bims-imicid 2022-11-13 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022‒11‒13
thirty-one papers selected by
Dylan Ryan
University of Cambridge

LRG1 is an adipokine that promotes insulin sensitivity and suppresses inflammation.
CD1d-dependent rewiring of lipid metabolism in macrophages regulates innate immune responses.
Glycolytic activity in human immune cells: inter-individual variation and functional implications during health and diabetes.
SLC7A8 is a key amino acids supplier for the metabolic programs that sustain homeostasis and activation of type 2 innate lymphoid cells.
Age-induced prostaglandin E2 impairs mitochondrial fitness and increases mortality to influenza infection.
Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC).
Lactate facilitates classical swine fever virus replication by enhancing cholesterol biosynthesis.
Obesity enhances antiviral immunity in the genital mucosa through a microbiota-mediated effect on γδ T cells.
Pyrroloquinoline Quinone Administration Alleviates Allergic Airway Inflammation in Mice by Regulating the JAK-STAT Signaling Pathway.
Steroid hormone regulation of immune responses in cancer.
Role of CAR T Cell Metabolism for Therapeutic Efficacy.
Astaxanthin Exerts Immunomodulatory Effect by Regulating SDH-HIF-1α Axis and Reprogramming Mitochondrial Metabolism in LPS-Stimulated RAW264.7 Cells.
Mycobacterium tuberculosis ketol-acid reductoisomerase down-regulation affects its ability to persist, and its survival in macrophages and in mice.
Cellular Stress-Induced Metabolites in Escherichia coli.
Butyrate: Connecting the gut-lung axis to the management of pulmonary disorders.
Secreted immune metabolites that mediate immune cell communication and function.
EGFR tyrosine kinase activity and Rab GTPases coordinate EGFR trafficking to regulate macrophage activation in sepsis.
Using a multiomics approach to unravel a septic shock specific signature in skeletal muscle.
Reprogramming Metabolism to Enhance Kidney Tolerance during Sepsis: The Role of Fatty Acid Oxidation, Aerobic Glycolysis, and Epithelial De-Differentiation.
Metabolic Reprogramming in Tumor-Associated Macrophages in the Ovarian Tumor Microenvironment.
Inhibition of Glucose Uptake Blocks Proliferation but Not Cytotoxic Activity of NK Cells.
M. tuberculosis curli pili (MTP) facilitates a reduction of microbicidal activity of infected THP-1 macrophages during early stages of infection.
MsrB1-regulated GAPDH oxidation plays programmatic roles in shaping metabolic and inflammatory signatures during macrophage activation.
Cytokine and metabolic regulation of adipose tissue Tregs.
IGF1R is a mediator of sex-specific metabolism in mice: Effects of age and high-fat diet.
Metabolite activation of tumorigenic signaling pathways in the tumor microenvironment.
Non-heme iron overload impairs monocyte to macrophage differentiation via mitochondrial oxidative stress.
Role of metabolic reprogramming in pro-inflammatory cytokine secretion from LPS or silica-activated macrophages.
The intersection of metabolism and inflammation is governed by the intracellular topology of hexokinases and the metabolic fate of glucose.
Regulatory T cells as metabolic sensors.
Defining newly formed and tissue-resident bone marrow-derived macrophages in adult mice based on lysozyme expression.

Elife. 2022 Nov 08. pii: e81559. [Epub ahead of print]11

LRG1 is an adipokine that promotes insulin sensitivity and suppresses inflammation.

Chan Hee J Choi, William Barr, Samir Zaman, Corey Model, Annsea Park, Mascha Koenen, Zeran Lin, Sarah K Szwed, François Marchildon, Audrey Crane, Thomas S Carroll, Henrik Molina, Paul Cohen.

  While dysregulation of adipocyte endocrine function plays a central role in obesity and its complications, the vast majority of adipokines remain uncharacterized. We employed bio-orthogonal non-canonical amino acid tagging (BONCAT) and mass spectrometry to comprehensively characterize the secretome of murine visceral and subcutaneous white and interscapular brown adipocytes. Over 600 proteins were identified, the majority of which showed cell type-specific enrichment. We here describe a metabolic role for leucine-rich α-2 glycoprotein 1 (LRG1) as an obesity-regulated adipokine secreted by mature adipocytes. LRG1 overexpression significantly improved glucose homeostasis in diet-induced and genetically obese mice. This was associated with markedly reduced white adipose tissue macrophage accumulation and systemic inflammation. Mechanistically, we found LRG1 binds cytochrome c in circulation to dampen its pro-inflammatory effect. These data support a new role for LRG1 as an insulin sensitizer with therapeutic potential given its immunomodulatory function at the nexus of obesity, inflammation, and associated pathology.

Keywords:  cell biology; mouse

DOI:  https://doi.org/10.7554/eLife.81559
Nat Commun. 2022 Nov 07. 13(1): 6723

CD1d-dependent rewiring of lipid metabolism in macrophages regulates innate immune responses.

Phillip M Brailey, Lauren Evans, Juan Carlos López-Rodríguez, Anthony Sinadinos, Victoria Tyrrel, Gavin Kelly, Valerie O'Donnell, Peter Ghazal, Susan John, Patricia Barral.

Alterations in cellular metabolism underpin macrophage activation, yet little is known regarding how key immunological molecules regulate metabolic programs in macrophages. Here we uncover a function for the antigen presenting molecule CD1d in the control of lipid metabolism. We show that CD1d-deficient macrophages exhibit a metabolic reprogramming, with a downregulation of lipid metabolic pathways and an increase in exogenous lipid import. This metabolic rewiring primes macrophages for enhanced responses to innate signals, as CD1d-KO cells show higher signalling and cytokine secretion upon Toll-like receptor stimulation. Mechanistically, CD1d modulates lipid import by controlling the internalization of the lipid transporter CD36, while blocking lipid uptake through CD36 restores metabolic and immune responses in macrophages. Thus, our data reveal CD1d as a key regulator of an inflammatory-metabolic circuit in macrophages, independent of its function in the control of T cell responses.

DOI: https://doi.org/10.1038/s41467-022-34532-x
Immunometabolism (Cobham). 2022 Oct;4(4): e00008

Glycolytic activity in human immune cells: inter-individual variation and functional implications during health and diabetes.

Frank Vrieling, Xanthe A M H van Dierendonck, Martin Jaeger, Anna W M Janssen, Anneke Hijmans, Mihai G Netea, Cees J Tack, Rinke Stienstra.

  An increase in glucose uptake driving aerobic glycolysis is a robust hallmark of immune cell activation. The glycolytic response supports functional alterations of the innate immune cells including the production and release of cytokines. Large inter-individual differences in the magnitude of this cytokine response are known to exist. In addition, the presence of disease is known to impact on immune cell function. Whether variation in metabolic responses of immune cells exist between individuals during health or disease is currently unknown. Here, we explore inter-individual differences in the glycolytic rate of immune cells using lactate production as readout upon activation using a variety of different stimuli. Glycolytic responses are subsequently associated to functional immune cell responses in healthy humans. In addition, we determined the glycolytic rate of immune cells and its association with immune function using patients diagnosed with diabetes mellitus. Based on the relative increase in lactate production after activation, distinct clusters of low, intermediate, and high responders could be identified, illustrating the existence of variation in glycolytic responses in healthy subjects. Interestingly, the production of cytokines mirrored these high-, intermediate-, and low-lactate patterns after pathogenic stimulation. In patients with diabetes mellitus, a reduced correlation was found between lactate and cytokine production, specifically for IL-6. Furthermore, based on the relative increase in lactate production, variability in the glycolytic response was reduced compared to healthy subjects. In conclusion, our results show a specific association between the glycolytic rate and function in human immune cells after stimulation with different pathogens. In addition to demonstrating the existence of glycolytic variability and specificity depending on the type of stimulus, the association between glycolysis and function in innate immune cells is altered during the presence of diabetes.

Keywords:  glycolysis; human immune cell function; lactate

DOI:  https://doi.org/10.1097/IN9.0000000000000008
Proc Natl Acad Sci U S A. 2022 11 16. 119(46): e2215528119

SLC7A8 is a key amino acids supplier for the metabolic programs that sustain homeostasis and activation of type 2 innate lymphoid cells.

Santosh K Panda, Do-Hyun Kim, Pritesh Desai, Patrick F Rodrigues, Raki Sudan, Susan Gilfillan, Marina Cella, Steven J Van Dyken, Marco Colonna.

 Group 2 innate lymphoid cells (ILC2) are innate counterparts of T helper 2 (Th2) cells that maintain tissue homeostasis and respond to injuries through rapid interleukin (IL)-5 and IL-13 secretion. ILC2s depend on availability of arginine and branched-chain amino acids for sustaining cellular fitness, proliferation, and cytokine secretion in both steady state and upon activation. However, the contribution of amino acid transporters to ILC2 functions is not known. Here, we found that ILC2s selectively express Slc7a8, encoding a transporter for arginine and large amino acids. Slc7a8 was expressed in ILC2s in a tissue-specific manner in steady state and was further increased upon activation. Genetic ablation of Slc7a8 in lymphocytes reduced the frequency of ILC2s, suppressed IL-5 and IL-13 production upon stimulation, and impaired type 2 immune responses to helminth infection. Consistent with this, Slc7a8-deficient ILC2s also failed to induce cytokine production and recruit eosinophils in a model of allergic lung inflammation. Mechanistically, reduced amino acid availability due to Slc7a8 deficiency led to compromised mitochondrial oxidative phosphorylation, as well as impaired activation of mammalian target of rapamycin and c-Myc signaling pathways. These findings identify Slc7a8 as a key supplier of amino acids for the metabolic programs underpinning fitness and activation of ILC2s.

Keywords: allergy; amino acid; asthma; innate lymphoid cells; transporter

DOI: https://doi.org/10.1073/pnas.2215528119
Nat Commun. 2022 Nov 09. 13(1): 6759

Age-induced prostaglandin E2 impairs mitochondrial fitness and increases mortality to influenza infection.

Judy Chen, Jane C Deng, Rachel L Zemans, Karim Bahmed, Beata Kosmider, Min Zhang, Marc Peters-Golden, Daniel R Goldstein.

Aging impairs the immune responses to influenza A virus (IAV), resulting in increased mortality to IAV infections in older adults. However, the factors within the aged lung that compromise host defense to IAV remain unknown. Using a murine model and human samples, we identified prostaglandin E2 (PGE2), as such a factor. Senescent type II alveolar epithelial cells (AECs) are overproducers of PGE2 within the aged lung. PGE2 impairs the proliferation of alveolar macrophages (AMs), critical cells for defense against respiratory pathogens, via reduction of oxidative phosphorylation and mitophagy. Importantly, blockade of the PGE2 receptor EP2 in aged mice improves AM mitochondrial function, increases AM numbers and enhances survival to IAV infection. In conclusion, our study reveals a key mechanism that compromises host defense to IAV, and possibly other respiratory infections, with aging and suggests potential new therapeutic or preventative avenues to protect against viral respiratory disease in older adults.

DOI: https://doi.org/10.1038/s41467-022-34593-y
Metabolites. 2022 Oct 26. pii: 1026. [Epub ahead of print]12(11):

Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC).

Vamsi P Guntur, Travis Nemkov, Esther de Boer, Michael P Mohning, David Baraghoshi, Francesca I Cendali, Inigo San-Millán, Irina Petrache, Angelo D'Alessandro.

  Exercise intolerance is a major manifestation of post-acute sequelae of severe acute respiratory syndrome coronavirus infection (PASC, or "long-COVID"). Exercise intolerance in PASC is associated with higher arterial blood lactate accumulation and lower fatty acid oxidation rates during graded exercise tests to volitional exertion, suggesting altered metabolism and mitochondrial dysfunction. It remains unclear whether the profound disturbances in metabolism that have been identified in plasma from patients suffering from acute coronavirus disease 2019 (COVID-19) are also present in PASC. To bridge this gap, individuals with a history of previous acute COVID-19 infection that did not require hospitalization were enrolled at National Jewish Health (Denver, CO, USA) and were grouped into those that developed PASC (n = 29) and those that fully recovered (n = 16). Plasma samples from the two groups were analyzed via mass spectrometry-based untargeted metabolomics and compared against plasma metabolic profiles of healthy control individuals (n = 30). Observational demographic and clinical data were retrospectively abstracted from the medical record. Compared to plasma of healthy controls or individuals who recovered from COVID-19, PASC plasma exhibited significantly higher free- and carnitine-conjugated mono-, poly-, and highly unsaturated fatty acids, accompanied by markedly lower levels of mono-, di- and tricarboxylates (pyruvate, lactate, citrate, succinate, and malate), polyamines (spermine) and taurine. Plasma from individuals who fully recovered from COVID-19 exhibited an intermediary metabolic phenotype, with milder disturbances in fatty acid metabolism and higher levels of spermine and taurine. Of note, depletion of tryptophan-a hallmark of disease severity in COVID-19-is not normalized in PASC patients, despite normalization of kynurenine levels-a tryptophan metabolite that predicts mortality in hospitalized COVID-19 patients. In conclusion, PASC plasma metabolites are indicative of altered fatty acid metabolism and dysfunctional mitochondria-dependent lipid catabolism. These metabolic profiles obtained at rest are consistent with previously reported mitochondrial dysfunction during exercise, and may pave the way for therapeutic intervention focused on restoring mitochondrial fat-burning capacity.

Keywords:  exercise intolerance; keyword post-acute sequelae of COVID-19; long COVID; metabolomics; plasma

DOI:  https://doi.org/10.3390/metabo12111026
iScience. 2022 Nov 18. 25(11): 105353

Lactate facilitates classical swine fever virus replication by enhancing cholesterol biosynthesis.

Xiaodong Zou, Yang Yang, Feng Lin, Jiahuan Chen, Huanyu Zhang, Linquan Li, Hongsheng Ouyang, Daxin Pang, Linzhu Ren, Xiaochun Tang.

  An emerging topic in virology is that viral replication is closely linked with the metabolic reprogramming of host cells. Understanding the effects of reprogramming host cell metabolism due to classical swine fever virus (CSFV) infection and the underling mechanisms would facilitate controlling the spread of classical swine fever (CSF). In the current study, we found that CSFV infection enhanced aerobic glycolysis in PK-15 cells. Blocking glycolysis with 2-deoxy-d-glycose or disrupting the enzymes PFKL and LDHA decreased CSFV replication. Lactate was identified as an important molecule in CSFV replication, independent of the pentose phosphate pathway and tricarboxylic acid cycle. Further analysis demonstrated that the accumulated lactate in cells promoted cholesterol biosynthesis, which facilitated CSFV replication and disrupted the type I interferon response during CSFV replication, and the disruption of cholesterol synthesis abolished the lactate effects on CSFV replication. The results provided more insights into the complex pathological mechanisms of CSFV.

Keywords:  Human metabolism; Virology

DOI:  https://doi.org/10.1016/j.isci.2022.105353
Cell Rep. 2022 Nov 08. pii: S2211-1247(22)01459-0. [Epub ahead of print]41(6): 111594

Obesity enhances antiviral immunity in the genital mucosa through a microbiota-mediated effect on γδ T cells.

Jang Hyun Park, In Kang, Hyeon Cheol Kim, Younghoon Lee, Sung Ki Lee, Heung Kyu Lee.

  Obesity is detrimental to the immune system. It impairs lymphatics, T cell development, and lymphopoiesis; induces dysfunction of antitumor immunity; and also promotes tumor progression. However, direct evidence of the impact of obesity on viral infection is lacking. We report a protective role of obesity against herpes simplex virus 2 infection of the genital mucosa in mice. Although conventional antiviral immunity is comparable between obese mice and lean mice, obesity enhances the cytotoxic subset of γδ T cells. This effect is mediated by L-arginine produced by commensal microbiota in the genital mucosa, which induces "pseudonormoxia" of γδ T cells, resulting in increased natural killer (NK) group 2 D (NKG2D) expression of γδ T cells through the downregulation of hypoxia-inducible factor 1-alpha (HIF1A) by inducing nitric oxide (NO) production, thereby protecting mice from lethal genital herpes. Thus, our work illuminates one mechanism by which obesity-induced compositional changes in the vaginal microbiota can affect mucosal immune responses against viral infection.

Keywords:  CP: Immunology; CP: Microbiology; HSV-2; L-arginine; genital mucosa; obesity; viral infection; γδ T cells

DOI:  https://doi.org/10.1016/j.celrep.2022.111594
Mediators Inflamm. 2022 ;2022 1267841

Pyrroloquinoline Quinone Administration Alleviates Allergic Airway Inflammation in Mice by Regulating the JAK-STAT Signaling Pathway.

Zhihui Min, Jiebai Zhou, Ruolin Mao, Bo Cui, Yunfeng Cheng, Zhihong Chen.

The current asthma therapies are inadequate for many patients with severe asthma. Pyrroloquinoline quinone (PQQ) is a naturally-occurring redox cofactor and nutrient that can exert a multitude of physiological effects, including anti-inflammatory and antioxidative effects. We sought to explore the effects of PQQ on allergic airway inflammation and reveal the underlying mechanisms. In vitro, the effects of PQQ on the secretion of epithelial-derived cytokines by house dust mite- (HDM-) incubated 16-HBE cells and on the differentiation potential of CD4+ T cells were investigated. In vivo, PQQ was administered to mice with ovalbumin- (OVA-) induced asthma, and lung pathology and inflammatory cell infiltration were assessed. The changes in T cell subsets and signal transducers and activators of transcription (STATs) were evaluated by flow cytometry. Pretreatment with PQQ significantly decreased HDM-stimulated thymic stromal lymphopoietin (TSLP) production in a dose-dependent manner in 16-HBE cells and inhibited Th2 cell differentiation in vitro. Treatment with PQQ significantly reduced bronchoalveolar lavage fluid (BALF) inflammatory cell counts in the OVA-induced mouse model. PQQ administration also changed the secretion of IFN-γ and IL-4 as well as the percentages of Th1, Th2, Th17, and Treg cells in the peripheral blood and lung tissues, along with inhibition the phosphorylation of STAT1, STAT3, and STAT6 while promoting that of STAT4 in allergic airway inflammation model mice. PQQ can alleviate allergic airway inflammation in mice by improving the immune microenvironment and regulating the JAK-STAT signaling pathway. Our findings suggest that PQQ has great potential as a novel therapeutic agent for inflammatory diseases, including asthma.

DOI: https://doi.org/10.1155/2022/1267841
Immunometabolism (Cobham). 2022 Oct;4(4): e00012

Steroid hormone regulation of immune responses in cancer.

Ana C Anderson, Nandini Acharya.

  Steroid hormones are derived from cholesterol and can be classified into sex hormones (estrogens, androgens, progesterone) that are primarily synthesized in the gonads and adrenal hormones (glucocorticoids and mineralocorticoids) that are primarily synthesized in the adrenal gland. Although, it has long been known that steroid hormones have potent effects on the immune system, recent studies have led to renewed interest in their role in regulating anti-tumor immunity. Extra-glandular cells, such as epithelial cells and immune cells, have been shown to synthesize glucocorticoids and thereby modulate immune responses in the tumor microenvironment. Additionally, new insight into the role of androgens on immune cell responses have shed light on mechanisms underpinning the observed sex bias in cancer survival outcomes. Here, we review the role of steroid hormones, specifically glucocorticoids and androgens, in regulating anti-tumor immunity and discuss how their modulation could pave the way for designing novel therapeutic strategies to improve anti-tumor immune responses.

Keywords:  T cell dysfunction/exhaustion; androgens; cancer; glucocorticoids; immunotherapy; sex bias

DOI:  https://doi.org/10.1097/IN9.0000000000000012
Cancers (Basel). 2022 Nov 04. pii: 5442. [Epub ahead of print]14(21):

Role of CAR T Cell Metabolism for Therapeutic Efficacy.

Judit Rial Saborido, Simon Völkl, Michael Aigner, Andreas Mackensen, Dimitrios Mougiakakos.

  Chimeric antigen receptor (CAR) T cells hold enormous potential. However, a substantial proportion of patients receiving CAR T cells will not reach long-term full remission. One of the causes lies in their premature exhaustion, which also includes a metabolic anergy of adoptively transferred CAR T cells. T cell phenotypes that have been shown to be particularly well suited for CAR T cell therapy display certain metabolic characteristics; whereas T-stem cell memory (TSCM) cells, characterized by self-renewal and persistence, preferentially meet their energetic demands through oxidative phosphorylation (OXPHOS), effector T cells (TEFF) rely on glycolysis to support their cytotoxic function. Various parameters of CAR T cell design and manufacture co-determine the metabolic profile of the final cell product. A co-stimulatory 4-1BB domain promotes OXPHOS and formation of central memory T cells (TCM), while T cells expressing CARs with CD28 domains predominantly utilize aerobic glycolysis and differentiate into effector memory T cells (TEM). Therefore, modification of CAR co-stimulation represents one of the many strategies currently being investigated for improving CAR T cells' metabolic fitness and survivability within a hostile tumor microenvironment (TME). In this review, we will focus on the role of CAR T cell metabolism in therapeutic efficacy together with potential targets of intervention.

Keywords:  CAR T cells; bioenergetics; immune escape; immunometabolism; metabolism; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers14215442
Mar Drugs. 2022 Oct 25. pii: 660. [Epub ahead of print]20(11):

Astaxanthin Exerts Immunomodulatory Effect by Regulating SDH-HIF-1α Axis and Reprogramming Mitochondrial Metabolism in LPS-Stimulated RAW264.7 Cells.

Luchuanyang Sun, Sangeun Kim, Ryoichi Mori, Nobuyuki Miyaji, Takeshi Nikawa, Katsuya Hirasaka.

  Astaxanthin (AX) is a carotenoid that exerts potent antioxidant activity and acts in cell membranes and mitochondria, which consist of the bilayer molecules. Targeting mitochondria to ameliorate inflammatory diseases by regulating mitochondrial metabolism has become possible and topical. Although AX has been shown to have anti-inflammatory effects in various cells, the mechanisms are quite different. In particular, the role of AX on mitochondrial metabolism in macrophages is still unknown. In this study, we investigated the effect of AX on mitochondria-mediated inflammation and its mechanisms in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. AX attenuated the mitochondrial O2- production and maintained the mitochondrial membrane potential, implying that AX preserved mitochondrial homeostasis to avoid LPS stimulation-induced mitochondrial dysfunction. Additionally, AX prevented the decrease in mitochondrial complexes I, II, and III, which were caused by LPS stimulation. Especially, AX inhibited the reduction in mitochondrial succinate dehydrogenase (SDH; complex II) activity and upregulated the protein and mRNA level of SDH complex, subunit B. Furthermore, AX blocked the IL-1β expression by regulating the SDH-HIF-1α axis and suppressed the energy shift from an OXPHOS phenotype to a glycolysis phenotype. These findings revealed important effects of AX on mitochondrial enzymes as well as on mitochondrial energy metabolism in the immune response. In addition, these raised the possibility that AX plays an important role in other diseases caused by SDH mutation and metabolic disorders.

Keywords:  astaxanthin; hypoxia-inducible factor-1α; interleukin-1β; mitochondrial ROS; mitochondrial energy metabolism; mitochondrial succinate dehydrogenase

DOI:  https://doi.org/10.3390/md20110660
Microbes Infect. 2022 Nov-Dec;24(8):pii: S1286-4579(22)00070-3. [Epub ahead of print]24(8): 105000

Mycobacterium tuberculosis ketol-acid reductoisomerase down-regulation affects its ability to persist, and its survival in macrophages and in mice.

Nirbhay Singh, Anu Chauhan, Ram Kumar, Sudheer Kumar Singh.

  Branched-chain amino acids (BCAAs) leucine, isoleucine and valine biosynthetic pathways have been reported from plants, fungi and bacteria including Mycobacterium tuberculosis (Mtb) but are absent in animals. This makes interventions with BCAAs biosynthesis an attractive proposition for antimycobacterial drug discovery. In the present study, Mycobacterium tuberculosis H37Ra (Mtb-Ra) ketol-acid reductoisomerase encoding ORF MRA_3031 was studied to establish its role in Mtb-Ra growth and survival. Recombinant knockdown (KD) and complemented (KDC) strains along with wild-type (WT) Mtb-Ra were studied under in-vitro and ex-vivo conditions. KD was defective for survival inside macrophages and showed time dependent decrease in its colony forming unit (CFU) counts, while, WT and KDC showed time dependent increase in CFUs, after macrophage infection. Also, KD showed reduced ability to form persister cells, had altered membrane permeability against ethidium bromide and nile red dyes, and had reduced biofilm maturation, compared to WT and KDC. The in-vivo studies showed that KD infected mice had lower CFU counts in lungs, compared to WT. In summary Mtb shows survival deficit in macrophages and in mice after ketol-acid reductoisomerase down-regulation.

Keywords:  Branched-chain amino acids; Ketol-acid reductoisomerase; Macrophage and in-vivo survival; Mycobacterium tuberculosis; Permeability; Persistence

DOI:  https://doi.org/10.1016/j.micinf.2022.105000
J Nat Prod. 2022 Nov 08.

Cellular Stress-Induced Metabolites in Escherichia coli.

Alexandra Gatsios, Chung Sub Kim, Autumn G York, Richard A Flavell, Jason M Crawford.

Escherichia coli isolates commonly inhabit the human microbiota, yet the majority of E. coli's small-molecule repertoire remains uncharacterized. We previously employed erythromycin-induced translational stress to facilitate the characterization of autoinducer-3 (AI-3) and structurally related pyrazinones derived from "abortive" tRNA synthetase reactions in pathogenic, commensal, and probiotic E. coli isolates. In this study, we explored the "missing" tryptophan-derived pyrazinone reaction and characterized two other families of metabolites that were similarly upregulated under erythromycin stress. Strikingly, the abortive tryptophanyl-tRNA synthetase reaction leads to a tetracyclic indole alkaloid metabolite (1) rather than a pyrazinone. Furthermore, erythromycin induced two naphthoquinone-functionalized metabolites (MK-hCys, 2; and MK-Cys, 3) and four lumazines (7-10). Using genetic and metabolite analyses coupled with biomimetic synthesis, we provide support that the naphthoquinones are derived from 4-dihydroxy-2-naphthoic acid (DHNA), an intermediate in the menaquinone biosynthetic pathway, and the amino acids homocysteine and cysteine. In contrast, the lumazines are dependent on a flavin intermediate and α-ketoacids from the aminotransferases AspC and TyrB. We show that one of the lumazine members (9), an indole-functionalized analogue, possesses antioxidant properties, modulates the anti-inflammatory fate of isolated TH17 cells, and serves as an aryl-hydrocarbon receptor (AhR) agonist. These three systems described here serve to illustrate that new metabolic branches could be more commonly derived from well-established primary metabolic pathways.

DOI: https://doi.org/10.1021/acs.jnatprod.2c00706
Front Nutr. 2022 ;9 1011732

Butyrate: Connecting the gut-lung axis to the management of pulmonary disorders.

Renan Oliveira Corrêa, Pollyana Ribeiro Castro, René Moser, Caroline Marcantonio Ferreira, Valerie F J Quesniaux, Marco Aurélio Ramirez Vinolo, Bernhard Ryffel.

  Short-chain fatty acids (SCFAs) are metabolites released by bacterial components of the microbiota. These molecules have a wide range of effects in the microbiota itself, but also in host cells in which they are known for contributing to the regulation of cell metabolism, barrier function, and immunological responses. Recent studies indicate that these molecules are important players in the gut-lung axis and highlight the possibility of using strategies that alter their intestinal production to prevent or treat distinct lung inflammatory diseases. Here, we review the effects of the SCFA butyrate and its derivatives in vitro and in vivo on murine models of respiratory disorders, besides discussing the potential therapeutic use of butyrate and the other SCFAs in lung diseases.

Keywords:  butyrate; inflammation; lung-gut axis; pulmonary disorders; short-chain fatty acids (SCFA)

DOI:  https://doi.org/10.3389/fnut.2022.1011732
Trends Immunol. 2022 Nov 05. pii: S1471-4906(22)00214-9. [Epub ahead of print]

Secreted immune metabolites that mediate immune cell communication and function.

Baihao Zhang, Alexis Vogelzang, Sidonia Fagarasan.

  Metabolites are emerging as essential factors for the immune system that are involved in both metabolic circuits and signaling cascades. Accumulated evidence suggests that altered metabolic programs initiated by the activation and maturation of immune cell types are accompanied by the delivery of various metabolites into the local environment. We propose that, in addition to protein/peptide ligands, secreted immune metabolites (SIMets) are essential components of immune communication networks that fine-tune immune responses under homeostatic and pathological conditions. We summarize recent advances in our understanding of SIMets and discuss the potential mechanisms by which some metabolites engage in immunological responses through receptor-, transporter-, and post-translational-mediated regulation. These insights may contribute to understanding physiology and developing effective therapeutics for inflammatory and immune-mediated diseases.

Keywords:  flux of metabolites; immune cell subsets; modification; receptor; transporter

DOI:  https://doi.org/10.1016/j.it.2022.10.006
Cell Death Dis. 2022 Nov 07. 13(11): 934

EGFR tyrosine kinase activity and Rab GTPases coordinate EGFR trafficking to regulate macrophage activation in sepsis.

Xuedi Zhang, Cuiping Chen, Chunxiu Ling, Shuhua Luo, Ziying Xiong, Xiaolei Liu, Chaoxiong Liao, Pengyun Xie, Youtan Liu, Liangqing Zhang, Zhanghui Chen, Zhifeng Liu, Jing Tang.

EGFR phosphorylation is required for TLR4-mediated macrophage activation during sepsis. However, whether and how intracellular EGFR is transported during endotoxemia have largely been unknown. Here, we show that LPS promotes high levels cell surface expression of EGFR in macrophages through two different transport mechanisms. On one hand, Rab10 is required for EEA1-mediated the membrane translocation of EGFR from the Golgi. On the other hand, EGFR phosphorylation prevents its endocytosis in a kinase activity-dependent manner. Erlotinib, an EGFR tyrosine kinase inhibitor, significantly reduced membrane EGFR expression in LPS-activated macrophage. Mechanistically, upon LPS induced TLR4/EGFR phosphorylation, MAPK14 phosphorylated Rab7a at S72 impaired membrane receptor late endocytosis, which maintains EGFR membrane localization though blocking its lysosomal degradation. Meanwhile, Rab5a is also involved in the early endocytosis of EGFR. Subsequently, inhibition of EGFR phosphorylation switches M1 phenotype to M2 phenotype and alleviates sepsis-induced acute lung injury. Mechanistic study demonstrated that Erlotinib suppressed glycolysis-dependent M1 polarization via PKM2/HIF-1ɑ pathway and promoted M2 polarization through up-regulating PPARγ induced glutamine metabolism. Collectively, our data elucidated a more in-depth mechanism of macrophages activation, and provided stronger evidence supporting EGFR as a potential therapeutic target for the treatment of sepsis.

DOI: https://doi.org/10.1038/s41419-022-05370-y
Sci Rep. 2022 Nov 05. 12(1): 18776

Using a multiomics approach to unravel a septic shock specific signature in skeletal muscle.

Baptiste Duceau, Michael Blatzer, Jean Bardon, Thibault Chaze, Quentin Giai Gianetto, Florence Castelli, François Fenaille, Lucie Duarte, Thomas Lescot, Christophe Tresallet, Bruno Riou, Mariette Matondo, Olivier Langeron, Pierre Rocheteau, Fabrice Chrétien, Adrien Bouglé.

Sepsis is defined as a dysregulated host response to infection leading to organs failure. Among them, sepsis induces skeletal muscle (SM) alterations that contribute to acquired-weakness in critically ill patients. Proteomics and metabolomics could unravel biological mechanisms in sepsis-related organ dysfunction. Our objective was to characterize a distinctive signature of septic shock in human SM by using an integrative multi-omics approach. Muscle biopsies were obtained as part of a multicenter non-interventional prospective study. Study population included patients in septic shock (S group, with intra-abdominal source of sepsis) and two critically ill control populations: cardiogenic shock (C group) and brain dead (BD group). The proteins and metabolites were extracted and analyzed by High-Performance Liquid Chromatography-coupled to tandem Mass Spectrometry, respectively. Fifty patients were included, 19 for the S group (53% male, 64 ± 17 years, SAPS II 45 ± 14), 12 for the C group (75% male, 63 ± 4 years, SAPS II 43 ± 15), 19 for the BD group (63% male, 58 ± 10 years, SAPS II 58 ± 9). Biopsies were performed in median 3 days [interquartile range 1-4]) after intensive care unit admission. Respectively 31 patients and 40 patients were included in the proteomics and metabolomics analyses of 2264 proteins and 259 annotated metabolites. Enrichment analysis revealed that mitochondrial pathways were significantly decreased in the S group at protein level: oxidative phosphorylation (adjusted p = 0.008); branched chained amino acids degradation (adjusted p = 0.005); citrate cycle (adjusted p = 0.005); ketone body metabolism (adjusted p = 0.003) or fatty acid degradation (adjusted p = 0.008). Metabolic reprogramming was also suggested (i) by the differential abundance of the peroxisome proliferator-activated receptors signaling pathway (adjusted p = 0.007), and (ii) by the accumulation of fatty acids like octanedioic acid dimethyl or hydroxydecanoic. Increased polyamines and depletion of mitochondrial thioredoxin or mitochondrial peroxiredoxin indicated a high level of oxidative stress in the S group. Coordinated alterations in the proteomic and metabolomic profiles reveal a septic shock signature in SM, highlighting a global impairment of mitochondria-related metabolic pathways, the depletion of antioxidant capacities, and a metabolic shift towards lipid accumulation.ClinicalTrial registration: NCT02789995. Date of first registration 03/06/2016.

DOI: https://doi.org/10.1038/s41598-022-23544-8
Nephron. 2022 Nov 04. 1-4

Reprogramming Metabolism to Enhance Kidney Tolerance during Sepsis: The Role of Fatty Acid Oxidation, Aerobic Glycolysis, and Epithelial De-Differentiation.

Hernando Gómez.

  BACKGROUND: The recognition that sepsis induces acute kidney injury (AKI) in the absence of overt necrosis or apoptosis and even in the presence of increased renal blood flow has led to the consideration that kidney tubular epithelial cells (TECs) may deploy defense mechanisms to survive the insult.SUMMARY: This concept dovetails well with the notion that the defense against infection not only depends on the capacity of the immune system to limit the microbial burden or resistance capacity but also on the capacity of the host to limit tissue injury, collectively known as tolerance. To sustain the high energy requirement that ion transport mandates, kidney TECs use fatty acid oxidation (FAO) as one of the preferred sources of energy. Inflammatory processes like endotoxemia and sepsis decrease mitochondrial FAO and hinder mitochondrial respiration. Impaired FAO is associated with TEC de-differentiation, loss of kidney function, and TEC injury through lipotoxicity and oxidative stress in the acute setting, and with maladaptive repair and fibrosis after AKI in the latter stages. AMP-activated protein kinase (AMPK) is a master regulator of energy and promoter of FAO that can be activated pharmacologically to protect against AKI and death during experimental sepsis, operating through a tolerance mechanism.
KEY MESSAGES: Organ dysfunction during sepsis is the expression of tissue injury and adaptive defense mechanisms operating through resistance or tolerance that prioritize cell survival over organ function. Metabolic reprogramming away from FAO/oxidative phosphorylation seems to be a common pathological denominator throughout the AKI continuum that may be targeted through the activation of AMPK.

Keywords:  Acute kidney injury; Metabolism; Mitochondria; Sepsis; Tolerance

DOI:  https://doi.org/10.1159/000527392
Cancers (Basel). 2022 Oct 25. pii: 5224. [Epub ahead of print]14(21):

Metabolic Reprogramming in Tumor-Associated Macrophages in the Ovarian Tumor Microenvironment.

Sudhir Kumar, Sonam Mittal, Prachi Gupta, Mona Singh, Pradeep Chaluvally-Raghavan, Sunila Pradeep.

  The interaction between tumor cells and macrophages in the tumor microenvironment plays an essential role in metabolic changes in macrophages and reprograms them towards a pro-tumorigenic phenotype. Increasing evidence indicates that macrophage metabolism is a highly complex process and may not be as simple as previously thought. Pro-inflammatory stimuli switch macrophages towards an M1-like phenotype and rely mainly on aerobic glycolysis and fatty acid synthesis, whereas anti-inflammatory stimuli switch macrophages towards an M2-like phenotype. M2-like macrophages depend more on oxidative phosphorylation (OXPHOS) and fatty acid oxidation. However, this metabolically reprogrammed phenotypic switch in macrophages remained a mystery for a while. Therefore, through this review, we tend to describe how macrophage immunometabolism determines macrophage phenotypes and functions in tumor microenvironments (TMEs). Furthermore, we have discussed how metabolic reprogramming in TAM can be used for therapeutic intervention and drug resistance in ovarian cancer.

Keywords:  extracellular vesicles (EVs); metabolic reprogramming; metabolism; ovarian cancer; tumor microenvironment (TME); tumor-associated macrophages (TAMs)

DOI:  https://doi.org/10.3390/cancers14215224
Cells. 2022 Nov 03. pii: 3489. [Epub ahead of print]11(21):

Inhibition of Glucose Uptake Blocks Proliferation but Not Cytotoxic Activity of NK Cells.

Lea Katharina Picard, Elisabeth Littwitz-Salomon, Herbert Waldmann, Carsten Watzl.

  Tumor cells often have very high energy demands. Inhibition of glucose uptake is therefore a possible approach to limit the proliferation and survival of transformed cells. However, immune cells also require energy to initiate and to maintain anti-tumor immune reactions. Here, we investigate the effect of Glutor, an inhibitor of glucose transporters, on the function of human Natural Killer (NK) cells, which are important for the immunosurveillance of cancer. Glutor treatment effectively inhibits glycolysis in NK cells. However, acute treatment with the inhibitor has no effect on NK cell effector functions. Prolonged inhibition of glucose uptake by Glutor prevents the proliferation of NK cells, increases their pro-inflammatory regulatory function and reduces the stimulation-dependent production of IFN-γ. Interestingly, even after prolonged Glutor treatment NK cell cytotoxicity and serial killing activity were still intact, demonstrating that cytotoxic NK cell effector functions are remarkably robust against metabolic disturbances.

Keywords:  cytokines; degranulation; glucose transporter; metabolism; natural killer cells

DOI:  https://doi.org/10.3390/cells11213489
Comp Immunol Microbiol Infect Dis. 2022 Nov 04. pii: S0147-9571(22)00164-3. [Epub ahead of print]90-91 101907

M. tuberculosis curli pili (MTP) facilitates a reduction of microbicidal activity of infected THP-1 macrophages during early stages of infection.

Shinese Ashokcoomar, Kajal Soulakshana Reedoy, Du Toit Loots, Derylize Beukes, Mari van Reenen, Balakrishna Pillay, Manormoney Pillay.

  Mycobacterium tuberculosis (M. tuberculosis) curli pili (MTP) is a surface located adhesin, which is involved in the initial point-of-contact between the pathogen and the host. Host-pathogen interaction is essential for establishing infection. M. tuberculosis has the ability to infect various host lung cell types, which includes both the epithelial cells and macrophages, and subsequent differences in their cellular function will be evident in their metabolic profiles. Understanding the differences between these cell types and their individual metabolic response to M. tuberculosis infection, with and without the presence of the MTP, will aid to better elucidate the role of this adhesin in modulating metabolic pathways during infection. This may further contribute to the development of improved diagnostic and therapeutic interventions, much needed at present in order to improve control the global tuberculosis (TB) epidemic. This study used a two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GC×GC-TOFMS) metabolomics approach to compare the metabolite profiles of A549 epithelial cells to that of THP-1 macrophages, infected with M. tuberculosis, in the presence and absence of MTP. Significant metabolites were identified using various univariate and multivariate statistical analysis. A total of 44, 40, 50 and 34 metabolites were differentially detected when comparing the (a) uninfected A549 epithelial cells to uninfected THP-1 macrophages, (b) wild-type infected A549 epithelial cells to wild-type infected THP-1 macrophages, (c) ∆mtp-infected A549 epithelial cells to ∆mtp-infected THP-1 macrophages (d) complement-infected A549 epithelial cells to complement-infected THP-1 macrophages, respectively. These included metabolites that were involved in amino acid metabolism, fatty acid metabolism, general central carbon metabolism, and nucleic acid metabolism. In the absence of the M. tuberculosis MTP adhesin, the THP-1 macrophages predominantly displayed higher concentrations of amino acids and their metabolic intermediates, than the A549 epithelial cells. The deletion of MTP from M. tuberculosis in the host infection models potentially elicited a pro-inflammatory phenotype, particularly in the macrophage model. In the presence of MTP, the metabolite profile changes indicate potential regulation of host defence mechanisms, accompanied by a reduction in microbicidal abilities of host cells. Hence MTP can be considered a virulence factor of M. tuberculosis. Therefore, blocking MTP interaction with the host may facilitate a faster pathogen clearance during the initial stages of infection, and potentially enhance current therapeutic interventions.

Keywords:  A549 epithelial cells; Adhesin; GC×GC-TOFMS; Infection; M. tuberculosis; MTP; Metabolomics; THP-1 macrophages

DOI:  https://doi.org/10.1016/j.cimid.2022.101907
Cell Rep. 2022 Nov 08. pii: S2211-1247(22)01463-2. [Epub ahead of print]41(6): 111598

MsrB1-regulated GAPDH oxidation plays programmatic roles in shaping metabolic and inflammatory signatures during macrophage activation.

Hyun Jung Yoo, Dong Wook Choi, Yeon Jin Roh, Yoon-Mi Lee, Ji-Hong Lim, Soohak Eo, Ho-Jae Lee, Na Young Kim, Seohyun Kim, Sumin Cho, Gyumin Im, Byung Cheon Lee, Ji Hyung Kim.

  Classically activated pro-inflammatory macrophages are generated from naive macrophages by pro-inflammatory cues that dynamically reprogram their fuel metabolism toward glycolysis. This increases their intracellular reactive oxygen species (ROS) levels, which then activate the transcription and release of pro-inflammatory mediators. Our study on mice that lack methionine sulfoxide reductase (Msr)-B1 shows that the resulting partial loss of protein methionine reduction in pro-inflammatory macrophages creates a unique metabolic signature characterized by altered fuel utilization, including glucose and pyruvate. This change also associates with hyper-inflammation that is at least partly due to sustained oxidation of an exposed methionine residue (M44) on glyceraldehyde 3-phosphate dehydrogenase (GAPDH), thereby inducing GAPDH aggregation, inflammasome activation, and subsequent increased interleukin (IL)-1β secretion. Since MsrB1-knockout mice exhibit increased susceptibility to lipopolysaccharide (LPS)-induced sepsis, the MsrB1-GAPDH axis may be a key molecular mechanism by which protein redox homeostasis controls the metabolic profile of macrophages and thereby regulates their functions.

Keywords:  CP: Metabolism; GAPDH; MsrB1; ROS; inflammasome; macrophage; metabolic reprogramming; sepsis

DOI:  https://doi.org/10.1016/j.celrep.2022.111598
Immunometabolism (Cobham). 2022 Oct;4(4): e00013

Cytokine and metabolic regulation of adipose tissue Tregs.

Cody Elkins, Chaoran Li.

  Since their discovery over a decade ago, much has been learned regarding the importance and function of visceral adipose tissue (VAT)-resident regulatory T cells (Tregs). VAT Tregs play a critical role in controlling VAT inflammation and alleviating metabolic disease. However, this population is disrupted in obesity which exacerbates VAT inflammation and metabolic abnormalities. Therefore, understanding the factors governing the accumulation and maintenance of VAT Tregs, both at steady state and under disease conditions, is crucial for identifying the mechanisms underlying obesity-associated metabolic disease and developing novel therapies. Expansion and maintenance of the VAT Treg compartment is strongly influenced by factors in the local tissue microenvironment, including cytokines, T-cell receptor ligands, hormones, and various metabolites. This mini-review will primarily focus on recent advances in our understandings regarding the regulation of mouse epididymal VAT (eVAT) Tregs, which are the most thoroughly characterized VAT Treg population, by tissue microenvironmental factors and cellular metabolic processes. We will also briefly discuss the limited knowledge available regarding the regulation of mouse ovarian VAT (oVAT) Tregs and human omental VAT Tregs, highlight some lingering questions, and provide a prospective view on where the field is heading.

Keywords:  VAT Treg; cytokine; inflammation; metabolism; obesity

DOI:  https://doi.org/10.1097/IN9.0000000000000013
Front Endocrinol (Lausanne). 2022 ;13 1033208

IGF1R is a mediator of sex-specific metabolism in mice: Effects of age and high-fat diet.

Patricia Pérez-Matute, Icíar P López, María Íñiguez, Emma Recio-Fernández, Raquel Torrens, Sergio Piñeiro-Hermida, Elvira Alfaro-Arnedo, Luong Chau, Christina Walz, Andreas Hoeflich, José A Oteo, José G Pichel.

  Objective: We aimed to investigate the short and long-term metabolic consequences of IGF1R systemic gene deficiency in mice.Methods: UBC-CreERT2, Igf1rfl/fl mutant mice were used to suppress IGF1R signaling in adult tissues by inducing postnatal generalized Igf1r deletion with tamoxifen. Animals were analyzed at two different ages: i) 13-weeks old young mice, and ii) 12-months old middle-aged mice. In addition, the effects of 10 weeks-long high-fat diet (HFD) were investigated in middle-aged mice.
Results: Young IGF1R-deficient mice were insulin-resistant, with high IGF1, growth hormone (GH) and IGFBP3, as well as low IGFBP2 circulating levels. Males also presented increased triglycerides in liver. In contrast, middle-aged mice did not clearly show all of these alterations, suggesting possible compensatory effects. Middle-aged IGF1R-deficient male mice were able to counteract the negative effects induced by aging and HFD in adiposity, inflammation and glucose metabolism. A metabolic sexual dimorphism dependent on IGF1R was observed, especially in middle-aged mice.
Conclusions: These results demonstrate that IGF1R is involved in metabolic homeostasis, with effects modulated by diet-induced obesity and aging in a sex dependent manner. Thus, IGF1R deficiency in mice is proposed as a useful tool to understand metabolic alterations observed in patients with IGF1R gene deletions.

Keywords:  IGF1R; Insulin-like growth factors; aging; diet-induced obesity; fatty liver; inflammation; insulin resistance; sexual dimorphism

DOI:  https://doi.org/10.3389/fendo.2022.1033208
Sci Signal. 2022 Nov 08. 15(759): eabj4220

Metabolite activation of tumorigenic signaling pathways in the tumor microenvironment.

Vivien Low, Zhongchi Li, John Blenis.

The role of metabolites exchanged in the tumor microenvironment is largely thought of as fuels to drive the increased biosynthetic and bioenergetic demands of growing tumors. However, this view is shifting as metabolites are increasingly shown to function as signaling molecules that directly regulate oncogenic pathways. Combined with our growing understanding of the essential role of stromal cells, this shift has led to increased interest in how the collective and interconnected metabolome of the tumor microenvironment can drive malignant transformation, epithelial-to-mesenchymal transition, drug resistance, immune evasion, and metastasis. In this review, we discuss how metabolite exchange between tumors and various cell types in the tumor microenvironment-such as fibroblasts, adipocytes, and immune cells-can activate signaling pathways that drive cancer progression.

DOI: https://doi.org/10.1126/scisignal.abj4220
Front Immunol. 2022 ;13 998059

Non-heme iron overload impairs monocyte to macrophage differentiation via mitochondrial oxidative stress.

Yue Cui, Saray Gutierrez, Sheller Ariai, Lisa Öberg, Kristofer Thörn, Ulf Gehrmann, Suzanne M Cloonan, Thomas Naessens, Henric Olsson.

 Iron is a key element for systemic oxygen delivery and cellular energy metabolism. Thus regulation of systemic and local iron metabolism is key for maintaining energy homeostasis. Significant changes in iron levels due to malnutrition or hemorrhage, have been associated with several diseases such as hemochromatosis, liver cirrhosis and COPD. Macrophages are key cells in regulating iron levels in tissues as they sequester excess iron. How iron overload affects macrophage differentiation and function remains a subject of debate. Here we used an in vitro model of monocyte-to-macrophage differentiation to study the effect of iron overload on macrophage function. We found that providing excess iron as soluble ferric ammonium citrate (FAC) rather than as heme-iron complexes derived from stressed red blood cells (sRBC) interferes with macrophage differentiation and phagocytosis. Impaired macrophage differentiation coincided with increased expression of oxidative stress-related genes. Addition of FAC also led to increased levels of cellular and mitochondrial reactive oxygen species (ROS) and interfered with mitochondrial function and ATP generation. The effects of iron overload were reproduced by the mitochondrial ROS-inducer rotenone while treatment with the ROS-scavenger N-Acetylcysteine partially reversed FAC-induced effects. Finally, we found that iron-induced oxidative stress interfered with upregulation of M-CSFR and MAFB, two crucial determinants of macrophage differentiation and function. In summary, our findings suggest that high levels of non-heme iron interfere with macrophage differentiation by inducing mitochondrial oxidative stress. These findings might be important to consider in the context of diseases like chronic obstructive pulmonary disease (COPD) where both iron overload and defective macrophage function have been suggested to play a role in disease pathogenesis.

Keywords: COPD; MAFB; differentiation; heme; iron; macrophage; mitochondria; oxidative stress

DOI: https://doi.org/10.3389/fimmu.2022.998059
Front Immunol. 2022 ;13 936167

Role of metabolic reprogramming in pro-inflammatory cytokine secretion from LPS or silica-activated macrophages.

Antonella Marrocco, Luis A Ortiz.

  In the lungs, macrophages constitute the first line of defense against pathogens and foreign bodies and play a fundamental role in maintaining tissue homeostasis. Activated macrophages show altered immunometabolism and metabolic changes governing immune effector mechanisms, such as cytokine secretion characterizing their classic (M1) or alternative (M2) activation. Lipopolysaccharide (LPS)-stimulated macrophages demonstrate enhanced glycolysis, blocked succinate dehydrogenase (SDH), and increased secretion of interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). Glycolysis suppression using 2 deoxyglucose in LPS-stimulated macrophages inhibits IL-1β secretion, but not TNF-α, indicating metabolic pathway specificity that determines cytokine production. In contrast to LPS, the nature of the immunometabolic responses induced by non-organic particles, such as silica, in macrophages, its contribution to cytokine specification, and disease pathogenesis are not well understood. Silica-stimulated macrophages activate pattern recognition receptors (PRRs) and NLRP3 inflammasome and release IL-1β, TNF-α, and interferons, which are the key mediators of silicosis pathogenesis. In contrast to bacteria, silica particles cannot be degraded, and the persistent macrophage activation results in an increased NADPH oxidase (Phox) activation and mitochondrial reactive oxygen species (ROS) production, ultimately leading to macrophage death and release of silica particles that perpetuate inflammation. In this manuscript, we reviewed the effects of silica on macrophage mitochondrial respiration and central carbon metabolism determining cytokine specification responsible for the sustained inflammatory responses in the lungs.

Keywords:  M1 macrophages; complex II; electron transport chain; macrophage immunometabolism; macrophage metabolic adaptation; mitochondria; respirable crystalline silica

DOI:  https://doi.org/10.3389/fimmu.2022.936167
Immunometabolism (Cobham). 2022 Oct;4(4): e00011

The intersection of metabolism and inflammation is governed by the intracellular topology of hexokinases and the metabolic fate of glucose.

Juan F Codocedo, Gary E Landreth.

  Hexokinases (HKs) catalyze the first and irreversible step of glucose metabolism. Its product, glucose-6-phosphate (G-6P) serves as a precursor for catabolic processes like glycolysis for adenosine 5'-triphosphate (ATP) production and anabolic pathways including the pentose phosphate pathway (PPP) for the generation of intermediaries like nicotinamide adenine dinucleotide phosphate (NADPH) and ribulose-5-P. Thus, the cellular fate of glucose is important not only for growth and maintenance, but also to determine different cellular activities. Studies in immune cells have demonstrated an intimate linkage between metabolic pathways and inflammation, however the precise molecular mechanisms that determine the cellular fate of glucose during inflammation or aging are not completely understood. Here we discuss a study by De Jesus et al that describes the role of HK1 cytosolic localization as a critical regulator of glucose flux by shunting glucose into the PPP at the expense of glycolysis, exacerbating the inflammatory response of macrophages. The authors convincingly demonstrate a novel mechanism that is independent of its mitochondrial functions, but involve the association to a protein complex that inhibits glycolysis at the level of glyceraldehyde 3-phosphate dehydrogenase. We expand the discussion by comparing previous studies related to the HK2 isoform and how cells have evolved to regulate the mitochondrial association of these two isoforms by non-redundant mechanism.

Keywords:  glucose; hexokinase

DOI:  https://doi.org/10.1097/IN9.0000000000000011
Immunity. 2022 Nov 08. pii: S1074-7613(22)00547-7. [Epub ahead of print]55(11): 1981-1992

Regulatory T cells as metabolic sensors.

Paola de Candia, Claudio Procaccini, Claudia Russo, Maria Teresa Lepore, Giuseppe Matarese.

  Compelling experimental evidence links immunity and metabolism. In this perspective, we propose forkhead-box-P3 (FoxP3)+CD4+CD25+ regulatory T (Treg) cells as key metabolic sensors controlling the immunological state in response to their intrinsic capacity to perceive nutritional changes. Treg cell high anabolic state in vivo, residency in metabolically crucial districts, and recirculation between lymphoid and non-lymphoid sites enable them to recognize the metabolic cues and adapt their intracellular metabolism and anti-inflammatory function at the paracrine and systemic levels. As privileged regulators at the interface between neuroendocrine and immune systems, the role of Treg cells in maintaining metabolic homeostasis makes these cells promising targets of therapeutic strategies aimed at restoring organismal homeostasis not only in autoimmune but also metabolic disorders.

Keywords:  Treg cells; autoimmunity; immunometabolism; metabolic disease

DOI:  https://doi.org/10.1016/j.immuni.2022.10.006
Cell Mol Immunol. 2022 Nov 08.

Defining newly formed and tissue-resident bone marrow-derived macrophages in adult mice based on lysozyme expression.

Tong Lei, Jiayu Zhang, Qian Zhang, Xinran Ma, Yanan Xu, Yang Zhao, Lianfeng Zhang, Zhongbing Lu, Yong Zhao.

  Tissue-resident macrophages are derived from different precursor cells and display different phenotypes. Reconstitution of the tissue-resident macrophages of inflamed or damaged tissues in adults can be achieved by bone marrow-derived monocytes/macrophages. Using lysozyme (Lysm)-GFP-reporter mice, we found that alveolar macrophages (AMs), Kupffer cells, red pulp macrophages (RpMacs), and kidney-resident macrophages were Lysm-GFP-, whereas all monocytes in the fetal liver, adult bone marrow, and blood were Lysm-GFP+. Donor-derived Lysm-GFP+ resident macrophages gradually became Lysm-GFP- in recipients and developed gene expression profiles characteristic of tissue-resident macrophages. Thus, Lysm may be used to distinguish newly formed and long-term surviving tissue-resident macrophages that were derived from bone marrow precursor cells in adult mice under pathological conditions. Furthermore, we found that Irf4 might be essential for resident macrophage differentiation in all tissues, while cytokine and receptor pathways, mTOR signaling pathways, and fatty acid metabolic processes predominantly regulated the differentiation of RpMacs, Kupffer cells, and kidney macrophages, respectively. Deficiencies in ST2, mechanistic target of rapamycin (mTOR) and fatty acid-binding protein 5 (FABP5) differentially impaired the differentiation of tissue-resident macrophages from bone marrow-derived monocytes/macrophages in the lungs, liver, and kidneys. These results indicate that a combination of shared and unique signaling pathways coordinately shape tissue-resident macrophage differentiation in various tissues.

Keywords:  Cytokine; Inflammation; Kupffer cells; Lysozyme; Metabolism; Tissue-resident macrophages

DOI:  https://doi.org/10.1038/s41423-022-00936-4