bims-imicid 2023-11-12 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023–11–12
25 papers selected by
Dylan Ryan, University of Cambridge

Interferon signaling drives epithelial metabolic reprogramming to promote secondary bacterial infection.
Fumarate hydratase as a metabolic regulator of immunity.
Formaldehyde promotes tumor-associated macrophage polarizations and functions through induction of HIF-1α-mediated glycolysis.
13C tracer analysis reveals the landscape of metabolic checkpoints in human CD8+ T cell differentiation and exhaustion.
Engineering metabolism to modulate immunity.
Myeloid cell ACE shapes cellular metabolism and function in PCSK-9 induced atherosclerosis.
Altered kynurenine pathway metabolism and association with disease activity in patients with systemic lupus.
Maladaptive T-Cell Metabolic Fitness in Autoimmune Diseases.
Immuno-metabolic dendritic cell vaccine signatures associate with overall survival in vaccinated melanoma patients.
Amino acid metabolism reprogramming: shedding new light on T cell anti-tumor immunity.
Gut microbiota-mediated IL-22 alleviates metabolic inflammation.
M. tb Rv0927c suppresses the activation of HIF-1α pathway through VHL-mediated ubiquitination and NF-κB/COX-2 pathway to enhance mycobacteria survival.
A metabolic gene survey pinpoints fucosylation as a key pathway underlying the suppressive function of regulatory T cells in cancer.
Drug screen identifies verteporfin as a regulator of lipid metabolism in macrophage foam cells.
Lipid metabolism extinguishes cGAS-STING-induced inflammation.
Colonic macrophages eat and feed.
Danger-associated metabolites trigger metaflammation: a crowbar in cardiometabolic diseases.
Downregulation of 15-PGDH enhances MASH-HCC development via fatty acid-induced T-cell exhaustion.
The bidirectional immune crosstalk in metabolic dysfunction-associated steatotic liver disease.
A ketogenic diet can mitigate SARS-CoV-2 induced systemic reprogramming and inflammation.
Glycolysis-derived alanine from glia fuels neuronal mitochondria for memory in Drosophila.
Metabolomics and machine learning approaches for diagnostic and prognostic biomarkers screening in sepsis.
Plasma essential fatty acid on hospital admission is a marker of COVID-19 disease severity.
The dysfunctional immune response in renal cell carcinoma correlates with changes in the metabolic landscape of ccRCC during disease progression.
Immune inhibitory receptor-mediated immune response, metabolic adaptation, and clinical characterization in patients with COVID-19.

PLoS Pathog. 2023 Nov;19(11): e1011719

Interferon signaling drives epithelial metabolic reprogramming to promote secondary bacterial infection.

Grace P Carreno-Florez, Brian R Kocak, Matthew R Hendricks, Jeffrey A Melvin, Katrina B Mar, Jessica Kosanovich, Rachel L Cumberland, Greg M Delgoffe, Sruti Shiva, Kerry M Empey, John W Schoggins, Jennifer M Bomberger.

Clinical studies report that viral infections promote acute or chronic bacterial infections at multiple host sites. These viral-bacterial co-infections are widely linked to more severe clinical outcomes. In experimental models in vitro and in vivo, virus-induced interferon responses can augment host susceptibility to secondary bacterial infection. Here, we used a cell-based screen to assess 389 interferon-stimulated genes (ISGs) for their ability to induce chronic Pseudomonas aeruginosa infection. We identified and validated five ISGs that were sufficient to promote bacterial infection. Furthermore, we dissected the mechanism of action of hexokinase 2 (HK2), a gene involved in the induction of aerobic glycolysis, commonly known as the Warburg effect. We report that HK2 upregulation mediates the induction of Warburg effect and secretion of L-lactate, which enhances chronic P. aeruginosa infection. These findings elucidate how the antiviral immune response renders the host susceptible to secondary bacterial infection, revealing potential strategies for viral-bacterial co-infection treatment.

DOI: https://doi.org/10.1371/journal.ppat.1011719
Trends Cell Biol. 2023 Nov 06. pii: S0962-8924(23)00209-X. [Epub ahead of print]

Fumarate hydratase as a metabolic regulator of immunity.

Christian G Peace, Shane M O'Carroll, Luke A J O'Neill.

  Tricarboxylic acid (TCA) cycle metabolites have been implicated in modulating signalling pathways in immune cells. Notable examples include succinate and itaconate, which have pro- and anti-inflammatory roles, respectively. Recently, fumarate has emerged as having specific roles in macrophage activation, regulating the production of such cytokines as interleukin (IL)-10 and type I interferons (IFNs). Fumarate hydratase (FH) has been identified as a control point. Notably, FH loss in different models and cell types has been found to lead to DNA and RNA release from mitochondria which are sensed by cytosolic nucleic acid sensors including retinoic acid-inducible gene (RIG)-I, melanoma differentiation-associated protein (MDA)5, and cyclic GMP-AMP synthase (cGAS) to upregulate IFN-β production. These findings may have relevance in the pathogenesis and treatment of diseases associated with decreased FH levels such as systemic lupus erythematosus (SLE) or FH-deficient kidney cancer.

Keywords:  immunometabolism; innate immunity; interferon; mitochondria

DOI:  https://doi.org/10.1016/j.tcb.2023.10.005
Toxicol Lett. 2023 Nov 07. pii: S0378-4274(23)01087-1. [Epub ahead of print]

Formaldehyde promotes tumor-associated macrophage polarizations and functions through induction of HIF-1α-mediated glycolysis.

Qi Shu, Huijuan Ma, Tingqian Wang, Peiyao Wang, Huan Xu.

  Formaldehyde (FA) exposure has been positively correlated with many diseases including various types of cancers. However, the mechanisms of FA-related carcinogenesis are still unclear. Tumor-associated macrophages (TAMs) are the most abundant immune cells in tumor microenvironment, which is a heterogeneous population consist of both pro-inflammatory (M1) and immunosuppressive (M2) cells. TAMs are deeply involved in tumor development and progression. Our previous studies demonstrated that FA enhanced M1 polarization of macrophages through induction of HIF-1α-mediated glycolysis. To examine if TAM polarizations are also potentiated by FA, BALB/c nude mice were inoculated with A549 cells to develop subcutaneous tumors and exposed to 2.0mg/m3 FA for 14 days. Significant increases of both M1 and M2 polarizations of TAMs were observed in tumor tissues of FA-exposed mice. After confirmation of the potentiation effects in RAW264.7 and THP-1-derived in vitro TAM models, FA at 25 and 50μM was found to enhance TAM immunosuppressive functions and glycolytic metabolism. In addition, FA-induced glycolysis in TAMs was reversed by a specific HIF-1α inhibitor PX-478 at 5μM, and suppression of glycolytic metabolism with a glucose analog 2-DG at 1mM also alleviated FA-potentiated TAM functions, which indicated that FA induced TAM polarizations through the upregulation of HIF-1α-mediated glycolysis. These results illustrated a potential carcinogenic mechanism of FA through metabolic disturbance of tumor immunity, which could be utilized to develop preventative or therapeutic agents for FA-induced carcinogenesis and immune disorders.

Keywords:  Formaldehyde; Glycolytic metabolism; HIF-1α; T cell suppression; Tumor cell proliferation; Tumor-associated macrophage

DOI:  https://doi.org/10.1016/j.toxlet.2023.11.002
Front Immunol. 2023 ;14 1267816

13C tracer analysis reveals the landscape of metabolic checkpoints in human CD8+ T cell differentiation and exhaustion.

Alexander Kirchmair, Niloofar Nemati, Giorgia Lamberti, Marcel Trefny, Anne Krogsdam, Anita Siller, Paul Hörtnagl, Petra Schumacher, Sieghart Sopper, Adolf Sandbichler, Alfred Zippelius, Bart Ghesquière, Zlatko Trajanoski.

   Introduction: Naïve T cells remain in an actively maintained state of quiescence until activation by antigenic signals, upon which they start to proliferate and generate effector cells to initiate a functional immune response. Metabolic reprogramming is essential to meet the biosynthetic demands of the differentiation process, and failure to do so can promote the development of hypofunctional exhausted T cells.
Methods: Here we used 13C metabolomics and transcriptomics to study the metabolism of CD8+ T cells in their complete course of differentiation from naïve over stem-like memory to effector cells and in exhaustion-inducing conditions.
Results: The quiescence of naïve T cells was evident in a profound suppression of glucose oxidation and a decreased expression of ENO1, downstream of which no glycolytic flux was detectable. Moreover, TCA cycle activity was low in naïve T cells and associated with a downregulation of SDH subunits. Upon stimulation and exit from quiescence, the initiation of cell growth and proliferation was accompanied by differential expression of metabolic enzymes and metabolic reprogramming towards aerobic glycolysis with high rates of nutrient uptake, respiration and lactate production. High flux in anabolic pathways imposed a strain on NADH homeostasis, which coincided with engagement of the proline cycle for mitochondrial redox shuttling. With acquisition of effector functions, cells increasingly relied on glycolysis as opposed to oxidative phosphorylation, which was, however, not linked to changes in mitochondrial abundance. In exhaustion, decreased effector function concurred with a reduction in mitochondrial metabolism, glycolysis and amino acid import, and an upregulation of quiescence-associated genes, TXNIP and KLF2, and the T cell suppressive metabolites succinate and itaconate.
Discussion: Overall, these results identify multiple metabolic features that regulate quiescence, proliferation and effector function, but also exhaustion of CD8+ T cells during differentiation. Thus, targeting these metabolic checkpoints may be a promising therapeutic strategy for both prevention of exhaustion and promotion of stemness of anti-tumor T cells.

Keywords:  13C tracer analysis; RNA sequencing; differentiation; exhaustion; immunometabolism; stem cell memory cells

DOI:  https://doi.org/10.3389/fimmu.2023.1267816
Adv Drug Deliv Rev. 2023 Nov 05. pii: S0169-409X(23)00437-4. [Epub ahead of print] 115122

Engineering metabolism to modulate immunity.

Senta M Kapnick, Corinne A Martin, Christopher M Jewell.

  Metabolic programming and reprogramming have emerged as pivotal mechanisms for altering immune cell function. Thus, immunometabolism has become an attractive target area for treatment of immune-mediated disorders. Nonetheless, many hurdles to delivering metabolic cues persist. In this review, we consider how biomaterials are poised to transform manipulation of immune cell metabolism through integrated control of metabolic configurations to affect outcomes in autoimmunity, regeneration, transplant, and cancer. We emphasize the features of nanoparticles and other biomaterials that permit delivery of metabolic cues to the intracellular compartment of immune cells, or strategies for altering signals in the extracellular space. We then provide perspectives on the potential for reciprocal regulation of immunometabolism by the physical properties of materials themselves. Lastly, opportunities for clinical translation are highlighted. This discussion contributes to our understanding of immunometabolism, biomaterials-based strategies for altering metabolic configurations in immune cells, and emerging concepts in this evolving field.

Keywords:  biomaterials; immune engineering; immunometabolism

DOI:  https://doi.org/10.1016/j.addr.2023.115122
Front Immunol. 2023 ;14 1278383

Myeloid cell ACE shapes cellular metabolism and function in PCSK-9 induced atherosclerosis.

DuoYao Cao, Suguru Saito, LiMin Xu, Wei Fan, Xiaomo Li, Faizan Ahmed, Predrag Jovanovic, Tomohiro Shibata, Mingtian Che, Ellen A Bernstein, Jorge Gianni, Ajit S Divakaruni, Derick Okwan-Duodu, Zakir Khan, Celine E Riera, Fanfan Chen, Kenneth E Bernstein.

  The pathogenesis of atherosclerosis is defined by impaired lipid handling by macrophages which increases intracellular lipid accumulation. This dysregulation of macrophages triggers the accumulation of apoptotic cells and chronic inflammation which contributes to disease progression. We previously reported that mice with increased macrophage-specific angiotensin-converting enzyme, termed ACE10/10 mice, resist atherosclerosis in an adeno-associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9)-induced model. This is due to increased lipid metabolism by macrophages which contributes to plaque resolution. However, the importance of ACE in peripheral blood monocytes, which are the primary precursors of lesional-infiltrating macrophages, is still unknown in atherosclerosis. Here, we show that the ACE-mediated metabolic phenotype is already triggered in peripheral blood circulating monocytes and that this functional modification is directly transferred to differentiated macrophages in ACE10/10 mice. We found that Ly-6Clo monocytes were increased in atherosclerotic ACE10/10 mice. The monocytes isolated from atherosclerotic ACE10/10 mice showed enhanced lipid metabolism, elevated mitochondrial activity, and increased adenosine triphosphate (ATP) levels which implies that ACE overexpression is already altered in atherosclerosis. Furthermore, we observed increased oxygen consumption (VO2), respiratory exchange ratio (RER), and spontaneous physical activity in ACE10/10 mice compared to WT mice in atherosclerotic conditions, indicating enhanced systemic energy consumption. Thus, ACE overexpression in myeloid lineage cells modifies the metabolic function of peripheral blood circulating monocytes which differentiate to macrophages and protect against atherosclerotic lesion progression due to better lipid metabolism.

Keywords:  Ly-6Clo; angiotensin converting enzyme (ACE); atherosclerosis; lipid metabolism; macrophages; monocytes

DOI:  https://doi.org/10.3389/fimmu.2023.1278383
Amino Acids. 2023 Nov 05.

Altered kynurenine pathway metabolism and association with disease activity in patients with systemic lupus.

Duygu Eryavuz Onmaz, Dilek Tezcan, Sema Yilmaz, Mustafa Onmaz, Ali Unlu.

  Systemic lupus erythematosus (SLE) is an autoimmune disease accompanied by increased release of proinflammatory cytokines that are known to activate the indoleamine 2,3-dioxygenase (IDO-1) enzyme, which catalyzes the rate-limiting step of the kynurenine pathway (KP). This study aimed to measure KP metabolite levels in patients with SLE and investigate the relationship between disease activity, clinical findings, and KP. The study included 100 patients with SLE and 100 healthy controls. Serum tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxyanthranilic acid (3HAA), 3-hydroxykynurenine (3HK), quinolinic acid (QA) concentrations were measured with tandem mass spectrometry. Serum KYN, KYNA, 3HAA, 3HK, and QA levels of the patients with SLE were significantly higher than the control group. Serum QA levels were elevated in patients with neurological involvement (four patients with peripheral neuropathy and two patients with mononeuropathy), serum KYN levels and KYN/TRP ratio increased in patients with joint involvement, and serum KYN, 3HK, and 3HAA levels and the KYN/TRP ratio were increased in patients with renal involvement. Moreover, KYN and KYN/TRP ratios were positively correlated with the disease activity score. These findings indicated that imbalances in KP metabolites may be associated with the pathogenesis, activation, and clinical manifestations of SLE.

Keywords:  Cytokines; Inflammation; Kynurenine pathway; Systemic lupus erythematosus; Tryptophan

DOI:  https://doi.org/10.1007/s00726-023-03353-7
Cells. 2023 Oct 29. pii: 2541. [Epub ahead of print]12(21):

Maladaptive T-Cell Metabolic Fitness in Autoimmune Diseases.

Irene Rose Antony, Brandon Han Siang Wong, Dermot Kelleher, Navin Kumar Verma.

  Immune surveillance and adaptive immune responses, involving continuously circulating and tissue-resident T-lymphocytes, provide host defense against infectious agents and possible malignant transformation while avoiding autoimmune tissue damage. Activation, migration, and deployment of T-cells to affected tissue sites are crucial for mounting an adaptive immune response. An effective adaptive immune defense depends on the ability of T-cells to dynamically reprogram their metabolic requirements in response to environmental cues. Inability of the T-cells to adapt to specific metabolic demands may skew cells to become either hyporesponsive (creating immunocompromised conditions) or hyperactive (causing autoimmune tissue destruction). Here, we review maladaptive T-cell metabolic fitness that can cause autoimmune diseases and discuss how T-cell metabolic programs can potentially be modulated to achieve therapeutic benefits.

Keywords:  LFA-1; T-cell function; T-cell motility; autoimmunity; glycolysis; metabolites; psoriasis; rheumatoid arthritis

DOI:  https://doi.org/10.3390/cells12212541
Nat Commun. 2023 Nov 08. 14(1): 7211

Immuno-metabolic dendritic cell vaccine signatures associate with overall survival in vaccinated melanoma patients.

Juraj Adamik, Paul V Munson, Deena M Maurer, Felix J Hartmann, Sean C Bendall, Rafael J Argüello, Lisa H Butterfield.

Efficacy of cancer vaccines remains low and mechanistic understanding of antigen presenting cell function in cancer may improve vaccine design and outcomes. Here, we analyze the transcriptomic and immune-metabolic profiles of Dendritic Cells (DCs) from 35 subjects enrolled in a trial of DC vaccines in late-stage melanoma (NCT01622933). Multiple platforms identify metabolism as an important biomarker of DC function and patient overall survival (OS). We demonstrate multiple immune and metabolic gene expression pathway alterations, a functional decrease in OCR/OXPHOS and increase in ECAR/glycolysis in patient vaccines. To dissect molecular mechanisms, we utilize single cell SCENITH functional profiling and show patient clinical outcomes (OS) correlate with DC metabolic profile, and that metabolism is linked to immune phenotype. With single cell metabolic regulome profiling, we show that MCT1 (monocarboxylate transporter-1), a lactate transporter, is increased in patient DCs, as is glucose uptake and lactate secretion. Importantly, pre-vaccination circulating myeloid cells in patients used as precursors for DC vaccine generation are significantly skewed metabolically as are several DC subsets. Together, we demonstrate that the metabolic profile of DC is tightly associated with the immunostimulatory potential of DC vaccines from cancer patients. We link phenotypic and functional metabolic changes to immune signatures that correspond to suppressed DC differentiation.

DOI: https://doi.org/10.1038/s41467-023-42881-4
J Exp Clin Cancer Res. 2023 Nov 03. 42(1): 291

Amino acid metabolism reprogramming: shedding new light on T cell anti-tumor immunity.

Yue Zheng, Yiran Yao, Tongxin Ge, Shengfang Ge, Renbing Jia, Xin Song, Ai Zhuang.

  Metabolic reprogramming of amino acids has been increasingly recognized to initiate and fuel tumorigenesis and survival. Therefore, there is emerging interest in the application of amino acid metabolic strategies in antitumor therapy. Tremendous efforts have been made to develop amino acid metabolic node interventions such as amino acid antagonists and targeting amino acid transporters, key enzymes of amino acid metabolism, and common downstream pathways of amino acid metabolism. In addition to playing an essential role in sustaining tumor growth, new technologies and studies has revealed amino acid metabolic reprograming to have wide implications in the regulation of antitumor immune responses. Specifically, extensive crosstalk between amino acid metabolism and T cell immunity has been reported. Tumor cells can inhibit T cell immunity by depleting amino acids in the microenvironment through nutrient competition, and toxic metabolites of amino acids can also inhibit T cell function. In addition, amino acids can interfere with T cells by regulating glucose and lipid metabolism. This crucial crosstalk inspires the exploitation of novel strategies of immunotherapy enhancement and combination, owing to the unprecedented benefits of immunotherapy and the limited population it can benefit. Herein, we review recent findings related to the crosstalk between amino acid metabolism and T cell immunity. We also describe possible approaches to intervene in amino acid metabolic pathways by targeting various signaling nodes. Novel efforts to combine with and unleash potential immunotherapy are also discussed. Hopefully, some strategies that take the lead in the pipeline may soon be used for the common good.

Keywords:  Amino acid; Immunotherapy; Metabolism reprogramming; T cell; Tumor microenvironment

DOI:  https://doi.org/10.1186/s13046-023-02845-4
Life Sci. 2023 Nov 01. pii: S0024-3205(23)00864-0. [Epub ahead of print]334 122229

Gut microbiota-mediated IL-22 alleviates metabolic inflammation.

Kaijun Wang, Miao Zhou, Hongbin Si, Jie Ma.

  Low-grade chronic inflammation, also known as metabolic inflammation, promotes the development of metabolic diseases. Increasing evidence suggests that changes in gut microbes and metabolites disrupt the integrity of the gut barrier and exert significant effects on the metabolism of various tissues, including the liver and adipose tissue, thereby contributing to metabolic inflammation. We observed that IL-22 is a key signaling molecule that serves as a bridge between intestinal microbes and the host, effectively alleviating metabolic inflammation by modulating the host immunomodulatory network. Here, we focused on elucidating the underlying mechanisms by which the gut microbiota and their metabolites reduce inflammation via IL-22, highlighting the favorable impact of IL-22 on metabolic inflammation. Furthermore, we discuss the potential of IL-22 as a therapeutic target for the management of metabolic inflammation and related diseases.

Keywords:  Disease; Gut microbiota; IL-22; Inflammation; Metabolism

DOI:  https://doi.org/10.1016/j.lfs.2023.122229
Microbiol Res. 2023 Oct 20. pii: S0944-5013(23)00231-8. [Epub ahead of print]278 127529

M. tb Rv0927c suppresses the activation of HIF-1α pathway through VHL-mediated ubiquitination and NF-κB/COX-2 pathway to enhance mycobacteria survival.

Aihong Xia, Jiaxu Wan, Xin Li, Juanjuan Quan, Xiang Chen, Zhengzhong Xu, Xinan Jiao.

  Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis, employs various effector proteins to target and modulate host defenses. Our previous study showed that M. tuberculosis protein Rv0927c can promote the survival of intracellular mycobacteria, but the underlying mechanisms remain poorly understood. Here, we found that Rv0927c inhibited Mycobacterium smegmatis (M. smegmatis) induced hypoxia-inducible factor-1α (HIF-1α) activation in macrophages, and HIF-1α is required for Rv0927c to promote mycobacteria survival. Western blot analysis showed that Rv0927c promoted the proteasomal degradation of HIF-1α via Von Hippel-Lindau (VHL)-mediated ubiquitination and inhibited the nuclear localization of HIF-1α through the NF-κB/COX-2 pathway, thereby suppressing HIF-1α pathway activation. Furthermore, Rv0927c suppressed the host glycolytic metabolism, which is known to be regulated by HIF-1α and depended on the glycolysis process to promote mycobacterial survival. Our findings provide evidence that Rv0927c inhibits the activation of HIF-1α pathway, allowing pathogens to evade host immune responses, suggesting that targeting Rv0927c or HIF-1α might be a potential anti-tuberculosis therapy.

Keywords:  Glycolysis; HIF-1α pathway; Intracellular survival; Mycobacterium tuberculosis; Rv0927c

DOI:  https://doi.org/10.1016/j.micres.2023.127529
Cancer Immunol Res. 2023 Nov 07.

A metabolic gene survey pinpoints fucosylation as a key pathway underlying the suppressive function of regulatory T cells in cancer.

Sotiria Pinioti, Himal Sharma, Nina C Flerin, Qian Yu, Amalia Tzoumpa, Sarah Trusso Cafarello, Elien De Bousser, Nico Callewaert, Guillaume Oldenhove, Susan Schlenner, Bernard Thienpont, Abhishek D Garg, Mario Di Matteo, Massimiliano Mazzone.

Forkhead box P3 (Foxp3)-expressing regulatory T cells (Tregs) are the guardians of controlled immune reactions and prevent the development of autoimmune diseases. However, in the tumor context, their increased number suppresses antitumor immune responses, indicating the importance of understanding the mechanisms behind their function and stability. Metabolic reprogramming can affect Foxp3 regulation and, therefore, Treg suppressive function and fitness. Here, we performed a metabolic CRISPR/Cas9 screen and pinpointed novel candidate positive and negative metabolic regulators of Foxp3. Among the positive regulators, we revealed that targeting the GDP-fucose transporter Slc35c1, and more broadly fucosylation, in Tregs compromises their proliferation and suppressive function both in vitro and in vivo, leading to alteration of the tumor microenvironment (TME) and impaired tumor progression and pro-tumoral immune responses. Pharmacologic inhibition of fucosylation dampened tumor immunosuppression mostly by targeting Tregs, thus, resulting in reduced tumor growth. In order to substantiate these findings in humans, tumoral Tregs from colorectal cancer (CRC) patients were clustered based on the expression of fucosylation (Fuco)-related genes. FucoLOW Tregs were found to exhibit a more immunogenic profile compared to FucoHIGH Tregs. Furthermore, an enrichment of a FucoLOW signature, mainly derived from Tregs, correlated with better prognosis and response to immune checkpoint blockade in melanoma patients. In conclusion, Slc35c1-dependent fucosylation is able to regulate the suppressive function of Tregs, and measuring its expression in Tregs might pave the way towards a useful biomarker model for cancer patients.

DOI: https://doi.org/10.1158/2326-6066.CIR-22-0606
Sci Rep. 2023 Nov 09. 13(1): 19588

Drug screen identifies verteporfin as a regulator of lipid metabolism in macrophage foam cells.

Nicholas Hoeffner, Antoni Paul, Young-Hwa Goo.

Arterial macrophage foam cells are filled with cholesterol ester (CE) stored in cytosolic lipid droplets (LDs). Foam cells are central players in progression of atherosclerosis as regulators of lipid metabolism and inflammation, two major driving forces of atherosclerosis development. Thus, foam cells are considered plausible targets for intervention in atherosclerosis. However, a compound that directly regulates the lipid metabolism of LDs in the arterial foam cells has not yet been identified. In this study, we screened compounds that inhibit macrophage foam cell formation using a library of 2697 FDA-approved drugs. From the foam cells generated via loading of human oxidized low-density lipoprotein (oxLDL), we found 21 and 6 compounds that reduced and enhanced accumulations of lipids respectively. Among them, verteporfin most significantly reduced oxLDL-induced foam cell formation whereas it did not display a significant impact on foam cell formation induced by fatty acid. Mechanistically our data demonstrate that verteporfin acts via inhibition of oxLDL association with macrophages, reducing accumulation of CE. Interestingly, while other drugs that reduced foam cell formation did not have impact on pre-existing foam cells, verteporfin treatment significantly reduced their total lipids, CE, and pro-inflammatory gene expression. Together, our study identifies verteporfin as a novel regulator of foam cell lipid metabolism and inflammation and a potential compound for intervention in atherosclerosis.

DOI: https://doi.org/10.1038/s41598-023-46467-4
Nat Rev Immunol. 2023 Nov 03.

Lipid metabolism extinguishes cGAS-STING-induced inflammation.

Kirsty Minton.

DOI: https://doi.org/10.1038/s41577-023-00962-x
Cell Metab. 2023 Nov 07. pii: S1550-4131(23)00375-3. [Epub ahead of print]35(11): 1847-1848

Colonic macrophages eat and feed.

Jan Van den Bossche.

Macrophages not only secure host defense via phagocytosis but also play a key role in tissue homeostasis. A comprehensive study by Fritsch et al. reveals a novel mechanism by which macrophages in the colon deliver polyamines to epithelial cells to support self-renewal of the epithelium during periods of high proliferation.

DOI: https://doi.org/10.1016/j.cmet.2023.10.006
Pharmacol Res. 2023 Nov 04. pii: S1043-6618(23)00339-0. [Epub ahead of print] 106983

Danger-associated metabolites trigger metaflammation: a crowbar in cardiometabolic diseases.

Anlu Wang, Baoyi Guan, He Zhang, Hao Xu.

  Cardiometabolic diseases (CMDs) are characterized by a series of metabolic disorders and chronic low-grade inflammation. CMDs contribute to a high burden of mortality and morbidity worldwide. Host-microbial metabolic regulation that triggers metaflammation is an emerging field of study that promotes a new perspective for perceiving cardiovascular risks. The term metaflammation denotes the entire cascade of immune responses activated by a new class of metabolites known as "danger-associated metabolites" (DAMs). It is being proposed by the present review for the first time. We summarize current studies covering bench to bedside aspects of DAMS to better understand CMDs in the context of DAMs. We have focused on the involvement of DAMs in the pathophysiological development of CMDs, including the disruption of immune homeostasis and chronic inflammation-triggered damage leading to CMD-related adverse events, as well as emerging therapeutic approaches for targeting DAM metabolism in CMDs.

Keywords:  Danger-associated metabolites; cardiometabolic diseases; emerging therapeutic approaches; metaflammation

DOI:  https://doi.org/10.1016/j.phrs.2023.106983
JHEP Rep. 2023 Dec;5(12): 100892

Downregulation of 15-PGDH enhances MASH-HCC development via fatty acid-induced T-cell exhaustion.

Xichen Hu, Tadahito Yasuda, Noriko Yasuda-Yosihara, Atsuko Yonemura, Terumasa Umemoto, Yutaka Nakachi, Kohei Yamashita, Takashi Semba, Kota Arima, Tomoyuki Uchihara, Akiho Nishimura, Luke Bu, Lingfeng Fu, Feng Wei, Jun Zhang, Yilin Tong, Huaitao Wang, Kazuya Iwamoto, Takaichi Fukuda, Hayato Nakagawa, Koji Taniguchi, Yuji Miyamoto, Hideo Baba, Takatsugu Ishimoto.

   Background & Aims: Hepatocellular carcinoma (HCC) mainly develops from chronic hepatitis. Metabolic dysfunction-associated steatohepatitis (MASH) has gradually become the main pathogenic factor for HCC given the rising incidence of obesity and metabolic diseases. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) degrades prostaglandin 2 (PGE2), which is known to exacerbate inflammatory responses. However, the role of PGE2 accumulation caused by 15-PGDH downregulation in the development of MASH-HCC has not been determined.
Methods: We utilised the steric animal model to establish a MASH-HCC model using wild-type and 15-Pgdh+/- mice to assess the significance of PGE2 accumulation in the development of MASH-HCC. Additionally, we analysed clinical samples obtained from patients with MASH-HCC.
Results: PGE2 accumulation in the tumour microenvironment induced the production of reactive oxygen species in macrophages and the expression of cell growth-related genes and antiapoptotic genes. Conversely, the downregulation of fatty acid metabolism in the background liver promoted lipid accumulation in the tumour microenvironment, causing a decrease in mitochondrial membrane potential and CD8+ T-cell exhaustion, which led to enhanced development of MASH-HCC.
Conclusions: 15-PGDH downregulation inactivates immune surveillance by promoting the proliferation of exhausted effector T cells, which enhances hepatocyte survival and proliferation and leads to the development of MASH-HCC.
Impact and implications: The suppression of PGE2-related inflammation and subsequent lipid accumulation leads to a reduction in the severity of MASH and inhibition of subsequent progression toward MASH-HCC.

Keywords:  15-Hydroxyprostaglandin dehydrogenase; CD8+ T-cell exhaustion; Chronic inflammation; Cyclooxygenase 2; Metabolic dysfunction associated steatohepatitis-hepatocellular carcinoma; Nonalcoholic steatohepatitis-hepatocellular carcinoma; Prostaglandin E2

DOI:  https://doi.org/10.1016/j.jhepr.2023.100892
Cell Metab. 2023 Nov 07. pii: S1550-4131(23)00378-9. [Epub ahead of print]35(11): 1852-1871

The bidirectional immune crosstalk in metabolic dysfunction-associated steatotic liver disease.

Keisuke Sawada, Hak Chung, Samir Softic, Maria E Moreno-Fernandez, Senad Divanovic.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) is an unabated risk factor for end-stage liver diseases with no available therapies. Dysregulated immune responses are critical culprits of MASLD pathogenesis. Independent contributions from either the innate or adaptive arms of the immune system or their unidirectional interplay are commonly studied in MASLD. However, the bidirectional communication between innate and adaptive immune systems and its impact on MASLD remain insufficiently understood. Given that both innate and adaptive immune cells are indispensable for the development and progression of inflammation in MASLD, elucidating pathogenic contributions stemming from the bidirectional interplay between these two arms holds potential for development of novel therapeutics for MASLD. Here, we review the immune cell types and bidirectional pathways that influence the pathogenesis of MASLD and highlight potential pharmacologic approaches to combat MASLD based on current knowledge of this bidirectional crosstalk.

Keywords:  MASH; MASLD; NAFLD; NASH; adaptive immunity; immune crosstalk; innate immunity

DOI:  https://doi.org/10.1016/j.cmet.2023.10.009
Commun Biol. 2023 11 03. 6(1): 1115

A ketogenic diet can mitigate SARS-CoV-2 induced systemic reprogramming and inflammation.

Amelia Palermo, Shen Li, Johanna Ten Hoeve, Akshay Chellappa, Alexandra Morris, Barbara Dillon, Feiyang Ma, Yijie Wang, Edward Cao, Byourak Shabane, Rebeca Acín-Perez, Anton Petcherski, A Jake Lusis, Stanley Hazen, Orian S Shirihai, Matteo Pellegrini, Vaithilingaraja Arumugaswami, Thomas G Graeber, Arjun Deb.

The ketogenic diet (KD) has demonstrated benefits in numerous clinical studies and animal models of disease in modulating the immune response and promoting a systemic anti-inflammatory state. Here we investigate the effects of a KD on systemic toxicity in mice following SARS-CoV-2 infection. Our data indicate that under KD, SARS-CoV-2 reduces weight loss with overall improved animal survival. Muted multi-organ transcriptional reprogramming and metabolism rewiring suggest that a KD initiates and mitigates systemic changes induced by the virus. We observed reduced metalloproteases and increased inflammatory homeostatic protein transcription in the heart, with decreased serum pro-inflammatory cytokines (i.e., TNF-α, IL-15, IL-22, G-CSF, M-CSF, MCP-1), metabolic markers of inflammation (i.e., kynurenine/tryptophane ratio), and inflammatory prostaglandins, indicative of reduced systemic inflammation in animals infected under a KD. Taken together, these data suggest that a KD can alter the transcriptional and metabolic response in animals following SARS-CoV-2 infection with improved mice health, reduced inflammation, and restored amino acid, nucleotide, lipid, and energy currency metabolism.

DOI: https://doi.org/10.1038/s42003-023-05478-7
Nat Metab. 2023 Nov 06.

Glycolysis-derived alanine from glia fuels neuronal mitochondria for memory in Drosophila.

Yasmine Rabah, Raquel Francés, Julia Minatchy, Laura Guédon, Coraline Desnous, Pierre-Yves Plaçais, Thomas Preat.

Glucose is the primary source of energy for the brain; however, it remains controversial whether, upon neuronal activation, glucose is primarily used by neurons for ATP production or if it is partially oxidized in astrocytes, as proposed by the astrocyte-neuron lactate shuttle model for glutamatergic neurons. Thus, an in vivo picture of glucose metabolism during cognitive processes is missing. Here, we uncover in Drosophila melanogaster a glia-to-neuron alanine transfer involving alanine aminotransferase that sustains memory formation. Following associative conditioning, glycolysis in glial cells produces alanine, which is back-converted into pyruvate in cholinergic neurons of the olfactory memory center to uphold their increased mitochondrial needs. Alanine, as a mediator of glia-neuron coupling, could be an alternative to lactate in cholinergic systems. In parallel, a dedicated glial glucose transporter imports glucose specifically for long-term memory, by directly transferring it to neurons for use by the pentose phosphate pathway. Our results demonstrate in vivo the compartmentalization of glucose metabolism between neurons and glial cells during memory formation.

DOI: https://doi.org/10.1038/s42255-023-00910-y
BMC Anesthesiol. 2023 Nov 09. 23(1): 367

Metabolomics and machine learning approaches for diagnostic and prognostic biomarkers screening in sepsis.

Han She, Yuanlin Du, Yunxia Du, Lei Tan, Shunxin Yang, Xi Luo, Qinghui Li, Xinming Xiang, Haibin Lu, Yi Hu, Liangming Liu, Tao Li.

   BACKGROUND: Sepsis is a life-threatening disease with a poor prognosis, and metabolic disorders play a crucial role in its development. This study aims to identify key metabolites that may be associated with the accurate diagnosis and prognosis of sepsis.
METHODS: Septic patients and healthy individuals were enrolled to investigate metabolic changes using non-targeted liquid chromatography-high-resolution mass spectrometry metabolomics. Machine learning algorithms were subsequently employed to identify key differentially expressed metabolites (DEMs). Prognostic-related DEMs were then identified using univariate and multivariate Cox regression analyses. The septic rat model was established to verify the effect of phenylalanine metabolism-related gene MAOA on survival and mean arterial pressure after sepsis.
RESULTS: A total of 532 DEMs were identified between healthy control and septic patients using metabolomics. The main pathways affected by these DEMs were amino acid biosynthesis, phenylalanine metabolism, tyrosine metabolism, glycine, serine and threonine metabolism, and arginine and proline metabolism. To identify sepsis diagnosis-related biomarkers, support vector machine (SVM) and random forest (RF) algorithms were employed, leading to the identification of four biomarkers. Additionally, analysis of transcriptome data from sepsis patients in the GEO database revealed a significant up-regulation of the phenylalanine metabolism-related gene MAOA in sepsis. Further investigation showed that inhibition of MAOA using the inhibitor RS-8359 reduced phenylalanine levels and improved mean arterial pressure and survival rate in septic rats. Finally, using univariate and multivariate cox regression analysis, six DEMs were identified as prognostic markers for sepsis.
CONCLUSIONS: This study employed metabolomics and machine learning algorithms to identify differential metabolites that are associated with the diagnosis and prognosis of sepsis patients. Unraveling the relationship between metabolic characteristics and sepsis provides new insights into the underlying biological mechanisms, which could potentially assist in the diagnosis and treatment of sepsis.
TRIAL REGISTRATION: This human study was approved by the Ethics Committee of the Research Institute of Surgery (2021-179) and was registered by the Chinese Clinical Trial Registry (Date: 09/12/2021, ChiCTR2200055772).

Keywords:  Biomarker; Machine learning; Metabolomics; Phenylalanine metabolism; Sepsis

DOI:  https://doi.org/10.1186/s12871-023-02317-4
Sci Rep. 2023 11 03. 13(1): 18973

Plasma essential fatty acid on hospital admission is a marker of COVID-19 disease severity.

Vera C Mazurak, Irma Magaly Rivas-Serna, Sarah R Parsons, Md Monirujjaman, Krista E Maybank, Stanley K Woo, Oleksa G Rewa, Andrew J Cave, Caroline Richard, M Thomas Clandinin.

It is important for allocation of resources to predict those COVID patients at high risk of dying or organ failure. Early signals to initiate cellular events of host immunity can be derived from essential fatty acid metabolites preceding the cascade of proinflammatory signals. Much research has focused on understanding later proinflammatory responses. We assessed if remodelling of plasma phospholipid content of essential fatty acids by the COVID-19 virus provides early markers for potential death and disease severity. Here we show that, at hospital admission, COVID-19 infected subjects who survive exhibit higher proportions of C20:4n-6 in plasma phospholipids concurrent with marked proinflammatory cytokine elevation in plasma compared to healthy subjects. In contrast, more than half of subjects who die of this virus exhibit very low C18:2n-6 and C20:4n-6 content in plasma phospholipids on hospital admission compared with healthy control subjects. Moreover, in these subjects who die, the low level of primary inflammatory signals indicates limited or aberrant stimulation of host immunity. We conclude that COVID-19 infection results in early fundamental remodelling of essential fatty acid metabolism. In subjects with high mortality, it appears that plasma n-6 fatty acid content is too low to stimulate cellular events of host immunity.

DOI: https://doi.org/10.1038/s41598-023-46247-0
Cancer Immunol Immunother. 2023 Nov 08.

The dysfunctional immune response in renal cell carcinoma correlates with changes in the metabolic landscape of ccRCC during disease progression.

Nicola E Annels, M Denyer, D Nicol, S Hazell, A Silvanto, M Crockett, M Hussain, Carla Moller-Levet, Hardev Pandha.

  Renal cell carcinoma is an immunogenic tumour with a prominent dysfunctional immune cell infiltrate, unable to control tumour growth. Although tyrosine kinase inhibitors and immunotherapy have improved the outlook for some patients, many individuals are non-responders or relapse despite treatment. The hostile metabolic environment in RCC affects the ability of T-cells to maintain their own metabolic programme constraining T-cell immunity in RCC. We investigated the phenotype, function and metabolic capability of RCC TILs correlating this with clinicopathological features of the tumour and metabolic environment at the different disease stages. Flow cytometric analysis of freshly isolated TILs showed the emergence of exhausted T-cells in advanced disease based on their PD-1high and CD39 expression and reduced production of inflammatory cytokines upon in vitro stimulation. Exhausted T-cells from advanced stage disease also displayed an overall phenotype of metabolic insufficiency, characterized by mitochondrial alterations and defects in glucose uptake. Nanostring nCounter cancer metabolism assay on RNA obtained from 30 ccRCC cases revealed significant over-expression of metabolic genes even at early stage disease (pT1-2), while at pT3-4 and the locally advanced thrombi stages, there was an overall decrease in differentially expressed metabolic genes. Notably, the gene PPARGC1A was the most significantly down-regulated gene from pT1-2 to pT3-4 RCC which correlated with loss of mitochondrial function in tumour-infiltrating T-cells evident at this tumour stage. Down-regulation of PPARGC1A into stage pT3-4 may be the 'tipping-point' in RCC disease progression, modulating immune activity in ccRCC and potentially reducing the efficacy of immunotherapies in RCC and poorer patient outcomes.

Keywords:  Renal Cell carcinoma; T-cell exhaustion metabolic

DOI:  https://doi.org/10.1007/s00262-023-03558-5
Sci Rep. 2023 11 06. 13(1): 19221

Immune inhibitory receptor-mediated immune response, metabolic adaptation, and clinical characterization in patients with COVID-19.

Huaying An, Congrui Yan, Jun Ma, Jiayuan Gong, Fenghua Gao, Changwen Ning, Fei Wang, Meng Zhang, Baoyi Li, Yunqi Su, Pengyu Liu, Hanqi Wei, Xingwei Jiang, Qun Yu.

Immune inhibitory receptors (IRs) play a critical role in the regulation of immune responses to various respiratory viral infections. However, in coronavirus disease 2019 (COVID-19), the roles of these IRs in immune modulation, metabolic reprogramming, and clinical characterization remain to be determined. Through consensus clustering analysis of IR transcription in the peripheral blood of patients with COVID-19, we identified two distinct IR patterns in patients with COVID-19, which were named IR_cluster1 and IR_cluster2. Compared to IR_cluster1 patients, IR_cluster2 patients with lower expressions of immune inhibitory receptors presented with a suppressed immune response, lower nutrient metabolism, and worse clinical manifestations or prognosis. Considering the critical influence of the integrated regulation of multiple IRs on disease severity, we established a scoring system named IRscore, which was based on principal component analysis, to evaluate the combined effect of multiple IRs on the disease status of individual patients with COVID-19. Similar to IR_cluster2 patients, patients with high IRscores had longer hospital-free days at day 45, required ICU admission and mechanical ventilatory support, and presented higher Charlson comorbidity index and SOFA scores. A high IRscore was also linked to acute infection phase and absence of drug intervention. Our investigation comprehensively elucidates the potential role of IR patterns in regulating the immune response, modulating metabolic processes, and shaping clinical manifestations of COVID-19. All of this evidence suggests the essential role of prognostic stratification and biomarker screening based on IR patterns in the clinical management and drug development of future emerging infectious diseases such as COVID-19.

DOI: https://doi.org/10.1038/s41598-023-45883-w