bims-imicid 2024-03-03 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024‒03‒03
34 papers selected by
Dylan Ryan, University of Cambridge

Lactate modulates RNA splicing to promote CTLA-4 expression in tumor-infiltrating regulatory T cells.
Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk.
Metabolic rewiring and communication in cancer immunity.
PRMT6 deficiency or inhibition alleviates neuropathic pain by decreasing glycolysis and inflammation in microglia.
Metabolic rewiring of macrophages by epidermal-derived lactate promotes sterile inflammation in the murine skin.
Induction of MTHFD2 in Macrophages Inhibits Reactive Oxygen Species-mediated NF-κB Activation and Protects against Inflammatory Responses.
Advances in reprogramming of energy metabolism in tumor T cells.
CD8+ T-cell metabolism is related to cerebrovascular function in middle-aged adults.
From monocyte-derived macrophages to resident macrophages-how metabolism leads their way in cancer.
Songorine modulates macrophage polarization and metabolic reprogramming to alleviate inflammation in osteoarthritis.
Serine Supports Epithelial and Immune Cell Function in Colitis.
A New Strategy for Targeting UCP2 to Modulate Glycolytic Reprogramming as a Treatment for Sepsis A New Strategy for Targeting UCP2.
Metabolites that feed upper glycolytic branches support glucose independent human cytomegalovirus replication.
Somatostatin-SSTR3-GSK3 modulates human T-cell responses by inhibiting OXPHOS.
The mitochondrial thiolase ACAT1 regulates monocyte/macrophage type I interferon via epigenetic control.
Nutrients: Signal 4 in T cell immunity.
Modulation of PKM2 inhibits follicular helper T cell differentiation and ameliorates inflammation in lupus-prone mice.
The role of 27-hydroxycholesterol in meta-inflammation.
Inflammation-mediated metabolic regulation in adipose tissue.
Altered microbial bile acid metabolism exacerbates T cell-driven inflammation during graft-versus-host disease.
Indoleamine 2,3-dioxygenase 1-mediated iron metabolism in macrophages contributes to lipid deposition in nonalcoholic steatohepatitis.
Immunometabolic features of natural killer cells are associated with infection outcomes in critical illness.
Circadian rhythms of macrophages are altered by the acidic pH of the tumor microenvironment.
S-nitrosothiol homeostasis maintained by ADH5 facilitates STING-dependent host defense against pathogens.
Lactate/GPR81 recruits regulatory T cells by modulating CX3CL1 to promote immune resistance in a highly glycolytic gastric cancer.
Targeting PHGDH reverses the immunosuppressive phenotype of tumor-associated macrophages through α-ketoglutarate and mTORC1 signaling.
Differential impact of high-salt levels in vitro and in vivo on macrophage core functions.
Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19.
Oral supplementation of gut microbial metabolite indole-3-acetate alleviates diet-induced steatosis and inflammation in mice.
An iron rheostat controls hematopoietic stem cell fate.
Targeting ABCG1 and SREBP-2 mediated cholesterol homeostasis ameliorates Zika virus-induced ocular pathology.
IL-37 dampens immunosuppressive functions of MDSCs via metabolic reprogramming in the tumor microenvironment.
Synthesis of urolithin derivatives and their anti-inflammatory activity.
A homoeostatic switch causing glycerol-3-phosphate and phosphoethanolamine accumulation triggers senescence by rewiring lipid metabolism.

Immunity. 2024 Feb 15. pii: S1074-7613(24)00045-1. [Epub ahead of print]

Lactate modulates RNA splicing to promote CTLA-4 expression in tumor-infiltrating regulatory T cells.

Rui Ding, Xiaoyan Yu, Zhilin Hu, Yu Dong, Haiyan Huang, Yuerong Zhang, Qiaoqiao Han, Zhi-Yu Ni, Ren Zhao, Youqiong Ye, Qiang Zou.

  RNA splicing is involved in cancer initiation and progression, but how it influences host antitumor immunity in the metabolically abnormal tumor microenvironment (TME) remains unclear. Here, we demonstrate that lactate modulates Foxp3-dependent RNA splicing to maintain the phenotypic and functional status of tumor-infiltrating regulatory T (Treg) cells via CTLA-4. RNA splicing in Treg cells was correlated with the Treg cell signatures in the TME. Ubiquitin-specific peptidase 39 (USP39), a component of the RNA splicing machinery, maintained RNA-splicing-mediated CTLA-4 expression to control Treg cell function. Mechanistically, lactate promoted USP39-mediated RNA splicing to facilitate CTLA-4 expression in a Foxp3-dependent manner. Moreover, the efficiency of CTLA-4 RNA splicing was increased in tumor-infiltrating Treg cells from patients with colorectal cancer. These findings highlight the immunological relevance of RNA splicing in Treg cells and provide important insights into the environmental mechanism governing CTLA-4 expression in Treg cells.

Keywords:  CTLA-4; RNA splicing; Treg cells; lactate

DOI:  https://doi.org/10.1016/j.immuni.2024.01.019
Nat Metab. 2024 Feb;6(2): 359-377

Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk.

Xiangyu Zhang, Divya Kapoor, Se-Jin Jeong, Alan Fappi, Jeremiah Stitham, Vasavi Shabrish, Ismail Sergin, Eman Yousif, Astrid Rodriguez-Velez, Yu-Sheng Yeh, Arick Park, Arif Yurdagul, Oren Rom, Slava Epelman, Joel D Schilling, Marco Sardiello, Abhinav Diwan, Jaehyung Cho, Nathan O Stitziel, Ali Javaheri, Irfan J Lodhi, Bettina Mittendorfer, Babak Razani.

High protein intake is common in western societies and is often promoted as part of a healthy lifestyle; however, amino-acid-mediated mammalian target of rapamycin (mTOR) signalling in macrophages has been implicated in the pathogenesis of ischaemic cardiovascular disease. In a series of clinical studies on male and female participants ( NCT03946774 and NCT03994367 ) that involved graded amounts of protein ingestion together with detailed plasma amino acid analysis and human monocyte/macrophage experiments, we identify leucine as the key activator of mTOR signalling in macrophages. We describe a threshold effect of high protein intake and circulating leucine on monocytes/macrophages wherein only protein in excess of ∼25 g per meal induces mTOR activation and functional effects. By designing specific diets modified in protein and leucine content representative of the intake in the general population, we confirm this threshold effect in mouse models and find ingestion of protein in excess of ∼22% of dietary energy requirements drives atherosclerosis in male mice. These data demonstrate a mechanistic basis for the adverse impact of excessive dietary protein on cardiovascular risk.

DOI: https://doi.org/10.1038/s42255-024-00984-2
Cell Chem Biol. 2024 Feb 26. pii: S2451-9456(24)00075-8. [Epub ahead of print]

Metabolic rewiring and communication in cancer immunity.

Nicole M Chapman, Hongbo Chi.

The immune system shapes tumor development and progression. Although immunotherapy has transformed cancer treatment, its overall efficacy remains limited, underscoring the need to uncover mechanisms to improve therapeutic effects. Metabolism-associated processes, including intracellular metabolic reprogramming and intercellular metabolic crosstalk, are emerging as instructive signals for anti-tumor immunity. Here, we first summarize the roles of intracellular metabolic pathways in controlling immune cell function in the tumor microenvironment. How intercellular metabolic communication regulates anti-tumor immunity, and the impact of metabolites or nutrients on signaling events, are also discussed. We then describe how targeting metabolic pathways in tumor cells or intratumoral immune cells or via nutrient-based interventions may boost cancer immunotherapies. Finally, we conclude with discussions on profiling and functional perturbation methods of metabolic activity in intratumoral immune cells, and perspectives on future directions. Uncovering the mechanisms for metabolic rewiring and communication in the tumor microenvironment may enable development of novel cancer immunotherapies.

DOI: https://doi.org/10.1016/j.chembiol.2024.02.001
Brain Behav Immun. 2024 Feb 24. pii: S0889-1591(24)00270-8. [Epub ahead of print]118 101-114

PRMT6 deficiency or inhibition alleviates neuropathic pain by decreasing glycolysis and inflammation in microglia.

Tong Hua, Erliang Kong, Hailing Zhang, Jinfang Lu, Kesheng Huang, Ruifeng Ding, Haowei Wang, Jian Li, Chaofeng Han, Hongbin Yuan.

  Microglia induced chronic inflammation is the critical pathology of Neuropathic pain (NP). Metabolic reprogramming of macrophage has been intensively reported in various chronic inflammation diseases. However, the metabolic reprogramming of microglia in chronic pain remains to be elusive. Here, we reported that immuno-metabolic markers (HIF-1α, PKM2, GLUT1 and lactate) were related with increased expression of PRMT6 in the ipsilateral spinal cord dorsal horn of the chronic construction injury (CCI) mice. PRMT6 deficiency or prophylactic and therapeutic intrathecal administration of PRMT6 inhibitor (EPZ020411) ameliorated CCI-induced NP, inflammation and glycolysis in the ipsilateral spinal cord dorsal horn. PRMT6 knockout or knockdown inhibited LPS-induced inflammation, proliferation and glycolysis in microglia cells. While PRMT6 overexpression exacerbated LPS-induced inflammation, proliferation and glycolysis in BV2 cells. Recent research revealed that PRMT6 could interact with and methylate HIF-1α, which increased HIF-1α protein stability. In sum, increased expression of PRMT6 exacerbates NP progress by increasing glycolysis and neuroinflammation through interacting with and stabilizing HIF-1α in a methyltransferase manner, which outlines novel pathological mechanism and drug target for NP.

Keywords:  Immunometabolism; Microglia; Neuroinflammation; Neuropathic pain; PRMT6

DOI:  https://doi.org/10.1016/j.bbi.2024.02.027
EMBO J. 2024 Feb 28.

Metabolic rewiring of macrophages by epidermal-derived lactate promotes sterile inflammation in the murine skin.

Uttkarsh Ayyangar, Aneesh Karkhanis, Heather Tay, Aliya Farissa Binte Afandi, Oindrila Bhattacharjee, Lalitha Ks, Sze Han Lee, James Chan, Srikala Raghavan.

  Dysregulated macrophage responses and changes in tissue metabolism are hallmarks of chronic inflammation in the skin. However, the metabolic cues that direct and support macrophage functions in the skin are poorly understood. Here, we show that during sterile skin inflammation, the epidermis and macrophages uniquely depend on glycolysis and the TCA cycle, respectively. This compartmentalisation is initiated by ROS-induced HIF-1α stabilization leading to enhanced glycolysis in the epidermis. The end-product of glycolysis, lactate, is then exported by epithelial cells and utilized by the dermal macrophages to induce their M2-like fates through NF-κB pathway activation. In addition, we show that psoriatic skin disorder is also driven by such lactate metabolite-mediated crosstalk between the epidermis and macrophages. Notably, small-molecule inhibitors of lactate transport in this setting attenuate sterile inflammation and psoriasis disease burden, and suppress M2-like fate acquisition in dermal macrophages. Our study identifies an essential role for the metabolite lactate in regulating macrophage responses to inflammation, which may be effectively targeted to treat inflammatory skin disorders such as psoriasis.

Keywords:  Epithelial-immune Crosstalk; Lactate Metabolism; Metabolic Compartmentation; Psoriasis; Sterile Inflammation

DOI:  https://doi.org/10.1038/s44318-024-00039-y
J Immunol. 2024 Feb 26. pii: ji2300209. [Epub ahead of print]

Induction of MTHFD2 in Macrophages Inhibits Reactive Oxygen Species-mediated NF-κB Activation and Protects against Inflammatory Responses.

Yan Cui, Zihan Li, Lina Ni, Sujun Yu, Xiao Shan, Penghui Hu, Zemin Ji, Weijia Jing, Yanzhao Zhou, Baochen Wang, Hongyuan Dong, Jinxue Zhou, Keliang Xie, Qiujing Yu.

The one-carbon metabolism enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is critical for cancer cell proliferation and immune cell phenotypes, but whether it can contribute to macrophage inflammatory responses remains unclear. In this study, we show that MTHFD2 was upregulated by LPS in murine macrophages upon activation of the TLR4-MyD88-IKKα/β-NF-κB signaling pathway. MTHFD2 significantly attenuated LPS-induced macrophage proinflammatory cytokine production through its enzymatic activity. Notably, ablation of myeloid MTHFD2 rendered mice more sensitive to septic shock and CCl4-induced acute hepatitis. Mechanistically, MTHFD2 restrained IKKα/β-NF-κB activation and macrophage inflammatory phenotype by scavenging reactive oxygen species through the generation of NADPH. Our study reveals MTHFD2 as a "self-control" mechanism in macrophage-mediated inflammatory responses.

DOI: https://doi.org/10.4049/jimmunol.2300209
Front Immunol. 2024 ;15 1347181

Advances in reprogramming of energy metabolism in tumor T cells.

Liu Xuekai, Song Yan, Chu Jian, Song Yifei, Wu Xinyue, Zhang Wenyuan, Han Shuwen, Yang Xi.

  Cancer is a leading cause of human death worldwide, and the modulation of the metabolic properties of T cells employed in cancer immunotherapy holds great promise for combating cancer. As a crucial factor, energy metabolism influences the activation, proliferation, and function of T cells, and thus metabolic reprogramming of T cells is a unique research perspective in cancer immunology. Special conditions within the tumor microenvironment and high-energy demands lead to alterations in the energy metabolism of T cells. In-depth research on the reprogramming of energy metabolism in T cells can reveal the mechanisms underlying tumor immune tolerance and provide important clues for the development of new tumor immunotherapy strategies as well. Therefore, the study of T cell energy metabolism has important clinical significance and potential applications. In the study, the current achievements in the reprogramming of T cell energy metabolism were reviewed. Then, the influencing factors associated with T cell energy metabolism were introduced. In addition, T cell energy metabolism in cancer immunotherapy was summarized, which highlighted its potential significance in enhancing T cell function and therapeutic outcomes. In summary, energy exhaustion of T cells leads to functional exhaustion, thus resulting in immune evasion by cancer cells. A better understanding of reprogramming of T cell energy metabolism may enable immunotherapy to combat cancer and holds promise for optimizing and enhancing existing therapeutic approaches.

Keywords:  T cells; energy metabolism; immune microenvironment; immunotherapy; metabolic reprogramming

DOI:  https://doi.org/10.3389/fimmu.2024.1347181
Am J Physiol Regul Integr Comp Physiol. 2024 Feb 26.

CD8+ T-cell metabolism is related to cerebrovascular function in middle-aged adults.

Theodore Mark DeConne, Ibra S Fancher, David G Edwards, Daniel W Trott, Christopher R Martens.

  Cerebrovascular reactivity (CVR) decreases with advancing age, contributing to increased risk of cognitive impairment; however, the mechanisms underlying the age-related decrease in CVR are incompletely understood. Age-related changes to T-cells, such as impaired mitochondrial respiration increase inflammation which likely contribute peripheral and cerebrovascular dysfunction in animals. However, whether T-cell mitochondrial respiration is related to cerebrovascular function in humans is not known. Therefore, we hypothesized that peripheral T-cell mitochondrial respiration would be positively associated with cerebrovascular reactivity (CVR) and that T-cell glycolytic metabolism would be negatively associated with CVR. Twenty (20) middle-aged adults (58 ± 5 years) were recruited for this study. T-cells were separated from peripheral blood mononuclear cells. Cellular oxygen consumption rate (OCR), and extracellular acidification rate (ECAR, a marker of glycolytic activity) were measured using extracellular flux analysis. CVR was quantified using the breath-hold index (BHI) which reflects the change in blood velocity in the middle-cerebral artery (MCAv) during a 30-second breath-hold. In contrast to our hypothesis, we found that basal OCR in CD8+ T-cells (β=-0.59, R2=0.27, P=0.019) was negatively associated with BHI. However, in accordance with our hypothesis, we found that basal ECAR (β=-2.20, R2=0.29, P=0.015) and maximum ECAR (β=-50, R2=0.24, P=0.029) were negatively associated with BHI in CD8+ T-cells. There were no associations observed in CD4+ T-cells. These associations appeared to be primarily mediated by an association with the pressor response to the breath-hold test. Overall, our findings suggest that CD8+ T-cell respiration and glycolytic activity may influence cerebrovascular reactivity in humans.

Keywords:  Cerebrovascular function; Mitochondrial respiration; T-cell

DOI:  https://doi.org/10.1152/ajpregu.00267.2023
Mol Oncol. 2024 Feb 27.

From monocyte-derived macrophages to resident macrophages-how metabolism leads their way in cancer.

Ummi Ammarah, Andreia Pereira-Nunes, Marcello Delfini, Massimiliano Mazzone.

  Macrophages are innate immune cells that play key roles during both homeostasis and disease. Depending on the microenvironmental cues sensed in different tissues, macrophages are known to acquire specific phenotypes and exhibit unique features that, ultimately, orchestrate tissue homeostasis, defense, and repair. Within the tumor microenvironment, macrophages are referred to as tumor-associated macrophages (TAMs) and constitute a heterogeneous population. Like their tissue resident counterpart, TAMs are plastic and can switch function and phenotype according to the niche-derived stimuli sensed. While changes in TAM phenotype are known to be accompanied by adaptive alterations in their cell metabolism, it is reported that metabolic reprogramming of macrophages can dictate their activation state and function. In line with these observations, recent research efforts have been focused on defining the metabolic traits of TAM subsets in different tumor malignancies and understanding their role in cancer progression and metastasis formation. This knowledge will pave the way to novel therapeutic strategies tailored to cancer subtype-specific metabolic landscapes. This review outlines the metabolic characteristics of distinct TAM subsets and their implications in tumorigenesis across multiple cancer types.

Keywords:  cancer metabolism; immunometabolism; monocyte-derived macrophages; tissue-resident macrophages; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.1002/1878-0261.13618
Front Immunol. 2024 ;15 1344949

Songorine modulates macrophage polarization and metabolic reprogramming to alleviate inflammation in osteoarthritis.

Xi-Xi He, Yuan-Jun Huang, Chun-Long Hu, Qiong-Qian Xu, Qing-Jun Wei.

  Introduction: Osteoarthritis (OA) is a prevalent joint disorder characterized by multifaceted pathogenesis, with macrophage dysregulation playing a critical role in perpetuating inflammation and joint degeneration.Methods: This study focuses on Songorine, derived from Aconitum soongaricum Stapf, aiming to unravel its therapeutic mechanisms in OA. Comprehensive analyses, including PCR, Western blot, and immunofluorescence, were employed to evaluate Songorine's impact on the joint microenvironment and macrophage polarization. RNA-seq analysis was conducted to unravel its anti-inflammatory mechanisms in macrophages. Metabolic alterations were explored through extracellular acidification rate monitoring, molecular docking simulations, and PCR assays. Oxygen consumption rate measurements were used to assess mitochondrial oxidative phosphorylation, and Songorine's influence on macrophage oxidative stress was evaluated through gene expression and ROS assays.
Results: Songorine effectively shifted macrophage polarization from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype. Notably, Songorine induced metabolic reprogramming, inhibiting glycolysis and promoting mitochondrial oxidative phosphorylation. This metabolic shift correlated with a reduction in macrophage oxidative stress, highlighting Songorine's potential as an oxidative stress inhibitor.
Discussion: In an in vivo rat model of OA, Songorine exhibited protective effects against cartilage damage and synovial inflammation, emphasizing its therapeutic potential. This comprehensive study elucidates Songorine's multifaceted impact on macrophage modulation, metabolic reprogramming, and the inflammatory microenvironment, providing a theoretical foundation for its therapeutic potential in OA.

Keywords:  Songorine; inflammation; metabolic alteration; osteoarthritis; oxidative stress

DOI:  https://doi.org/10.3389/fimmu.2024.1344949
Am J Pathol. 2024 Feb 26. pii: S0002-9440(24)00071-3. [Epub ahead of print]

Serine Supports Epithelial and Immune Cell Function in Colitis.

Ji Dong K Bai, Suchandrima Saha, Michael Wood, Bo Chen, Jinyu Li, Lukas E Dow, David C Montrose.

  Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract that are largely driven by immune cell activity, while mucosal healing is critical for remission. Serine is a non-essential amino acid that supports epithelial and immune cell metabolism and proliferation, however, whether these roles impact IBD pathogenesis is not well understood. Here, we show that serine synthesis increases selectively in the epithelial cells of colons from patients with IBD and murine models of colitis. Inhibiting serine synthesis impairs colonic mucosal healing and increases susceptibility to acute injury in mice, effects associated with impaired epithelial cell proliferation. Dietary removal of serine similarly sensitizes mice to acute chemically-induced colitis but ameliorates inflammation in chronic colitis models. The anti-inflammatory effect of exogenous serine depletion in chronic colitis is associated with mitochondrial dysfunction of macrophages, resulting in impaired nucleotide production and proliferation. Collectively, these results suggest that serine plays an important role in both epithelial and immune cell biology in the colon, and that modulating its availability could impact IBD pathogenesis.

Keywords:  MALDI; PSAT1; T cells

DOI:  https://doi.org/10.1016/j.ajpath.2024.01.021
Inflammation. 2024 Mar 02.

A New Strategy for Targeting UCP2 to Modulate Glycolytic Reprogramming as a Treatment for Sepsis A New Strategy for Targeting UCP2.

Na Li, Jiali Deng, Junli Zhang, Fei Yu, Fanghang Ye, Liyuan Hao, Shenghao Li, Xiaoyu Hu.

  Sepsis is a severe and life-threatening disease caused by infection, characterized by a dysregulated immune response. Unfortunately, effective treatment strategies for sepsis are still lacking. The intricate interplay between metabolism and the immune system limits the treatment options for sepsis. During sepsis, there is a profound shift in cellular energy metabolism, which triggers a metabolic reprogramming of immune cells. This metabolic alteration impairs immune responses, giving rise to excessive inflammation and immune suppression. Recent research has demonstrated that UCP2 not only serves as a critical target in sepsis but also functions as a key metabolic switch involved in immune cell-mediated inflammatory responses. However, the regulatory mechanisms underlying this modulation are complex. This article focuses on UCP2 as a target and discusses metabolic reprogramming during sepsis and the complex regulatory mechanisms between different stages of inflammation. Our research indicates that overexpression of UCP2 reduces the Warburg effect, restores mitochondrial function, and improves the prognosis of sepsis. This discovery aims to provide a promising approach to address the significant challenges associated with metabolic dysfunction and immune paralysis.

Keywords:  Excessive inflammation; Glycolysis; Immune suppression; Sepsis; UCP2 overexpression

DOI:  https://doi.org/10.1007/s10753-024-01998-4
bioRxiv. 2024 Feb 12. pii: 2024.02.12.579992. [Epub ahead of print]

Metabolites that feed upper glycolytic branches support glucose independent human cytomegalovirus replication.

Rebekah L Mokry, John G Purdy.

The broad tissue distribution and cell tropism of human cytomegalovirus indicates that the virus successfully replicates in tissues with various nutrient environments. HCMV requires and reprograms central carbon metabolism for viral replication. However, many studies focus on reprogramming of metabolism in high nutrient conditions that do not recapitulate physiological nutrient environments in the body. In this study, we investigate how HCMV successfully replicates when nutrients are suboptimal. We limited glucose following HCMV infection to determine how glucose supports virus replication and how nutrients potentially present in the physiological environment contribute to successful glucose independent HCMV replication. Glucose is required for HCMV viral genome synthesis, viral protein production and glycosylation, and virus production. However, supplement of glucose-free cultures with uridine, ribose, or UDP-GlcNAc-metabolites that support upper glycolytic branches-resulted in partially restored viral genome synthesis and subsequent partial restoration of viral protein levels. Low levels of virus production were also restored. Supplementing lower glycolysis in glucose-free cultures using pyruvate had no effect on virus replication. These results indicate nutrients that support upper glycolytic branches like the pentose phosphate pathway and hexosamine pathway can compensate for glucose during HCMV replication to support low levels of virus production. More broadly, our findings suggest that HCMV could successfully replicate in diverse metabolic niches, including those in the body with low levels of glucose, through alternative nutrient usage.IMPORTANCE: The metabolic environment is a determinant in the ability of a virus to successfully replicate. HCMV has broad cell tropism and replicates in various tissues that have diverse and/or limiting metabolic environments. We know that HCMV reprograms host central carbon metabolism to support viral replication, but we have little understanding of HCMV replication in diverse metabolic niches as most studies use high nutrient culture media. Here, we show that glucose limitation suppresses virus production through loss of viral genome synthesis and viral protein glycosylation. However, nutrient compensation by uridine, ribose, and UDP-GlcNAc, metabolites that fuel upper glycolytic branches such as the non-oxidative pentose phosphate pathway support low levels of glucose-independent virus production. Our work indicates that metabolite compensation may facilitate HCMV replication in nutrient limited niches in the body.

DOI: https://doi.org/10.1101/2024.02.12.579992
Front Immunol. 2024 ;15 1322670

Somatostatin-SSTR3-GSK3 modulates human T-cell responses by inhibiting OXPHOS.

Bo Zhang, Huiru Feng, Hui Lin, Rui Li.

  Introduction: Somatostatin (SST) is a peptide hormone primarily synthesized in the digestive and nervous systems. While its impact on the endocrine system is well-established, accumulating evidence suggests a crucial role for SST and its analogues in modulating immune responses. Despite this, the precise mechanism through which SST regulates T cells has remained largely unknown.Methods: To elucidate the impact of SST on human T cells, we conducted a series of experiments involving cell culture assays, molecular analyses, and metabolic profiling. Human T cells were treated with SST, and various parameters including proliferation, cytokine production, and metabolic activities were assessed. Additionally, we employed pharmacological inhibitors and genetic manipulations to dissect the signaling pathways mediating SST's effects on T cells.
Results: We showed that SST diminishes T-cell proliferation by influencing IL-2 production and T-cell mitochondrial respiration, while having no discernible impact on TCR-induced glycolysis. Our findings also identified that the regulatory influence of SST on T-cell responses and metabolism is contingent on its receptor, SSTR3. Moreover, we demonstrated that SST governs T-cell responses and metabolism by acting through the T-cell metabolic checkpoint GSK3.
Discussion: Our study provides novel insights into the immunoregulatory function of SST in human T cells, highlighting the complex interplay between hormonal signaling and immune regulation. Understanding the molecular mechanisms underlying SST's effects on T cells may offer therapeutic opportunities for manipulating immune responses in various pathological conditions.

Keywords:  T cells; metabolism; mitochondrial respiration and glycogen synthase kinase-3 (GSK3); somatostatin (SST); somatostatin receptor 3 (SSTR3)

DOI:  https://doi.org/10.3389/fimmu.2024.1322670
bioRxiv. 2024 Jan 31. pii: 2024.01.29.577773. [Epub ahead of print]

The mitochondrial thiolase ACAT1 regulates monocyte/macrophage type I interferon via epigenetic control.

Jing Wu, Komudi Singh, Vivian Shing, Anand K Gupta, Rebecca D Huffstutler, Duck-Yeon Lee, Michael N Sack.

Lipid-derived acetyl-CoA is shown to be the major carbon source for histone acetylation. However, there is no direct evidence demonstrating lipid metabolic pathway contribututions to this process. Mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) catalyzes the final step of ß-oxidation, the aerobic process catabolizing fatty acids (FA) into acetyl-CoA. To investigate this in the context of immunometabolism, we generated macrophage cell line lacking ACAT1. 13 C-carbon tracing combined with mass spectrometry confirmed incorporation of FA-derived carbons into histone H3 and this incorporation was reduced in ACAT1 KO macrophage cells. RNA-seq identified a subset of genes downregulated in ACAT1 KO cells including STAT1/2 and interferon stimulated genes (ISGs). CHIP analysis demonstrated reduced acetyl-H3 binding to STAT1 promoter/enhancer regions. Increasing histone acetylation rescued STAT1/2 expression in ACAT1 KO cells. Concomitantly, ligand triggered IFNβ release was blunted in ACAT1 KO cells and rescued by reconstitution of ACAT1. Furthermore, ACAT1 promotes FA-mediated histone acetylation in an acetylcarnitine shuttle-dependent manner. In patients with obesity, levels of ACAT1 and histone acetylation are abnormally elevated. Thus, our study identified a novel link between ACAT1 mediated FA metabolism and epigenetic modification on STAT1/2 that uncovers a regulatory role of lipid metabolism in innate immune signaling and opens novel avenues for interventions in human diseases such as obesity.

DOI: https://doi.org/10.1101/2024.01.29.577773
J Exp Med. 2024 Mar 04. pii: e20221839. [Epub ahead of print]221(3):

Nutrients: Signal 4 in T cell immunity.

Jana L Raynor, Hongbo Chi.

T cells are integral in mediating adaptive immunity to infection, autoimmunity, and cancer. Upon immune challenge, T cells exit from a quiescent state, followed by clonal expansion and effector differentiation. These processes are shaped by three established immune signals, namely antigen stimulation (Signal 1), costimulation (Signal 2), and cytokines (Signal 3). Emerging findings reveal that nutrients, including glucose, amino acids, and lipids, are crucial regulators of T cell responses and interplay with Signals 1-3, highlighting nutrients as Signal 4 to license T cell immunity. Here, we first summarize the functional importance of Signal 4 and the underlying mechanisms of nutrient transport, sensing, and signaling in orchestrating T cell activation and quiescence exit. We also discuss the roles of nutrients in programming T cell differentiation and functional fitness and how nutrients can be targeted to improve disease therapy. Understanding how T cells respond to Signal 4 nutrients in microenvironments will provide insights into context-dependent functions of adaptive immunity and therapeutic interventions.

DOI: https://doi.org/10.1084/jem.20221839
J Autoimmun. 2024 Feb 29. pii: S0896-8411(24)00032-5. [Epub ahead of print]145 103198

Modulation of PKM2 inhibits follicular helper T cell differentiation and ameliorates inflammation in lupus-prone mice.

Manna Lin, Liuting Huang, Junxia Huang, Jia Yu, Xue Yang, Ji Yang.

  OBJECTIVES: Expansion of follicular helper T (Tfh) cells and abnormal glucose metabolism are present in patients with systemic lupus erythematosus (SLE). Pyruvate kinase M2 (PKM2) is one of the key glycolytic enzymes, and the underlying mechanism of PKM2-mediated Tfh cell glycolysis in SLE pathogenesis remains elusive.METHODS: We analyzed the percentage of Tfh cells and glycolysis in CD4+ T cells from SLE patients and healthy donors and performed RNA sequencing analysis of peripheral blood CD4+ T cells and differentiated Tfh cells from SLE patients. Following Tfh cell development in vitro and following treatment with PKM2 activator TEPP-46, PKM2 expression, glycolysis, and signaling pathway proteins were analyzed. Finally, diseased MRL/lpr mice were treated with TEPP-46 and assessed for treatment effects.
RESULTS: We found that Tfh cell percentage and glycolysis levels were increased in SLE patients and MRL/lpr mice. TEPP-46 induced PKM2 tetramerization, thereby inhibiting Tfh cell glycolysis levels. On the one hand, TEPP-46 reduced the dimeric PKM2 entering the nucleus and reduced binding to the transcription factor BCL6. On the other hand, TEPP-46 inhibited the AKT/GSK-3β pathway and glycolysis during Tfh cell differentiation. Finally, we confirmed that TEPP-46 effectively alleviated inflammatory damage in lupus-prone mice and reduced the expansion of Tfh cells in vivo.
CONCLUSIONS: Our results demonstrate the involvement of PKM2-mediated glycolysis in Tfh cell differentiation and SLE pathogenesis, and PKM2 could be a key therapeutic target for the treatment of SLE.

Keywords:  Follicular helper T cells; Glycolysis; PKM2; Systemic lupus erythematosus

DOI:  https://doi.org/10.1016/j.jaut.2024.103198
Korean J Physiol Pharmacol. 2024 Mar 01. 28(2): 107-112

The role of 27-hydroxycholesterol in meta-inflammation.

Yonghae Son, Eunbeen Choi, Yujin Hwang, Koanhoi Kim.

  27-Hydroxycholesterol (27OHChol), a prominent cholesterol metabolite present in the bloodstream and peripheral tissues, is a kind of immune oxysterol that elicits immune response. Recent research indicates the involvement of 27OHChol in metabolic inflammation (meta-inflammation) characterized by chronic responses associated with metabolic irregularities. 27OHChol activates monocytic cells such that they secrete pro-inflammatory cytokines and chemokines, and increase the expression of cell surface molecules such as pattern-recognition receptors that play key roles in immune cell-cell communication and sensing metabolism-associated danger signals. Levels of 27OHChol increase when cholesterol metabolism is disrupted, and the resulting inflammatory responses can contribute to the development and complications of metabolic syndrome, including obesity, insulin resistance, and cardiovascular diseases. Since 27OHChol can induce chronic immune response by activating monocyte-macrophage lineage cells that play a crucial role in meta-inflammation, it is essential to understand the 27OHChol-induced inflammatory responses to unravel the roles and mechanisms of action of this cholesterol metabolite in chronic metabolic disorders.

Keywords:  27-Hydroxycholesterol; Atherosclerosis; Meta-inflammation; Monocytes/Macrophages; Obesity

DOI:  https://doi.org/10.4196/kjpp.2024.28.2.107
Obes Rev. 2024 Feb 26. e13724

Inflammation-mediated metabolic regulation in adipose tissue.

Shujie Xu, Feng Lu, Jianhua Gao, Yi Yuan.

  Chronic inflammation of adipose tissue is a prominent characteristic of many metabolic diseases. Lipid metabolism in adipose tissue is consistently dysregulated during inflammation, which is characterized by substantial infiltration by proinflammatory cells and high cytokine concentrations. Adipose tissue inflammation is caused by a variety of endogenous factors, such as mitochondrial dysfunction, reactive oxygen species (ROS) production, endoplasmic reticulum (ER) stress, cellular senescence, ceramides biosynthesis and mediators of lipopolysaccharides (LPS) signaling. Additionally, the gut microbiota also plays a crucial role in regulating adipose tissue inflammation. Essentially, adipose tissue inflammation arises from an imbalance in adipocyte metabolism and the regulation of immune cells. Specific inflammatory signals, including nuclear factor-κB (NF-κB) signaling, inflammasome signaling and inflammation-mediated autophagy, have been shown to be involved in the metabolic regulation. The pathogenesis of metabolic diseases characterized by chronic inflammation (obesity, insulin resistance, atherosclerosis and nonalcoholic fatty liver disease [NAFLD]) and recent research regarding potential therapeutic targets for these conditions are also discussed in this review.

Keywords:  adipose tissue; inflammation; lipid metabolism; metabolic diseases

DOI:  https://doi.org/10.1111/obr.13724
Nat Microbiol. 2024 Mar 01.

Altered microbial bile acid metabolism exacerbates T cell-driven inflammation during graft-versus-host disease.

Sarah Lindner, Oriana Miltiadous, Ruben J F Ramos, Jenny Paredes, Anastasia I Kousa, Anqi Dai, Teng Fei, Emma Lauder, John Frame, Nicholas R Waters, Keimya Sadeghi, Gabriel K Armijo, Romina Ghale, Kristen Victor, Brianna Gipson, Sebastien Monette, Marco Vincenzo Russo, Chi L Nguyen, John Slingerland, Ying Taur, Kate A Markey, Hana Andrlova, Sergio Giralt, Miguel-Angel Perales, Pavan Reddy, Jonathan U Peled, Melody Smith, Justin R Cross, Marina Burgos da Silva, Clarissa Campbell, Marcel R M van den Brink.

Microbial transformation of bile acids affects intestinal immune homoeostasis but its impact on inflammatory pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that T cell-driven inflammation decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of unconjugated and microbe-derived bile acids. Several microbe-derived bile acids attenuated farnesoid X receptor (FXR) activation, suggesting that loss of these metabolites during inflammation may increase FXR activity and exacerbate the course of disease. Indeed, mortality increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells during mouse GVHD. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and microbe-derived bile acids. In addition, the FXR antagonist ursodeoxycholic acid reduced the proliferation of human T cells and was associated with a lower risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of microbe-derived bile acids during inflammation may be an important mechanism to amplify T cell-mediated diseases.

DOI: https://doi.org/10.1038/s41564-024-01617-w
J Gastroenterol. 2024 Feb 24.

Indoleamine 2,3-dioxygenase 1-mediated iron metabolism in macrophages contributes to lipid deposition in nonalcoholic steatohepatitis.

Chaofeng Wu, Junjie Li, Hui Jia, Jiamin Zhao, Mengchen Qin, Hao Shi, Chang Liu, Jiajie Lin, Min Cai, Yong Gu, Bin Liu, Lei Gao.

  BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a rapidly progressing chronic liver disease of global significance. However, the underlying mechanisms responsible for NASH remain unknown. Indoleamine 2,3-dioxygenase 1 (IDO1) has been recognized as essential factor in immune response and metabolic regulation. Here we aimed to investigate the functions and mechanisms of the IDO1 in macrophages on hepatic lipid deposition and iron metabolism in NASH.METHODS: The effect of IDO1 in NASH was evaluated by WT and IDO1-/- mice model fed with methionine/choline-deficient (MCD) diet in vivo. Macrophages scavenger clodronate liposomes (CL) and overexpressing of IDO1 in macrophages by virus were employed as well. Lipid deposition was assessed through pathological examination and lipid droplet staining, while iron levels were measured using an iron assay kit and western blotting. Primary hepatocytes and bone marrow-derived macrophages were treated with oleic acid/palmitic acid (OA/PA) to assess IDO1 expression via Oil Red O staining and immunofluorescence staining in vitro.
RESULTS: Pathological images demonstrated that the increase of IDO1 exacerbated lipid accumulation in the livers of mice with MCD diet, while reduction of iron accumulation was observed in the liver and the serum of MCD-fed mice. Scavenging of macrophages effectively mitigated both lipid and iron accumulation. In addition, the deficiency of IDO1 in macrophages significantly mitigated lipid accumulation and iron overload in hepatic parenchymal cells. Finally, lentivirus-mediated overexpression of IDO1 in liver macrophages exacerbated hepatic steatosis and iron deposition in NASH.
CONCLUSIONS: Our results demonstrated that effective inhibition of IDO1 expression in macrophages in NASH alleviated hepatic parenchymal cell lipid accumulation and iron deposition, which provided new insights for the future treatment of NASH.

Keywords:  Indoleamine 2,3-dioxygenase 1; Iron deposition; Lipid accumulation; Non-alcoholic steatohepatitis

DOI:  https://doi.org/10.1007/s00535-024-02082-2
Front Immunol. 2024 ;15 1334882

Immunometabolic features of natural killer cells are associated with infection outcomes in critical illness.

Kuei-Pin Chung, Jia-Ying Su, Yi-Fu Wang, Bugi Ratno Budiarto, Yu-Chang Yeh, Jui-Chen Cheng, Li-Ta Keng, Yi-Jung Chen, Ya-Ting Lu, Yi-Hsiu Juan, Kiichi Nakahira, Sheng-Yuan Ruan, Jung-Yien Chien, Hou-Tai Chang, Jih-Shuin Jerng, Yen-Tsung Huang, Shih-Yu Chen, Chong-Jen Yu.

  Immunosuppression increases the risk of nosocomial infection in patients with chronic critical illness. This exploratory study aimed to determine the immunometabolic signature associated with nosocomial infection during chronic critical illness. We prospectively recruited patients who were admitted to the respiratory care center and who had received mechanical ventilator support for more than 10 days in the intensive care unit. The study subjects were followed for the occurrence of nosocomial infection until 6 weeks after admission, hospital discharge, or death. The cytokine levels in the plasma samples were measured. Single-cell immunometabolic regulome profiling by mass cytometry, which analyzed 16 metabolic regulators in 21 immune subsets, was performed to identify immunometabolic features associated with the risk of nosocomial infection. During the study period, 37 patients were enrolled, and 16 patients (43.2%) developed nosocomial infection. Unsupervised immunologic clustering using multidimensional scaling and logistic regression analyses revealed that expression of nuclear respiratory factor 1 (NRF1) and carnitine palmitoyltransferase 1a (CPT1a), key regulators of mitochondrial biogenesis and fatty acid transport, respectively, in natural killer (NK) cells was significantly associated with nosocomial infection. Downregulated NRF1 and upregulated CPT1a were found in all subsets of NK cells from patients who developed a nosocomial infection. The risk of nosocomial infection is significantly correlated with the predictive score developed by selecting NK cell-specific features using an elastic net algorithm. Findings were further examined in an independent cohort of COVID-19-infected patients, and the results confirm that COVID-19-related mortality is significantly associated with mitochondria biogenesis and fatty acid oxidation pathways in NK cells. In conclusion, this study uncovers that NK cell-specific immunometabolic features are significantly associated with the occurrence and fatal outcomes of infection in critically ill population, and provides mechanistic insights into NK cell-specific immunity against microbial invasion in critical illness.

Keywords:  CPT1a; NRF1; chronic critical illness; metabolism; natural killer cells; nosocomial infection

DOI:  https://doi.org/10.3389/fimmu.2024.1334882
bioRxiv. 2024 Feb 16. pii: 2024.02.14.580339. [Epub ahead of print]

Circadian rhythms of macrophages are altered by the acidic pH of the tumor microenvironment.

Amelia M Knudsen-Clark, Daniel Mwangi, Juliana Cazarin, Lauren M Hablitz, Minsoo Kim, Brian J Altman.

Macrophages are prime therapeutic targets due to their pro-tumorigenic and immunosuppressive functions in tumors, but varying efficacy of therapeutic approaches targeting macrophages highlights our incomplete understanding of how the tumor microenvironment (TME) can influence regulation of macrophages. The circadian clock is a key internal regulator of macrophage function, but how circadian rhythms of macrophages may be influenced by the tumor microenvironment remains unknown. We found that conditions associated with the TME such as polarizing stimuli, acidic pH, and elevated lactate concentrations can each alter circadian rhythms in macrophages. Circadian rhythms were enhanced in pro-resolution macrophages but suppressed in pro-inflammatory macrophages, while acidic pH had divergent effects on circadian rhythms depending on macrophage phenotype. While cyclic AMP (cAMP) has been reported to play a role in macrophage response to acidic pH, our results indicate that pH-driven changes in circadian rhythms are not mediated solely by the cAMP signaling pathway. Remarkably, clock correlation distance analysis of tumor-associated macrophages (TAMs) revealed evidence of circadian disorder in TAMs. This is the first report providing evidence that circadian rhythms of macrophages are altered within the TME. Our data suggest that heterogeneity in circadian rhythms at the population level may underlie this circadian disorder. Finally, we sought to determine how circadian regulation of macrophages impacts tumorigenesis, and found that tumor growth was suppressed when macrophages had a functional circadian clock. Our work demonstrates a novel mechanism by which the tumor microenvironment can influence macrophage biology through altering circadian rhythms, and the contribution of circadian rhythms in macrophages to suppressing tumor growth.

DOI: https://doi.org/10.1101/2024.02.14.580339
Nat Commun. 2024 Feb 26. 15(1): 1750

S-nitrosothiol homeostasis maintained by ADH5 facilitates STING-dependent host defense against pathogens.

Mutian Jia, Li Chai, Jie Wang, Mengge Wang, Danhui Qin, Hui Song, Yue Fu, Chunyuan Zhao, Chengjiang Gao, Jihui Jia, Wei Zhao.

Oxidative (or respiratory) burst confers host defense against pathogens by generating reactive species, including reactive nitrogen species (RNS). The microbial infection-induced excessive RNS damages many biological molecules via S-nitrosothiol (SNO) accumulation. However, the mechanism by which the host enables innate immunity activation during oxidative burst remains largely unknown. Here, we demonstrate that S-nitrosoglutathione (GSNO), the main endogenous SNO, attenuates innate immune responses against herpes simplex virus-1 (HSV-1) and Listeria monocytogenes infections. Mechanistically, GSNO induces the S-nitrosylation of stimulator of interferon genes (STING) at Cys257, inhibiting its binding to the second messenger cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). Alcohol dehydrogenase 5 (ADH5), the key enzyme that metabolizes GSNO to decrease cellular SNOs, facilitates STING activation by inhibiting S-nitrosylation. Concordantly, Adh5 deficiency show defective STING-dependent immune responses upon microbial challenge and facilitates viral replication. Thus, cellular oxidative burst-induced RNS attenuates the STING-mediated innate immune responses to microbial infection, while ADH5 licenses STING activation by maintaining cellular SNO homeostasis.

DOI: https://doi.org/10.1038/s41467-024-46212-z
Oncoimmunology. 2024 ;13(1): 2320951

Lactate/GPR81 recruits regulatory T cells by modulating CX3CL1 to promote immune resistance in a highly glycolytic gastric cancer.

Jin Su, Xinyuan Mao, Lingzhi Wang, Zhian Chen, Weisheng Wang, Cuiyin Zhao, Guoxin Li, Weihong Guo, Yanfeng Hu.

  Lactate plays an important role in shaping immune tolerance in tumor microenvironment (TME) and correlates with poor prognosis in various solid tumors. Overcoming the immune resistance in an acidic TME may improve the anti-tumor immunity. Here, this study elucidated that via G-protein-coupled receptor 81 (GPR81), lactate could modulate immune tolerance in TME by recruiting regulatory T cells (Tregs) in vitro and in vivo. A high concentration of lactate was detected in cell supernatant and tissues of gastric cancer (GC), which was modulated by lactic dehydrogenase A (LDHA). GPR81 was the natural receptor of lactate and was overexpressed in different GC cell lines and samples, which correlated with poor outcomes in GC patients. Lactate/GPR81 signaling could promote the infiltration of Tregs into TME by inducing the expression of chemokine CX3CL1. GPR81 deficiency could decrease the infiltration of Tregs into TME, thereby inhibiting GC progression by weakening the inhibition of CD8+T cell function in a humanized mouse model. In conclusion, targeting the lactate/GPR81 signaling may potentially serve as a critical process to overcome immune resistance in highly glycolytic GC.

Keywords:  Gastric cancer; immune resistance; lactate; regulatory T cells; tumor microenvironment

DOI:  https://doi.org/10.1080/2162402X.2024.2320951
Cell Mol Immunol. 2024 Feb 27.

Targeting PHGDH reverses the immunosuppressive phenotype of tumor-associated macrophages through α-ketoglutarate and mTORC1 signaling.

Zhengnan Cai, Wan Li, Sonja Hager, Jayne Louise Wilson, Leila Afjehi-Sadat, Elke H Heiss, Thomas Weichhart, Petra Heffeter, Wolfram Weckwerth.

  Phosphoglycerate dehydrogenase (PHGDH) has emerged as a crucial factor in macromolecule synthesis, neutralizing oxidative stress, and regulating methylation reactions in cancer cells, lymphocytes, and endothelial cells. However, the role of PHGDH in tumor-associated macrophages (TAMs) is poorly understood. Here, we found that the T helper 2 (Th2) cytokine interleukin-4 and tumor-conditioned media upregulate the expression of PHGDH in macrophages and promote immunosuppressive M2 macrophage activation and proliferation. Loss of PHGDH disrupts cellular metabolism and mitochondrial respiration, which are essential for immunosuppressive macrophages. Mechanistically, PHGDH-mediated serine biosynthesis promotes α-ketoglutarate production, which activates mTORC1 signaling and contributes to the maintenance of an M2-like macrophage phenotype in the tumor microenvironment. Genetic ablation of PHGDH in macrophages from tumor-bearing mice results in attenuated tumor growth, reduced TAM infiltration, a phenotypic shift of M2-like TAMs toward an M1-like phenotype, downregulated PD-L1 expression and enhanced antitumor T-cell immunity. Our study provides a strong basis for further exploration of PHGDH as a potential target to counteract TAM-mediated immunosuppression and hinder tumor progression.

Keywords:  PHGDH; de novo serine synthesis; mTORC1; protumorigenic; tumor-associated macrophages, metabolomics; α-ketoglutarate

DOI:  https://doi.org/10.1038/s41423-024-01134-0
Mol Biol Rep. 2024 Feb 24. 51(1): 343

Differential impact of high-salt levels in vitro and in vivo on macrophage core functions.

Linda Müller, Aya Rafea Nasr, Bettina Jux, Nikola Makdissi, Justin Wayne Trowbridge, Susanne V Schmidt, Joachim L Schultze, Thomas Quast, Jonas Schulte-Schrepping, Waldemar Kolanus, Elvira Mass.

  The consumption of processed food is on the rise leading to huge intake of excess dietary salt, which strongly correlates with development of hypertension, often leading to cardiovascular diseases such as stroke and heart attack, as well as activation of the immune system. The effect of salt on macrophages is especially interesting as they are able to sense high sodium levels in tissues leading to transcriptional changes. In the skin, macrophages were shown to influence lymphatic vessel growth which, in turn, enables the transport of excess salt and thereby prevents the development of high blood pressure. Furthermore, salt storage in the skin has been linked to the onset of pro-inflammatory effector functions of macrophages in pathogen defence. However, there is only little known about the mechanisms which are involved in changing macrophage function to salt exposure. Here, we characterize the response of macrophages to excess salt both in vitro and in vivo. Our results validate and strengthen the notion that macrophages exhibit chemotactic migration in response to salt gradients in vitro. Furthermore, we demonstrate a reduction in phagocytosis and efferocytosis following acute salt challenge in vitro. While acute exposure to a high-salt diet in vivo has a less pronounced impact on macrophage core functions such as phagocytosis, our data indicate that prolonged salt challenge may exert a distinct effect on the function of macrophages. These findings suggest a potential role for excessive salt sensing by macrophages in the manifestation of diseases related to high-salt diets and explicitly highlight the need for in vivo work to decipher the physiologically relevant impact of excess salt on tissue and cell function.

Keywords:  Efferocytosis; High-salt diet; Inflammation; Macrophage; Phagocytosis; Salt sensing

DOI:  https://doi.org/10.1007/s11033-024-09295-x
Nat Immunol. 2024 Mar;25(3): 471-482

Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19.

Cambridge Institute of Therapeutic Immunology and Infectious Disease–National Institute for Health Research (CITIID–NIHR) COVID BioResource Collaboration

Persistent symptoms following SARS-CoV-2 infection are increasingly reported, although the drivers of post-acute sequelae (PASC) of COVID-19 are unclear. Here we assessed 214 individuals infected with SARS-CoV-2, with varying disease severity, for one year from COVID-19 symptom onset to determine the early correlates of PASC. A multivariate signature detected beyond two weeks of disease, encompassing unresolving inflammation, anemia, low serum iron, altered iron-homeostasis gene expression and emerging stress erythropoiesis; differentiated those who reported PASC months later, irrespective of COVID-19 severity. A whole-blood heme-metabolism signature, enriched in hospitalized patients at month 1-3 post onset, coincided with pronounced iron-deficient reticulocytosis. Lymphopenia and low numbers of dendritic cells persisted in those with PASC, and single-cell analysis reported iron maldistribution, suggesting monocyte iron loading and increased iron demand in proliferating lymphocytes. Thus, defects in iron homeostasis, dysregulated erythropoiesis and immune dysfunction due to COVID-19 possibly contribute to inefficient oxygen transport, inflammatory disequilibrium and persisting symptomatology, and may be therapeutically tractable.

DOI: https://doi.org/10.1038/s41590-024-01754-8
Elife. 2024 Feb 27. pii: RP87458. [Epub ahead of print]12

Oral supplementation of gut microbial metabolite indole-3-acetate alleviates diet-induced steatosis and inflammation in mice.

Yufang Ding, Karin Yanagi, Fang Yang, Evelyn Callaway, Clint Cheng, Martha E Hensel, Rani Menon, Robert C Alaniz, Kyongbum Lee, Arul Jayaraman.

  Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. There is growing evidence that dysbiosis of the intestinal microbiota and disruption of microbiota-host interactions contribute to the pathology of NAFLD. We previously demonstrated that gut microbiota-derived tryptophan metabolite indole-3-acetate (I3A) was decreased in both cecum and liver of high-fat diet-fed mice and attenuated the expression of inflammatory cytokines in macrophages and Tnfa and fatty acid-induced inflammatory responses in an aryl-hydrocarbon receptor (AhR)-dependent manner in hepatocytes. In this study, we investigated the effect of orally administered I3A in a mouse model of diet-induced NAFLD. Western diet (WD)-fed mice given sugar water (SW) with I3A showed dramatically decreased serum ALT, hepatic triglycerides (TG), liver steatosis, hepatocyte ballooning, lobular inflammation, and hepatic production of inflammatory cytokines, compared to WD-fed mice given only SW. Metagenomic analysis show that I3A administration did not significantly modify the intestinal microbiome, suggesting that I3A's beneficial effects likely reflect the metabolite's direct actions on the liver. Administration of I3A partially reversed WD-induced alterations of liver metabolome and proteome, notably, decreasing expression of several enzymes in hepatic lipogenesis and β-oxidation. Mechanistically, we also show that AMP-activated protein kinase (AMPK) mediates the anti-inflammatory effects of I3A in macrophages. The potency of I3A in alleviating liver steatosis and inflammation clearly demonstrates its potential as a therapeutic modality for preventing the progression of steatosis to non-alcoholic steatohepatitis (NASH).

Keywords:  immunology; indole-3-acetic acid; inflammation; liver; medicine; microbiota; mouse

DOI:  https://doi.org/10.7554/eLife.87458
Cell Stem Cell. 2024 Feb 19. pii: S1934-5909(24)00041-9. [Epub ahead of print]

An iron rheostat controls hematopoietic stem cell fate.

Yun-Ruei Kao, Jiahao Chen, Rajni Kumari, Anita Ng, Aliona Zintiridou, Madhuri Tatiparthy, Yuhong Ma, Maria M Aivalioti, Deeposree Moulik, Sriram Sundaravel, Daqian Sun, Julie A Reisz, Juliane Grimm, Nuria Martinez-Lopez, Stephanie Stransky, Simone Sidoli, Ulrich Steidl, Rajat Singh, Angelo D'Alessandro, Britta Will.

  Mechanisms governing the maintenance of blood-producing hematopoietic stem and multipotent progenitor cells (HSPCs) are incompletely understood, particularly those regulating fate, ensuring long-term maintenance, and preventing aging-associated stem cell dysfunction. We uncovered a role for transitory free cytoplasmic iron as a rheostat for adult stem cell fate control. We found that HSPCs harbor comparatively small amounts of free iron and show the activation of a conserved molecular response to limited iron-particularly during mitosis. To study the functional and molecular consequences of iron restriction, we developed models allowing for transient iron bioavailability limitation and combined single-molecule RNA quantification, metabolomics, and single-cell transcriptomic analyses with functional studies. Our data reveal that the activation of the limited iron response triggers coordinated metabolic and epigenetic events, establishing stemness-conferring gene regulation. Notably, we find that aging-associated cytoplasmic iron loading reversibly attenuates iron-dependent cell fate control, explicating intervention strategies for dysfunctional aged stem cells.

Keywords:  Tip60/KAT5; aging; gene regulation; hematopoiesis; iron; metabolism; stem cells

DOI:  https://doi.org/10.1016/j.stem.2024.01.011
iScience. 2024 Mar 15. 27(3): 109088

Targeting ABCG1 and SREBP-2 mediated cholesterol homeostasis ameliorates Zika virus-induced ocular pathology.

Sneha Singh, Robert E Wright, Shailendra Giri, Vaithilingaraja Arumugaswami, Ashok Kumar.

  Zika virus (ZIKV) infection during pregnancy causes severe neurological and ocular abnormalities in infants, yet no vaccine or antivirals are available. Our transcriptomic analysis of ZIKV-infected retinal pigment epithelial (RPE) cells revealed alterations in the cholesterol pathway. Thus, we investigated the functional roles of ATP binding cassette transporter G1 (ABCG1) and sterol response element binding protein 2 (SREPB-2), two key players in cholesterol metabolism, during ocular ZIKV infection. Our in vitro data showed that increased ABCG1 activity via liver X receptors (LXRs), reduced ZIKV replication, while ABCG1 knockdown increased replication with elevated intracellular cholesterol. Conversely, inhibiting SREBP-2 or its knockdown reduced ZIKV replication by lowering cholesterol levels. In vivo, LXR agonist or SREBP-2 inhibitor treatment mitigated ZIKV-induced chorioretinal lesions in mice, concomitant with decreased expression of inflammatory mediators and increased activation of antiviral response genes. In summary, our study identifies ABCG1's antiviral role and SREBP-2's proviral effects in ocular ZIKV infection, offering cholesterol metabolism as a potential target to develop antiviral therapies.

Keywords:  Molecular biology; Virology

DOI:  https://doi.org/10.1016/j.isci.2024.109088
Cell Rep. 2024 Feb 26. pii: S2211-1247(24)00163-3. [Epub ahead of print]43(3): 113835

IL-37 dampens immunosuppressive functions of MDSCs via metabolic reprogramming in the tumor microenvironment.

Yu Mei, Ying Zhu, Kylie Su Mei Yong, Zuhairah Binte Hanafi, Huanle Gong, Yonghao Liu, Huey Yee Teo, Muslima Hussain, Yuan Song, Qingfeng Chen, Haiyan Liu.

  Interleukin-37 (IL-37) has been shown to inhibit tumor growth in various cancer types. However, the immune regulatory function of IL-37 in the tumor microenvironment is unclear. Here, we established a human leukocyte antigen-I (HLA-I)-matched humanized patient-derived xenograft hepatocellular carcinoma (HCC) model and three murine orthotopic HCC models to study the function of IL-37 in the tumor microenvironment. We found that IL-37 inhibited HCC growth and promoted T cell activation. Further study revealed that IL-37 impaired the immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs). Pretreatment of MDSCs with IL-37 before adoptive transfer attenuated their tumor-promoting function in HCC tumor-bearing mice. Moreover, IL-37 promoted both glycolysis and oxidative phosphorylation in MDSCs, resulting in the upregulation of ATP release, which impaired the immunosuppressive capacity of MDSCs. Collectively, we demonstrated that IL-37 inhibited tumor development through dampening MDSCs' immunosuppressive capacity in the tumor microenvironment via metabolic reprogramming, making it a promising target for future cancer immunotherapy.

Keywords:  ATP; CP: Cancer; CP: Immunology; Interleukin-37; hepatocellular carcinoma; metabolism; myeloid-derived suppressor cells

DOI:  https://doi.org/10.1016/j.celrep.2024.113835
Biochem Biophys Res Commun. 2024 Feb 23. pii: S0006-291X(24)00247-X. [Epub ahead of print]704 149711

Synthesis of urolithin derivatives and their anti-inflammatory activity.

Xintong Li, Zhengzheng Zhang, Guangsen Xu, Zhiying Li, Chunhua Lu, Yuemao Shen.

  Two series of urolithin derivatives, totally 38 compounds, were synthesized. Their anti-inflammatory activity was investigated by detecting the inhibitory effects on the expression of TNF-α in bone marrow-derived macrophages (BMDMs), showing that 24 of 38 ones reduced the expression of TNF-α. Compound B2, the ring C opened derivative of urolithin B with a butoxycarbonyl substitution in ring A, showed the strongest inhibitory activity compared with that of indomethacin. Furthermore, B2 treatment decreased the expression of pro-inflammatory factors IL-1β, IL-6, iNOS and COX-2. Mechanically, the anti-inflammatory effect of B2 was related to the inhibition of NF-κB signaling pathway. These results clearly illustrated that B2 hold potential for application as an anti-inflammatory agent. The present study provided a viable approach to modify the gut metabolites for anti-inflammatory drug development.

Keywords:  Anti-inflammation activity; NF-κB; Structure-activity relationship; Urolithin

DOI:  https://doi.org/10.1016/j.bbrc.2024.149711
Nat Metab. 2024 Feb;6(2): 323-342

A homoeostatic switch causing glycerol-3-phosphate and phosphoethanolamine accumulation triggers senescence by rewiring lipid metabolism.

Khaled Tighanimine, José Américo Nabuco Leva Ferreira Freitas, Ivan Nemazanyy, Alexia Bankolé, Delphine Benarroch-Popivker, Susanne Brodesser, Gregory Doré, Lucas Robinson, Paule Benit, Sophia Ladraa, Yara Bou Saada, Bertrand Friguet, Philippe Bertolino, David Bernard, Guillaume Canaud, Pierre Rustin, Eric Gilson, Oliver Bischof, Stefano Fumagalli, Mario Pende.

Cellular senescence affects many physiological and pathological processes and is characterized by durable cell cycle arrest, an inflammatory secretory phenotype and metabolic reprogramming. Here, by using dynamic transcriptome and metabolome profiling in human fibroblasts with different subtypes of senescence, we show that a homoeostatic switch that results in glycerol-3-phosphate (G3P) and phosphoethanolamine (pEtN) accumulation links lipid metabolism to the senescence gene expression programme. Mechanistically, p53-dependent glycerol kinase activation and post-translational inactivation of phosphate cytidylyltransferase 2, ethanolamine regulate this metabolic switch, which promotes triglyceride accumulation in lipid droplets and induces the senescence gene expression programme. Conversely, G3P phosphatase and ethanolamine-phosphate phospho-lyase-based scavenging of G3P and pEtN acts in a senomorphic way by reducing G3P and pEtN accumulation. Collectively, our study ties G3P and pEtN accumulation to controlling lipid droplet biogenesis and phospholipid flux in senescent cells, providing a potential therapeutic avenue for targeting senescence and related pathophysiology.

DOI: https://doi.org/10.1038/s42255-023-00972-y