excessive influenza A virus-specific responses. Enhanced priming is already manifest with hypomorphic FAMIN-I254V, for which ∼6% of mankind is homozygous. FAMIN controls membrane trafficking and restrains antigen presentation in an NADH/NAD+-dependent manner by balancing flux through adenine-guanine nucleotide interconversion cycles. FAMIN additionally converts hypoxanthine into inosine, which DCs release to dampen T cell activation. Compromised FAMIN consequently enhances immunosurveillance of syngeneic tumors. FAMIN is a biochemical checkpoint that protects against excessive antiviral T cell responses, autoimmunity, and autoinflammation.

Keywords:  NADH/NAD(+) reductive stress; T cell priming; autoimmunity; dendritic cells; membrane trafficking; purine nucleotide cycle

DOI:  https://doi.org/10.1016/j.cmet.2021.12.009
Cell Mol Immunol. 2022 Jan 04.

The transcription factor KLF14 regulates macrophage glycolysis and immune function by inhibiting HK2 in sepsis.

Yuan Yuan, Guangjian Fan, Yuqi Liu, Lu Liu, Tong Zhang, Pengfei Liu, Qing Tu, Xinyi Zhang, Shiyuan Luo, Liangfang Yao, Feng Chen, Jingbao Li.

  Sepsis is a heterogeneous syndrome induced by a dysregulated host response to infection. Glycolysis plays a role in maintaining the immune function of macrophages, which is crucial for severely septic patients. However, how the pathways that link glycolysis and macrophages are regulated is still largely unknown. Here, we provide evidence to support the function of KLF14, a novel Krüppel-like transcription factor, in the regulation of glycolysis and the immune function of macrophages during sepsis. KLF14 deletion led to significantly increased mortality in lethal models of murine endotoxemia and sepsis. Mechanistically, KLF14 decreased glycolysis and the secretion of inflammatory cytokines by macrophages by inhibiting the transcription of HK2. In addition, we confirmed that the expression of KLF14 was upregulated in septic patients. Furthermore, pharmacological activation of KLF14 conferred protection against sepsis in mice. These findings uncover a key role of KLF14 in modulating the inflammatory signaling pathway and shed light on the development of KLF14-targeted therapeutics for sepsis.

Keywords:  Glycolysis; HK2; KLF14; Macrophages; Perhexiline; Sepsis

DOI:  https://doi.org/10.1038/s41423-021-00806-5
Front Pharmacol. 2021 ;12 734078

Genetic Ablation of the Mitochondrial Calcium Uniporter (MCU) Does not Impair T Cell-Mediated Immunity In Vivo.

Hao Wu, Benjamin Brand, Miriam Eckstein, Sophia M Hochrein, Magdalena Shumanska, Jan Dudek, Alexander Nickel, Christoph Maack, Ivan Bogeski, Martin Vaeth.

  T cell activation and differentiation is associated with metabolic reprogramming to cope with the increased bioenergetic demand and to provide metabolic intermediates for the biosynthesis of building blocks. Antigen receptor stimulation not only promotes the metabolic switch of lymphocytes but also triggers the uptake of calcium (Ca2+) from the cytosol into the mitochondrial matrix. Whether mitochondrial Ca2+ influx through the mitochondrial Ca2+ uniporter (MCU) controls T cell metabolism and effector function remained, however, enigmatic. Using mice with T cell-specific deletion of MCU, we here show that genetic inactivation of mitochondrial Ca2+ uptake increased cytosolic Ca2+ levels following antigen receptor stimulation and store-operated Ca2+ entry (SOCE). However, ablation of MCU and the elevation of cytosolic Ca2+ did not affect mitochondrial respiration, differentiation and effector function of inflammatory and regulatory T cell subsets in vitro and in animal models of T cell-mediated autoimmunity and viral infection. These data suggest that MCU-mediated mitochondrial Ca2+ uptake is largely dispensable for murine T cell function. Our study has also important technical implications. Previous studies relied mostly on pharmacological inhibition or transient knockdown of mitochondrial Ca2+ uptake, but our results using mice with genetic deletion of MCU did not recapitulate these findings. The discrepancy of our study to previous reports hint at compensatory mechanisms in MCU-deficient mice and/or off-target effects of current MCU inhibitors.

Keywords:  calcium (Ca2+); immunometabolism; mitochondria; mitochondrial Ca2+ handling; mitochondrial calcium uniporter (MCU); oxidative phosphorylation; store-operated Ca2+ entry

DOI:  https://doi.org/10.3389/fphar.2021.734078
Immunity. 2021 Dec 24. pii: S1074-7613(21)00534-3. [Epub ahead of print]

Disruption of the IL-33-ST2-AKT signaling axis impairs neurodevelopment by inhibiting microglial metabolic adaptation and phagocytic function.

Danyang He, Heping Xu, Huiyuan Zhang, Ruihan Tang, Yangning Lan, Ruxiao Xing, Shaomin Li, Elena Christian, Yu Hou, Paul Lorello, Barbara Caldarone, Jiarui Ding, Lan Nguyen, Danielle Dionne, Pratiksha Thakore, Alexandra Schnell, Jun R Huh, Orit Rozenblatt-Rosen, Aviv Regev, Vijay K Kuchroo.

  To accommodate the changing needs of the developing brain, microglia must undergo substantial morphological, phenotypic, and functional reprogramming. Here, we examined whether cellular metabolism regulates microglial function during neurodevelopment. Microglial mitochondria bioenergetics correlated with and were functionally coupled to phagocytic activity in the developing brain. Transcriptional profiling of microglia with diverse metabolic profiles revealed an activation signature wherein the interleukin (IL)-33 signaling axis is associated with phagocytic activity. Genetic perturbation of IL-33 or its receptor ST2 led to microglial dystrophy, impaired synaptic function, and behavioral abnormalities. Conditional deletion of Il33 from astrocytes or Il1rl1, encoding ST2, in microglia increased susceptibility to seizures. Mechanistically, IL-33 promoted mitochondrial activity and phagocytosis in an AKT-dependent manner. Mitochondrial metabolism and AKT activity were temporally regulated in vivo. Thus, a microglia-astrocyte circuit mediated by the IL-33-ST2-AKT signaling axis supports microglial metabolic adaptation and phagocytic function during early development, with implications for neurodevelopmental and neuropsychiatric disorders.

Keywords:  IL-33; bioenergenetics; microglia; neurodevelopment; phagocytosis; seizure; synapse

DOI:  https://doi.org/10.1016/j.immuni.2021.12.001
Cell Mol Immunol. 2022 Jan 05.

Diet, lipids, and antitumor immunity.

Hannah Prendeville, Lydia Lynch.

  Tumour growth and dissemination is largely dependent on nutrient availability. It has recently emerged that the tumour microenvironment is rich in a diverse array of lipids that increase in abundance with tumour progression and play a role in promoting tumour growth and metastasis. Here, we describe the pro-tumorigenic roles of lipid uptake, metabolism and synthesis and detail the therapeutic potential of targeting lipid metabolism in cancer. Additionally, we highlight new insights into the distinct immunosuppressive effects of lipids in the tumour microenvironment. Lipids threaten an anti-tumour environment whereby metabolic adaptation to lipid metabolism is linked to immune dysfunction. Finally, we describe the differential effects of commondietary lipids on cancer growth which may uncover a role for specific dietary regimens in association with traditional cancer therapies. Understanding the relationship between dietary lipids, tumour, and immune cells is important in the context of obesity which may reveal a possibility to harness the diet in the treatment of cancers.

Keywords:  Lipids; anti-tumour immunity; cancer; obesity; β-oxidation

DOI:  https://doi.org/10.1038/s41423-021-00781-x
BMC Cancer. 2022 Jan 06. 22(1): 39

Restricting tumor lactic acid metabolism using dichloroacetate improves T cell functions.

Hosein Rostamian, Mohammad Khakpoor-Koosheh, Leila Jafarzadeh, Elham Masoumi, Keyvan Fallah-Mehrjardi, Mohammad Javad Tavassolifar, John M Pawelek, Hamid Reza Mirzaei, Jamshid Hadjati.

   BACKGROUND: Lactic acid produced by tumors has been shown to overcome immune surveillance, by suppressing the activation and function of T cells in the tumor microenvironment. The strategies employed to impair tumor cell glycolysis could improve immunosurveillance and tumor growth regulation. Dichloroacetate (DCA) limits the tumor-derived lactic acid by altering the cancer cell metabolism. In this study, the effects of lactic acid on the activation and function of T cells, were analyzed by assessing T cell proliferation, cytokine production and the cellular redox state of T cells. We examined the redox system in T cells by analyzing the intracellular level of reactive oxygen species (ROS), superoxide and glutathione and gene expression of some proteins that have a role in the redox system. Then we co-cultured DCA-treated tumor cells with T cells to examine the effect of reduced tumor-derived lactic acid on proliferative response, cytokine secretion and viability of T cells.
RESULT: We found that lactic acid could dampen T cell function through suppression of T cell proliferation and cytokine production as well as restrain the redox system of T cells by decreasing the production of oxidant and antioxidant molecules. DCA decreased the concentration of tumor lactic acid by manipulating glucose metabolism in tumor cells. This led to increases in T cell proliferation and cytokine production and also rescued the T cells from apoptosis.
CONCLUSION: Taken together, our results suggest accumulation of lactic acid in the tumor microenvironment restricts T cell responses and could prevent the success of T cell therapy. DCA supports anti-tumor responses of T cells by metabolic reprogramming of tumor cells.

Keywords:  Cancer; Dichloroacetate, Immunotherapy; Lactic acid; Metabolism; T cell

DOI:  https://doi.org/10.1186/s12885-021-09151-2
Endocr Metab Immune Disord Drug Targets. 2022 Jan 04.

Immunometabolism in bladder cancer microenvironment.

Mohammad Javad Fattahi, Mohammad Reza Haghshenas, Abbas Ghaderi.

  The initiation and progression of bladder cancer (BC), is dependent on its tumor microenvironment (TME). On the other hand, cancer cells shape and train TME to support their development, respond to treatment and migration in an organism. Immune cells exert key roles in the BC microenvironment and have complex interactions with BC cells. These complicated interplays result in metabolic competition in the TME leading to nutrient deprivation, acidosis, hypoxia and metabolite accumulation, which impair immune cell function. Recent studies have demonstrated that immune cells functions are closely correlated with their metabolism. Immunometabolism describes the functional metabolic alterations that take place within immune cells and the role of these cells in directing metabolism and immune response in tissues or diseases such as cancer. Some molecules and their metabolites in the TME including glucose, fatty acids and amino acids can regulate the phenotype, function and metabolism of immune cells. Hence, here we describe some recent advances in immunometabolism and relate them to BC progression. A profound understanding of the metabolic reprogramming of BC cells and immune cells in the TME will offer novel opportunities for targeted therapies in future.

Keywords:  Bladder cancer; Immunometabolism; Metabolic Reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.2174/1871530322666220104103905
Front Immunol. 2021 ;12 775326

Foam Cell Macrophages in Tuberculosis.

Pooja Agarwal, Siamon Gordon, Fernando O Martinez.

  Mycobacterium tuberculosis infects primarily macrophages in the lungs. Infected macrophages are surrounded by other immune cells in well organised structures called granulomata. As part of the response to TB, a type of macrophage loaded with lipid droplets arises which we call Foam cell macrophages. They are macrophages filled with lipid laden droplets, which are synthesised in response to increased uptake of extracellular lipids, metabolic changes and infection itself. They share the appearance with atherosclerosis foam cells, but their lipid contents and roles are different. In fact, lipid droplets are immune and metabolic organelles with emerging roles in Tuberculosis. Here we discuss lipid droplet and foam cell formation, evidence regarding the inflammatory and immune properties of foam cells in TB, and address gaps in our knowledge to guide further research.

Keywords:  Mycobacterium; foam cells; lipid droplets; macrophage; tuberculosis

DOI:  https://doi.org/10.3389/fimmu.2021.775326
J Allergy Clin Immunol. 2021 Dec 30. pii: S0091-6749(21)02745-7. [Epub ahead of print]

A mitochondrial STAT3-methionine metabolism axis promotes ILC2-driven allergic lung inflammation.

Liuhui Fu, Jie Zhao, Jiaoyan Huang, Na Li, Xin Dong, Yao He, Wenyan Wang, Yu Wang, Ju Qiu, Xiaohuan Guo.

   BACKGROUND: Group 2 innate lymphoid cells (ILC2s), the innate counterpart of T helper 2 cells (Th2), play a critical role in type 2 immune responses. However, the molecular regulatory mechanisms of ILC2s are still unclear.
OBJECTIVE: The aim of this study was to explore the importance of signal transducer and activator of transcription 3 (STAT3) to ILC2 function in allergic lung inflammation.
METHODS: Acute and chronic asthma models were established by intranasal administration of the protease allergen papain in VavicreStat3fl/fl, Il5tdtomato-creStat3fl/fl, and RorccreStat3fl/fl mice to verify the necessity of functional STAT3 for ILC2 allergic response. The intrinsic role of STAT3 in regulating ILC2 function was examined by generation of bone marrow chimera mice. The underlying mechanism was studied through confocal imaging, metabolomics analysis, and chromatin immunoprecipitation quantitative PCR.
RESULTS: STAT3 is essential for ILC2 effector function and promotes ILC2-driven allergic inflammation in the lung. Mechanistically, the alarmin cytokine interleukin (IL)-33 induces a non-canonical STAT3 phosphorylation at serine 727 in ILC2s, leading to translocation of STAT3 into the mitochondria. Mitochondrial STAT3 further facilitates adenosine triphosphate synthesis to fuel the methionine cycle and generation of S-adenosylmethionine, which supports the epigenetic reprogramming of type 2 cytokines in ILC2s. STAT3 deficiency, inhibition of STAT3 mitochondrial translocation, or blockade of methionine metabolism markedly dampened the ILC2 allergic response and ameliorated allergic lung inflammation.
CONCLUSION: The mitochondrial STAT3-methionine metabolism pathway is a key regulator that shapes ILC2 effector function through epigenetic regulation, and the related proteins or metabolites represent potential therapeutic targets for allergic lung inflammation.

Keywords:  Allergic lung inflammation; Histone methylation; ILC2; Mitochondria; STAT3; methionine metabolism

DOI:  https://doi.org/10.1016/j.jaci.2021.12.783
J Transl Med. 2022 Jan 03. 20(1): 1

Bilirubin ameliorates murine atherosclerosis through inhibiting cholesterol synthesis and reshaping the immune system.

Guanmei Wen, Leyi Yao, Yali Hao, Jinheng Wang, Jinbao Liu.

  Atherosclerosis is a chronic inflammatory disease caused mainly by lipid accumulation and excessive inflammatory immune response. Although the lipid-lowering and cardioprotective properties of bilirubin, as well as the negative relationship between bilirubin and atherosclerosis, were well documented, it is not yet clear whether bilirubin can attenuate atherosclerosis in vivo. In this study, we investigated the role of bilirubin in improving atherosclerosis. We found that mildly elevated bilirubin significantly reduced the risk factors of atherosclerosis, such as plasma glucose, total cholesterol, and low-density lipoprotein cholesterol, and the formation of atherosclerotic plaques, liver total cholesterol, and cholesterol ester concentration in apolipoprotein E-deficient (ApoE-/-) mice fed a western-type (high fat) diet. It was further found that bilirubin could promote the degradation of 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), a rate-limiting enzyme for endogenous cholesterol synthesis. Using mass cytometry-based high dimensional single cell analysis, we observed a decrease of natural killer cells and an increase of dendritic cells and myeloid-derived suppressor cells, which all are closely associated with atherosclerosis risk factors and contribute to the improvement of atherosclerosis, in ApoE-/- mice treated with bilirubin. By in-depth analysis, modulation of multiple spleen or peripheral blood T cell clusters exhibiting either positive or negative correlations with total cholesterol or low-density lipoprotein cholesterol was detected after bilirubin treatment. In this study, we demonstrate that bilirubin serves as a negative regulator of atherosclerosis and reduces atherosclerosis by inhibiting cholesterol synthesis and modulating the immune system.

Keywords:  3-Hydroxy-3-Methylglutaryl-CoA Reductase; Atherosclerosis; Bilirubin; Myeloid-derived suppressor cells; Natural killer cells

DOI:  https://doi.org/10.1186/s12967-021-03207-4
J Allergy Clin Immunol. 2021 Dec 30. pii: S0091-6749(21)02741-X. [Epub ahead of print]

Macrophages acquire a TNF-dependent inflammatory memory in allergic asthma.

Antonie Lechner, Fiona Henkel, Franziska Hartung, Sina Bohnacker, Francesca Alessandrini, Ekaterina O Gubernatorova, Marina S Drutskaya, Carlo Angioni, Yannick Schreiber, Pascal Haimerl, Yan Ge, Dominique Thomas, Agnieszka M Kabat, Edward J Pearce, Caspar Ohnmacht, Sergei A Nedospasov, Peter J Murray, Adam M Chaker, Carsten B Schmidt-Weber, Julia Esser-von Bieren.

   BACKGROUND: Infectious agents can reprogram or "train" macrophages and their progenitors to respond more readily to subsequent insults. However, whether such an inflammatory memory exists in type-2 inflammatory conditions such as allergic asthma was not known.
OBJECTIVE: To decipher macrophage trained immunity in allergic asthma.
METHODS: We used a combination of clinical sampling of house dust mite (HDM)-allergic patients, HDM-induced allergic airway inflammation (AAI) in mice and an in vitro training set-up to analyze persistent changes in macrophage eicosanoid-, cytokine- and chemokine production as well as underlying metabolic and epigenetic mechanisms. Transcriptional and metabolic profiles of patient-derived and in vitro trained macrophages were assessed by RNA sequencing or Seahorse and LC-MS/MS analysis, respectively.
RESULTS: We found that macrophages differentiated from bone marrow- or blood monocyte- progenitors of HDM-allergic mice or asthma patients show inflammatory transcriptional reprogramming and excessive mediator (TNF-α, CCL17, leukotriene, PGE2, IL-6) responses upon stimulation. Macrophages from HDM-allergic mice initially exhibited a type-2 imprint, which shifted towards a classical inflammatory training over time. HDM-induced AAI elicited a metabolically activated macrophage phenotype, producing high amounts of 2-hydroxyglutarate (2-HG). HDM-induced macrophage training in vitro was mediated by a formyl-peptide receptor 2 (FPR2)-TNF-2-HG-PGE2/EP2-axis, resulting in an M2-like macrophage phenotype with high CCL17 production. TNF blockade by etanercept or genetic ablation of Tnf in myeloid cells prevented the inflammatory imprinting of bone marrow-derived macrophages from HDM-allergic mice.
CONCLUSION: Allergen-triggered inflammation drives a TNF-dependent innate memory, which may perpetuate and exacerbate chronic type-2 airway inflammation and thus represents a target for asthma therapy.

Keywords:  CCL17; chemokines; eicosanoids; lipid mediators; macrophages; trained immunity; type 2 inflammation

DOI:  https://doi.org/10.1016/j.jaci.2021.11.026
Theranostics. 2022 ;12(2): 976-998

Mitochondrial STAT3 exacerbates LPS-induced sepsis by driving CPT1a-mediated fatty acid oxidation.

Rongqing Li, Xueqin Li, Jie Zhao, Fandong Meng, Chen Yao, Ensi Bao, Na Sun, Xin Chen, Wanpeng Cheng, Hui Hua, Xiangyang Li, Bo Wang, Hui Wang, Xiucheng Pan, Hongjuan You, Jing Yang, Takayuki Ikezoe.

  Rationale: We found that a subset of signal transducer and activator of transcription 3 (STAT3) translocated into mitochondria in phagocytes, including macrophages isolated from individuals with sepsis. However, the role of mitochondrial STAT3 in macrophages remains unclear. Method: To investigate the function of mitochondrial STAT3 in vivo, we generated inducible mitochondrial STAT3 knock-in mice. A cytokine array analysis, a CBA analysis, flow cytometry, immunofluorescence staining and quantification and metabolic analyses in vivo were subsequently performed in an LPS-induced sepsis model. Single-cell RNA sequencing, a microarray analysis, metabolic assays, mass spectrometry and ChIP assays were utilized to gain insight into the mechanisms of mitochondrial STAT3 in metabolic reprogramming in LPS-induced sepsis. Results: We found that mitochondrial STAT3 induced NF-κB nuclear localization and exacerbated LPS-induced sepsis in parallel with a metabolic switch from mainly using glucose to an increased reliance on fatty acid oxidation (FAO). Moreover, mitochondrial STAT3 abrogated carnitine palmitoyl transferase 1a (CPT1a) ubiquitination and degradation in LPS-treated macrophages. Meanwhile, an interaction between CPT1a and ubiquitin-specific peptidase 50 (USP50) was observed. In contrast, knocking down USP50 decreased CPT1a expression and FAO mediated by mitochondrial STAT3. The ChIP assays revealed that NF-κB bound the USP50 promoter. Curcumin alleviated LPS-mediated sepsis by suppressing the activities of mitochondrial STAT3 and NF-κB. Conclusion: Our findings reveal that mitochondrial STAT3 could trigger FAO by inducing CPT1a stabilization mediated by USP50 in macrophages, at least partially.

Keywords:  CPT1a stabilization; FAO; USP50; mitochondrial STAT3

DOI:  https://doi.org/10.7150/thno.63751
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2021 Nov;33(11): 1388-1392

[Research progress of itaconate on the regulation of macrophage inflammation].

Yutong Wu, Li Zheng, Hao Yang, Xin Lyu.

Macrophages are important innate immune cells. Under inflammatory stimulation, macrophages rapidly respond and subsequently produce large amounts of cellular metabolites through metabolic reprogramming. Itaconate is an immunomodulatory derivative from the tricarboxylic acid cycle which has antioxidative and anti-inflammatory effects. In recent years, it has been reported that itaconate promotes the transition of macrophage phenotype from M1 to M2 and the underlying mechanism may include the activation of nuclear factor E2-related factor 2 (Nrf2) by alkylation of Kelch-like ECH-associated protein 1 (Keap1), inhibition of succinate dehydrogenase (SDH) and reactive oxygen species (ROS), blockade of the inhibitor ζ of nuclear factor-κB (IκBζ) translation and inhibition of aerobic glycolysis. In this review, we describe the metabolic pathways of itaconate, clarify the relationship between itaconate and the immune response, and summarize the latest researches about the roles of itaconate on regulating the inflammatory response in macrophages in order to provide the basis for the clinical use of itaconate and new strategies for the treatment of inflammatory diseases.

DOI: https://doi.org/10.3760/cma.j.cn121430-20201127-00735
Front Immunol. 2021 ;12 730970

Chronic IL-15 Stimulation and Impaired mTOR Signaling and Metabolism in Natural Killer Cells During Acute Myeloid Leukemia.

Berna Bou-Tayeh, Vladimir Laletin, Nassim Salem, Sylvaine Just-Landi, Joanna Fares, Raphael Leblanc, Marielle Balzano, Yann M Kerdiles, Ghislain Bidaut, Olivier Hérault, Daniel Olive, Michel Aurrand-Lions, Thierry Walzer, Jacques A Nunès, Cyril Fauriat.

  Natural Killer (NK) cells are potent anti-leukemic immune effectors. However, they display multiple defects in acute myeloid leukemia (AML) patients leading to reduced anti-tumor potential. Our limited understanding of the mechanisms underlying these defects hampers the development of strategies to restore NK cell potential. Here, we have used a mouse model of AML to gain insight into these mechanisms. We found that leukemia progression resulted in NK cell maturation defects and functional alterations. Next, we assessed NK cell cytokine signaling governing their behavior. We showed that NK cells from leukemic mice exhibit constitutive IL-15/mTOR signaling and type I IFN signaling. However, these cells failed to respond to IL-15 stimulation in vitro as illustrated by reduced activation of the mTOR pathway. Moreover, our data suggest that mTOR-mediated metabolic responses were reduced in NK cells from AML-bearing mice. Noteworthy, the reduction of mTOR-mediated activation of NK cells during AML development partially rescued NK cell metabolic and functional defects. Altogether, our data strongly suggest that NK cells from leukemic mice are metabolically and functionally exhausted as a result of a chronic cytokine activation, at least partially IL-15/mTOR signaling. NK cells from AML patients also displayed reduced IL-2/15Rβ expression and showed cues of reduced metabolic response to IL-15 stimulation in vitro, suggesting that a similar mechanism might occur in AML patients. Our study pinpoints the dysregulation of cytokine stimulation pathways as a new mechanism leading to NK cell defects in AML.

Keywords:  IL-15/mTOR signaling; acute myeloid leukemia; chronic stimulation; exhaustion; metabolism; natural killer cells

DOI:  https://doi.org/10.3389/fimmu.2021.730970
Trends Immunol. 2021 Dec 29. pii: S1471-4906(21)00262-3. [Epub ahead of print]

Tumor microenvironment metabolites directing T cell differentiation and function.

Xia Liu, Daniel F Hoft, Guangyong Peng.

  Metabolic reprogramming of cancer cells creates a unique tumor microenvironment (TME) characterized by the limited availability of nutrients, which subsequently affects the metabolism, differentiation, and function of tumor-infiltrating T lymphocytes (TILs). TILs can also be inhibited by tumor-derived metabolic waste products and low oxygen. Therefore, a thorough understanding of how such unique metabolites influence mammalian T cell differentiation and function can inform novel anticancer therapeutic approaches. Here, we highlight the importance of these metabolites in modulating various T cell subsets within the TME, dissecting how these changes might alter clinical outcomes. We explore potential TME metabolic determinants that might constitute candidate targets for cancer immunotherapies, ideally leading to future strategies for reprogramming tumor metabolism to potentiate anticancer T cell functions.

Keywords:  T cells; metabolic reprogramming; metabolites; tumor immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.1016/j.it.2021.12.004
Immunometabolism. 2020 Apr 17. 2(2): e200015

CD11c-MHC2low Macrophages Are a New Inflammatory and Dynamic Subset in Murine Adipose Tissue.

Suzan Wetzels, Mitchell Bijnen, Erwin Wijnands, José van de Gaar, Andika Tan, Susan Coort, Erik A L Biessen, Casper G Schalkwijk, Kristiaan Wouters.

   Background: The prevalence of obesity is rising and leads to increased morbidity and mortality. Adipose tissue inflammation, due to accumulation and activation of adipose tissue macrophages (ATMs), is a key driver of this phenomenon. Macrophages are heterogeneous cells, adapting quickly to the microenvironment, resulting in so-called M1 or M2 macrophages. In this study, we describe the dynamics and inflammatory properties of a newly identified ATM subset in obese mice.
Methods: LDLR-/- mice received a high fat diet (HFD) for 5 weeks or 16 weeks to induce obesity. Adipose tissues were isolated and immune cell subsets were analyzed with flow cytometry or microarray analysis. Bone marrow transplantation (BMT) using CD45.1 and CD45.2 LDLR-/- mice was performed to determine ATM origin.
Results: Upon HFD, there is a massive increase of ATM subsets in the adipose tissue. CD11c-M2 ATMs could be subdivided based on their MHC2 expression into CD11c-MHC2high ATMs and previously unidentified CD11c-MHC2low ATMs. CD11c-MHC2low ATMs accumulated very rapidly after 10 days of HFD, after which they increased even further with prolonged HFD. Microarray data showed that CD11c-MHC2low ATMs resembled CD11c-MHC2high ATMs in the steady state, but became more inflammatory during development of obesity. In vitro stimulation of bone marrow-derived macrophages with palmitate, abundantly present in HFD, resulted in the induction of the CD11c-MHC2low phenotype.
Conclusions: Among M2 macrophages, a novel pro-inflammatory subset of macrophages was found based on their low level of MHC2 expression. This subset may play a role in the development of adipose tissue inflammation.

Keywords:  CD11c; MHC2; adipose tissue macrophages; bone marrow transplantation; flow cytometry; free fatty acids; visceral adipose tissue

DOI:  https://doi.org/10.20900/immunometab20200015
Infect Immun. 2022 Jan 03. iai0022221

Stabilization but no functional influence of HIF-1α expression in the intestinal epithelium during Salmonella Typhimurium infection.

Laura Robrahn, Aline Dupont, Sandra Jumpertz, Kaiyi Zhang, Christian H Holland, Joël Guillaume, Sabrina Rappold, Johanna Roth, Vuk Cerovic, Julio Saez-Rodriguez, Mathias W Hornef, Thorsten Cramer.

The hypoxia-inducible transcription factor 1 (HIF-1) has been shown to enhance microbial killing and to ameliorate the course of bacterial infections. While the impact of HIF-1 on inflammatory diseases of the gut has been studied intensively, its function in bacterial infections of the gastrointestinal tract remains largely elusive. With the help of a publicly available gene expression data set, we could infer significant activation of HIF-1 after oral infection of mice with Salmonella Typhimurium. Immunohistochemistry and western blot analysis confirmed marked HIF-1α protein stabilization, especially in the intestinal epithelium. This prompted us to analyze conditional Hif1a-deficient mice to examine cell type-specific functions of HIF-1 in this model. Our results demonstrate enhanced non-canonical induction of HIF-1 activity upon Salmonella infection in the intestinal epithelium as well as in macrophages. Surprisingly, Hif1a deletion in intestinal epithelial cells did not impact on inflammatory gene expression, bacterial spread or disease outcome. In contrast, Hif1a deletion in myeloid cells enhanced intestinal Cxcl2 expression and reduced the cecal Salmonella load. In vitro, HIF-1α-deficient macrophages showed an overall impaired transcription of mRNA encoding pro-inflammatory factors, however, intracellular survival of Salmonella was not impacted by HIF-1α deficiency.

DOI: https://doi.org/10.1128/iai.00222-21
Front Immunol. 2021 ;12 806110

Identification of Profound Metabolic Alterations in Human Dendritic Cells by Progesterone Through Integrated Bioinformatics Analysis.

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

  Maintaining the homeostasis of the decidual immune microenvironment at the maternal-fetal interface is essential for reproductive success. Dendritic cells (DCs) are the professional antigen-presenting cells and dominate this balance of immunogenicity and tolerance. Progesterone (P4) is highlighted as the "hormone of pregnancy" in most eutherian mammals because of its regulatory role in immune-endocrine behavior during pregnancy. Recent studies have shown that P4 is associated with the differentiation and function of DCs, however, the underlying mechanisms remain unidentified. In addition, while progress in the field of immunometabolism has highlighted the intimate connections between the metabolism phenotype and the immunogenic or tolerogenic fate of DCs, whether P4 can affect DCs metabolism and thus exert a functional manipulation has not yet been explored. In this study, we acquired human peripheral blood monocyte-derived DCs and conducted RNA sequencing (RNA-seq) on immature DCs (iDCs), P4-treated DCs (pDCs), and mature DCs (mDCs), aiming to comprehensively assess the effects of P4 on DCs. Our results showed pDCs performed a distinct differentially expressed genes (DEGs) profile compared with iDCs or mDCs. Further functional enrichment and weighted gene co-expression network (WGCNA) analysis found that these DEGs were related not only to the cellular components but also to the significant metabolic activities, including mitochondrial oxidative phosphorylation (OXPHOS) and fatty acid metabolism. In addition, these changes may be involved in the activation of various signaling pathways of PI3K/Akt/mTOR, AMPK/PGC1-α, and PPAR-γ. In summary, our work suggested that P4 induced profound metabolic alterations of mitochondrial OXPHOS and fatty acid metabolism in DCs. Our findings may provide new insights into the role of P4 in DCs.

Keywords:  OXPHOS; RNA-seq; dendritic cells; fatty acid metabolism; progesterone

DOI:  https://doi.org/10.3389/fimmu.2021.806110
Immunol Cell Biol. 2022 Jan 05.

Mastering an exhausting marathon: how CD8+ T cells fine-tune metabolic fitness.

Anna M Schulz, Dietmar Zehn.

A recent study by Gabriel et al. provides novel insight into the metabolic pathways that contribute to T cell differentiation in chronic infection. The researchers discovered that metabolic plasticity and the function of exhausted T cells is regulated via the TGF-β-mTOR signaling axis.

DOI: https://doi.org/10.1111/imcb.12517
Cell Mol Immunol. 2022 Jan 04.

Protein synthesis, degradation, and energy metabolism in T cell immunity.

Julia M Marchingo, Doreen A Cantrell.

  T cell activation, proliferation, and differentiation into effector and memory states involve massive remodeling of T cell size and molecular content and create a massive increase in demand for energy and amino acids. Protein synthesis is an energy- and resource-demanding process; as such, changes in T cell energy production are intrinsically linked to proteome remodeling. In this review, we discuss how protein synthesis and degradation change over the course of a T cell immune response and the crosstalk between these processes and T cell energy metabolism. We highlight how the use of high-resolution mass spectrometry to analyze T cell proteomes can improve our understanding of how these processes are regulated.

Keywords:  Immunometabolism; Protein Translation; Protein degradation; Proteomics; T lymphocyte

DOI:  https://doi.org/10.1038/s41423-021-00792-8
Cell Mol Immunol. 2022 Jan 04.

Conventional type 1 dendritic cells protect against age-related adipose tissue dysfunction and obesity.

Elena Hernández-García, Francisco J Cueto, Emma C L Cook, Ana Redondo-Urzainqui, Sara Charro-Zanca, Iñaki Robles-Vera, Ruth Conde-Garrosa, Ivana Nikolić, Guadalupe Sabio, David Sancho, Salvador Iborra.

  Conventional dendritic cells (cDCs) scan and integrate environmental cues in almost every tissue, including exogenous metabolic signals. While cDCs are critical in maintaining immune balance, their role in preserving energy homeostasis is unclear. Here, we showed that Batf3-deficient mice lacking conventional type 1 DCs (cDC1s) had increased body weight and adiposity during aging. This led to impaired energy expenditure and glucose tolerance, insulin resistance, dyslipidemia, and liver steatosis. cDC1 deficiency caused adipose tissue inflammation that was preceded by a paucity of NK1.1+ invariant NKT (iNKT) cells. Accordingly, among antigen-presenting cells, cDC1s exhibited notable induction of IFN-γ production by iNKT cells, which plays a metabolically protective role in lean adipose tissue. Flt3L treatment, which expands the dendritic cell (DC) compartment, mitigated diet-induced obesity and hyperlipidemia in a Batf3-dependent manner. This effect was partially mediated by NK1.1+ cells. These results reveal a new critical role for the cDC1-iNKT cell axis in the regulation of adipose tissue homeostasis.

Keywords:  Dendritic Cells; FLT3L; NKT; Obesity; ageing

DOI:  https://doi.org/10.1038/s41423-021-00812-7
Nat Metab. 2022 Jan 06.

GP73 links SARS-CoV-2 infection with dysglycaemia.

Katie C Coate.

DOI: https://doi.org/10.1038/s42255-021-00511-7
Front Cell Dev Biol. 2021 ;9 747863

Targeting Metabolic Pathways of Myeloid Cells Improves Cancer Immunotherapy.

Jianying Li, Chelsea Bolyard, Gang Xin, Zihai Li.

  Tumor-infiltrating myeloid cells are a prominent pro-tumorigenic immune cell population that limit host anti-tumor immunity and present a significant obstacle for many cancer immunotherapies. Targeting the mechanisms regulating myeloid cell function within the tumor microenvironment may overcome immunotherapy resistance in some cancers. Recent discoveries in the emerging field of immunometabolism reveal that the metabolic profiles of intratumoral myeloid cells are rewired to adapt to the nutrition-limited tumor microenvironment, and this shapes their pro-tumor phenotypes. Interestingly, metabolic modulation can shift these myeloid cells toward the immune-stimulating anti-tumor phenotype. In this review, we will highlight the roles of specific metabolic pathways in the activation and function of myeloid cells, and discuss the therapeutic value of metabolically reprogramming myeloid cells to augment and improve outcomes with cancer immunotherapy.

Keywords:  immunometabolism; immunotherapy; myeloid cells; myeloid-derived suppressor cells; tumor-associated dendritic cells; tumor-associated macrophages; tumor-associated neutrophils; tumor-infiltrating myeloid cells

DOI:  https://doi.org/10.3389/fcell.2021.747863
Trends Endocrinol Metab. 2022 Jan 04. pii: S1043-2760(21)00284-8. [Epub ahead of print]

Microglial metabolic flexibility: emerging roles for lactate.

Katia Monsorno, An Buckinx, Rosa C Paolicelli.

  Microglia, the resident macrophages of the central nervous system (CNS), play important functions in the healthy and diseased brain. In the emerging field of immunometabolism, progress has been made in understanding how cellular metabolism can orchestrate the key responses of tissue macrophages, such as phagocytosis and inflammation. However, very little is known about the metabolic control of microglia. Lactate, now recognized as a crucial metabolite and a central substrate in metabolic flexibility, is emerging not only as a novel bioenergetic fuel for microglial metabolism but also as a potential modulator of cellular function. Parallels with macrophages will help in understanding how microglial lactate metabolism is implicated in brain physiology and pathology, and how it could be targeted for therapeutic purposes.

Keywords:  CNS disease; lactate; metabolism; microglia; synaptic function

DOI:  https://doi.org/10.1016/j.tem.2021.12.001
Nat Metab. 2022 Jan 06.

GP73 is a glucogenic hormone contributing to SARS-CoV-2-induced hyperglycemia.

Luming Wan, Qi Gao, Yongqiang Deng, Yuehua Ke, Enhao Ma, Huan Yang, Haotian Lin, Huilong Li, Yilong Yang, Jing Gong, Jingfei Li, Yixin Xu, Jing Liu, Jianmin Li, Jialong Liu, Xuemiao Zhang, Linfei Huang, Jiangyue Feng, Yanhong Zhang, Hanqing Huang, Huapeng Wang, Changjun Wang, Qi Chen, Xingyao Huang, Qing Ye, Dongyu Li, Qiulin Yan, Muyi Liu, Meng Wei, Yunhai Mo, Dongrui Li, Ke Tang, Changqing Lin, Fei Zheng, Lei Xu, Gong Cheng, Peihui Wang, Xiaopan Yang, Feixang Wu, Zhiwei Sun, Chengfeng Qin, Congwen Wei, Hui Zhong.

Severe cases of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with elevated blood glucose levels and metabolic complications. However, the molecular mechanisms for how SARS-CoV-2 infection alters glycometabolic control are incompletely understood. Here, we connect the circulating protein GP73 with enhanced hepatic gluconeogenesis during SARS-CoV-2 infection. We first demonstrate that GP73 secretion is induced in multiple tissues upon fasting and that GP73 stimulates hepatic gluconeogenesis through the cAMP/PKA signaling pathway. We further show that GP73 secretion is increased in cultured cells infected with SARS-CoV-2, after overexpression of SARS-CoV-2 nucleocapsid and spike proteins and in lungs and livers of mice infected with a mouse-adapted SARS-CoV-2 strain. GP73 blockade with an antibody inhibits excessive glucogenesis stimulated by SARS-CoV-2 in vitro and lowers elevated fasting blood glucose levels in infected mice. In patients with COVID-19, plasma GP73 levels are elevated and positively correlate with blood glucose levels. Our data suggest that GP73 is a glucogenic hormone that likely contributes to SARS-CoV-2-induced abnormalities in systemic glucose metabolism.

DOI: https://doi.org/10.1038/s42255-021-00508-2
Nat Metab. 2022 Jan 03.

Viral infection as an NAD+ battlefield.

Charles Brenner.

DOI: https://doi.org/10.1038/s42255-021-00507-3
JCI Insight. 2022 Jan 06. pii: e146563. [Epub ahead of print]

Human CD206+ macrophages associate with diabetes and adipose tissue lymphoid clusters.

Lindsey A Muir, Kae Won Cho, Lynn M Geletka, Nicki A Baker, Carmen G Flesher, Anne P Ehlers, Niko Kaciroti, Stephen Lindsly, Scott Ronquist, Indika Rajapakse, Robert W O'Rourke, Carey N Lumeng.

  Increased adipose tissue macrophages (ATM) correlate with metabolic dysfunction in humans and are causal in development of insulin resistance in mice. Recent bulk and single cell transcriptomics studies reveal a wide spectrum of gene expression signatures possible for macrophages that depends on context, but the signatures of human ATM subtypes are not well defined in obesity and diabetes. We profiled three prominent ATM subtypes from human adipose tissue in obesity and determined their relationship to type 2 diabetes. Visceral (VAT) and subcutaneous (SAT) adipose tissue samples were collected from diabetic and non-diabetic obese subjects to evaluate cellular content and gene expression. VAT CD206+CD11c- ATMs were increased in diabetic subjects, scavenger receptor-rich with low intracellular lipids, secreted proinflammatory cytokines, and diverged significantly from two CD11c+ ATM subtypes, which were lipid-laden, lipid antigen presenting, and overlapped with monocyte signatures. Furthermore, diabetic VAT was enriched for CD206+CD11c- ATM and inflammatory signatures, scavenger receptors, and MHC II antigen presentation genes. VAT immunostaining found CD206+CD11c- ATMs concentrated in vascularized lymphoid clusters adjacent to CD206-CD11c+ ATMs, while CD206+CD11c+ were distributed between adipocytes. Our results suggest ATM subtype-specific profiles that uniquely contribute to the phenotypic variation in obesity.

Keywords:  Adipose tissue; Diabetes; Immunology; Macrophages; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.146563
Obes Rev. 2022 Jan 05.

Greasing the inflammatory pathogenesis of viral pneumonias in diabetes.

Michelle S M A Damen, Pablo C Alarcon, Amy S Shah, Senad Divanovic.

  Type 2 diabetes (T2D) and obesity are independent risk factors for increased morbidity and mortality associated with influenza and SARS-CoV-2 infection. Skewed cellular metabolism shapes immune cell inflammatory responsiveness and function in obesity, T2D, and infection. However, altered immune cell responsiveness and levels of systemic proinflammatory mediators, partly independent of peripheral immune cell contribution, are linked with SARS-CoV-2-associated disease severity. Despite such knowledge, the role of tissue parenchymal cell-driven inflammatory responses, and specifically those dominantly modified in obesity (e.g., adipocytes), in influenza and SARS-CoV-2 infection pathogenesis remain poorly defined. Whether obesity-dependent skewing of adipocyte cellular metabolism uncovers inflammatory clades and promotes the existence of a 'pathogenic-inflammatory' adipocyte phenotype that amplifies SARS-CoV-2 infection diseases severity in individuals with obesity and individuals with obesity and T2D has not been examined. Here, using the knowledge gained from studies of immune cell responses in obesity, T2D, and infection, we highlight the key knowledge gaps underlying adipocyte cellular functions that may sculpt and grease pathogenic processes associated with influenza and SARS-CoV-2 disease severity in diabetes.

Keywords:  SARS-CoV2; adipocytes; diabetes; immunometabolism; obesity

DOI:  https://doi.org/10.1111/obr.13415
Semin Immunol. 2021 Dec 29. pii: S1044-5323(21)00073-7. [Epub ahead of print] 101542

Promotion of trained innate immunity by nanoparticles.

Natalia Muñoz-Wolf, Ed C Lavelle.

  The dogma that immunological memory is an exclusive trait of adaptive immunity has been recently challenged by studies showing that priming of innate cells can also result in modified long-term responsiveness to secondary stimuli, once the cells have returned to a non-activated state. This phenomenon is known as 'innate immune memory', 'trained immunity' or 'innate training'. While the main known triggers of trained immunity are microbial-derived molecules such as β-glucan, endogenous particles such as oxidized low-density lipoprotein and monosodium urate crystals can also induce trained phenotypes in innate cells. Whether exogenous particles can induce trained immunity has been overlooked. Our exposure to particulates has dramatically increased in recent decades as a result of the broad medical use of particle-based drug carriers, theragnostics, adjuvants, prosthetics and an increase in environmental pollution. We recently showed that pristine graphene can induce trained immunity in macrophages, enhancing their inflammatory response to TLR agonists, proving that exogenous nanomaterials can affect the long-term response of innate cells. The consequences of trained immunity can be beneficial, for instance, enhancing protection against unrelated pathogens; however, they can also be deleterious if they enhance inflammatory disorders. Therefore, studying the ability of particulates and biomaterials to induce innate trained phenotypes in cells is warranted. Here we analyse the mechanisms whereby particles can induce trained immunity and discuss how physicochemical characteristics of particulates could influence the induction of innate memory. We review the implications of trained immunity in the context of particulate adjuvants, nanocarriers and nanovaccines and their potential applications in medicine. Finally, we reflect on the unanswered questions and the future of the field.

Keywords:  Biomaterials; Epigenetic remodeling; Innate memory; Metabolic reprogramming; Nanoparticles; Trained immunity

DOI:  https://doi.org/10.1016/j.smim.2021.101542
Cancer Sci. 2022 Jan 02.

C1QBP regulates T cells mitochondrial fitness to affect their survival, proliferation and anti-tumor immune function.

Hui Tian, Gang Wang, Qiping Wang, Baofu Zhang, Guan Jiang, Huizhong Li, Dafei Chai, Lin Fang, Meng Wang, Junnian Zheng.

  T cells survival, proliferation and anti-tumor response are tightly linked to their mitochondrial health. Complement C1q binding protein (C1QBP) promotes the mitochondrial fitness through regulation of mitochondrial metabolism and morphology. However, whether C1QBP regulates T cells survival, proliferation and anti-tumor immune function remains unclear. Our data demonstrated that C1QBP knocking down induced the accumulation of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential to impair T cells mitochondrial fitness. At the same time, C1QBP insufficiency led to the less recruitment of the anti-apoptotic proteins including Bcl-2 and Bcl-XL to repress caspase-3 activation and PARP cleavage, which consequently accelerated T cells apoptotic process. On the other hand, C1QBP knocking-down rendered T cells with the relatively weaker proliferation due to the inhibition of AKT/mTOR signaling pathway. In order to investigate the exact role of C1QBP in anti-tumor response, C1QBP+/- and C1QBP+/+ mice were given the subcutaneous injection of murine MC38 cells, respectively. We found that C1QBP deficiency attenuated T cells tumor infiltration and aggravated these tumor-infiltrating T lymphocytes (TILs) exhaustion. Moreover, we further clarified the potential function of C1QBP in the chimeric antigen receptor (CAR)-T cells immunotherapy. Our data showed that C1QBP+/- CAR-T cells exhibited relatively weaker anti-tumor response than the corresponding C1QBP+/+ CAR-T cells. Given that C1QBP knocking down impairs T cells anti-apoptotic capacity, proliferation as well as anti-tumor immune function, development of the strategy to potentiation of T cells mitochondrial fitness through C1QBP would have a promise to optimize their efficacy of the related immunotherapy.

Keywords:  Anti-tumor immune function; C1QBP; Mitochondrial fitness; Proliferation; T cells survival

DOI:  https://doi.org/10.1111/cas.15261
J Clin Invest. 2022 Jan 04. pii: e148546. [Epub ahead of print]132(1):

Targeting memory T cell metabolism to improve immunity.

Mauro Corrado, Erika L Pearce.

Vaccination affords protection from disease by activating pathogen-specific immune cells and facilitating the development of persistent immunologic memory toward the vaccine-specific pathogen. Current vaccine regimens are often based on the efficiency of the acute immune response, and not necessarily on the generation of memory cells, in part because the mechanisms underlying the development of efficient immune memory remain incompletely understood. This Review describes recent advances in defining memory T cell metabolism and how metabolism of these cells might be altered in patients affected by mitochondrial diseases or metabolic syndrome, who show higher susceptibility to recurrent infections and higher rates of vaccine failure. It discusses how this new understanding could add to the way we think about immunologic memory, vaccine development, and cancer immunotherapy.

DOI: https://doi.org/10.1172/JCI148546
Front Immunol. 2021 ;12 765477

Intracellular NAD+ Depletion Confers a Priming Signal for NLRP3 Inflammasome Activation.

Do-Wan Shim, Hyo-Joung Cho, Inhwa Hwang, Taek-Yeol Jung, Hyun-Seok Kim, Ju Hee Ryu, Je-Wook Yu.

  Nicotinamide adenine dinucleotide (NAD+) is an important cofactor in many redox and non-redox NAD+-consuming enzyme reactions. Intracellular NAD+ level steadily declines with age, but its role in the innate immune potential of myeloid cells remains elusive. In this study, we explored whether NAD+ depletion by FK866, a highly specific inhibitor of the NAD salvage pathway, can affect pattern recognition receptor-mediated responses in macrophages. NAD+-depleted mouse bone marrow-derived macrophages (BMDMs) exhibited similar levels of proinflammatory cytokine production in response to LPS or poly (I:C) stimulation compared with untreated cells. Instead, FK866 facilitated robust caspase-1 activation in BMDMs in the presence of NLRP3-activating signals such as ATP and nigericin, a potassium ionophore. However, this FK866-mediated caspase-1 activation was completely abolished in Nlrp3-deficient macrophages. FK866 plus nigericin stimulation caused an NLRP3-dependent assembly of inflammasome complex. In contrast, restoration of NAD+ level by supplementation with nicotinamide mononucleotide abrogated the FK866-mediated caspase-1 cleavage. FK866 did not induce or increase the expression levels of NLRP3 and interleukin (IL)-1β but drove mitochondrial retrograde transport into the perinuclear region. FK866-nigericin-induced mitochondrial transport is critical for caspase-1 cleavage in macrophages. Consistent with the in vitro experiments, intradermal coinjection of FK866 and ATP resulted in robust IL-1β expression and caspase-1 activation in the skin of wild-type, but not Nlrp3-deficient mice. Collectively, our data suggest that NAD+ depletion provides a non-transcriptional priming signal for NLRP3 activation via mitochondrial perinuclear clustering, and aging-associated NAD+ decline can trigger NLRP3 inflammasome activation in ATP-rich environments.

Keywords:  NAD; aging; inflammasome; macrophage; proinflammatory

DOI:  https://doi.org/10.3389/fimmu.2021.765477
Acta Physiol (Oxf). 2022 Jan 06. e13782

Costly immunometabolic remodeling in disused muscle buildup through physical exercise.

Camila S Padilha, Caique Figueiredo, Rafael Deminice, Karsten Krüger, Marília Seelaender, José Cesar Rosa-Neto, Fabio S Lira.

  The mechanisms underlying the immunometabolic disturbances during skeletal muscle atrophy caused by a plethora of circumstances ranging from hospitalization to spaceflight missions, remain unknown. Here, we outline the possible pathways that might be dysregulated in such conditions and assess the potential of physical exercise to mitigate and promote the recovery of muscle morphology, metabolism, and function after intervals of disuse. Studies applying exercise to attenuate disuse-induced muscle atrophy have shown a pivotal role of circulating myokines in the activation of anabolic signaling pathways. These muscle-derived factors induce accretion of contractile proteins in the myofibers, and at the same time decrease protein breakdown and loss. Regular exercise plays a crucial role in re-establishing adequate immunometabolism and increasing the migration and presence in the muscle of macrophages with an anti-inflammatory phenotype (M2) and T regulatory cells (Tregs) after disease-induced muscle loss. Additionally, the switch in metabolic pathways (glycolysis to oxidative phosphorylation [OXPHOS]) is important for achieving rapid metabolic homeostasis during muscle regeneration. In this review, we discuss the molecular aspects of the immunometabolic response elicited by exercise during skeletal muscle regeneration. There is not, nevertheless, consensus on a single optimal intensity of exercise required to improve muscle strength, mass, and functional capacity owing to the wide range of exercise protocols studied so far. Despite the absence of agreement on the specific strategy, physical exercise appears as a powerful complementary strategy to attenuate the harmful effects of muscle disuse in different scenarios.

Keywords:  cell metabolism; disuse; exercise; muscle remodeling; unloaded muscle

DOI:  https://doi.org/10.1111/apha.13782
Cell Rep. 2022 Jan 04. pii: S2211-1247(21)01680-6. [Epub ahead of print]38(1): 110180

Salmonella enterica serovar Typhimurium uses anaerobic respiration to overcome propionate-mediated colonization resistance.

Catherine D Shelton, Woongjae Yoo, Nicolas G Shealy, Teresa P Torres, Jacob K Zieba, M Wade Calcutt, Nora J Foegeding, Dajeong Kim, Jinshil Kim, Sangryeol Ryu, Mariana X Byndloss.

  The gut microbiota benefits the host by limiting enteric pathogen expansion (colonization resistance), partially via the production of inhibitory metabolites. Propionate, a short-chain fatty acid produced by microbiota members, is proposed to mediate colonization resistance against Salmonella enterica serovar Typhimurium (S. Tm). Here, we show that S. Tm overcomes the inhibitory effects of propionate by using it as a carbon source for anaerobic respiration. We determine that propionate metabolism provides an inflammation-dependent colonization advantage to S. Tm during infection. Such benefit is abolished in the intestinal lumen of Salmonella-infected germ-free mice. Interestingly, S. Tm propionate-mediated intestinal expansion is restored when germ-free mice are monocolonized with Bacteroides thetaiotaomicron (B. theta), a prominent propionate producer in the gut, but not when mice are monocolonized with a propionate-production-deficient B. theta strain. Taken together, our results reveal a strategy used by S. Tm to mitigate colonization resistance by metabolizing microbiota-derived propionate.

Keywords:  Salmonella; colonization resistance; gut microbiota; intestinal inflammation; microbial metabolism; propionate

DOI:  https://doi.org/10.1016/j.celrep.2021.110180